U.S. patent application number 14/412472 was filed with the patent office on 2015-10-22 for siox barrier for pharmaceutical package and coating process.
This patent application is currently assigned to SIO2 MEDICAL PRODUCTS, INC.. The applicant listed for this patent is SiO2 MEDICAL PRODUCTS, INC.. Invention is credited to Robert S. Abrams, John T. Felts, John Ferguson, Thomas E. Fisk, Jonathan R. Freedman, Robert J. Pangborn, Peter J. Sagona, Christopher Weikart.
Application Number | 20150297800 14/412472 |
Document ID | / |
Family ID | 54321083 |
Filed Date | 2015-10-22 |
United States Patent
Application |
20150297800 |
Kind Code |
A1 |
Weikart; Christopher ; et
al. |
October 22, 2015 |
SiOx BARRIER FOR PHARMACEUTICAL PACKAGE AND COATING PROCESS
Abstract
A vessel including a thermoplastic wall enclosing a lumen is
disclosed. The wall supports an SiO.sub.x composite barrier coating
or layer, for which x is from 1.8 to 2.4, between the wall and the
lumen. High Resolution X-ray Photoelectron Spectroscopy (XPS) shows
the presence of an interface between the composite barrier coating
or layer and the wall or substrate. In one aspect, the interface
has at least 1 mol.% O.sub.3--Si--C covalent bonding, as a
proportion of the O.sub.3--Si--C covalent bonding plus SiO.sub.4
bonding. In another aspect, the interface has an Si 2p chemical
shift to lower binding energy (eV), compared to the binding energy
of SiO.sub.4 bonding. The result is a tightly adherent composite
barrier coating or layer having a high degree of adhesion to the
substrate under practical use conditions. Methods of applying the
composite barrier coating or layer are also disclosed.
Inventors: |
Weikart; Christopher;
(Auburn, AL) ; Felts; John T.; (Alameda, CA)
; Fisk; Thomas E.; (Green Valley, AZ) ; Abrams;
Robert S.; (Albany, NY) ; Ferguson; John;
(Auburn, AL) ; Freedman; Jonathan R.; (Auburn,
AL) ; Pangborn; Robert J.; (Harbor Springs, MI)
; Sagona; Peter J.; (Pottstown, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SiO2 MEDICAL PRODUCTS, INC. |
Auburn |
AL |
US |
|
|
Assignee: |
SIO2 MEDICAL PRODUCTS, INC.
Auburn
AL
|
Family ID: |
54321083 |
Appl. No.: |
14/412472 |
Filed: |
June 28, 2013 |
PCT Filed: |
June 28, 2013 |
PCT NO: |
PCT/US13/48709 |
371 Date: |
January 2, 2015 |
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Current U.S.
Class: |
600/432 ;
128/203.12; 206/461; 422/430; 604/187; 604/294; 604/310; 604/403;
604/77 |
Current CPC
Class: |
A61M 5/3129 20130101;
A61M 2202/048 20130101; A61M 2205/0238 20130101; A61M 2205/19
20130101; A61L 29/106 20130101; A61L 2420/02 20130101; A61M 15/0001
20140204; A61J 1/035 20130101; A61F 9/0008 20130101; A61J 1/05
20130101; A61L 31/088 20130101 |
International
Class: |
A61L 31/08 20060101
A61L031/08; B65D 65/42 20060101 B65D065/42; A61M 15/00 20060101
A61M015/00; A61M 5/178 20060101 A61M005/178; A61J 1/05 20060101
A61J001/05; A61L 31/04 20060101 A61L031/04; A61F 9/00 20060101
A61F009/00; A61M 35/00 20060101 A61M035/00; A61M 5/00 20060101
A61M005/00; A61L 31/16 20060101 A61L031/16; A61L 31/14 20060101
A61L031/14; A61J 1/03 20060101 A61J001/03; A61J 7/00 20060101
A61J007/00 |
Claims
1. A vessel comprising a thermoplastic wall enclosing a lumen and
an SiO.sub.x composite barrier coating or layer, for which x is
from 1.8 to 2.4, supported by the wall between the wall and the
lumen, an interior surface of the composite barrier coating or
layer facing the lumen, and a pH protective coating or layer of
SiO.sub.xC.sub.y or SiN.sub.xC.sub.y wherein x is from about 0.5 to
about 2.4 and y is from about 0.6 and about 3, the pH protective
coating or layer having an interior surface facing the lumen and an
outer surface facing the interior surface of the composite barrier
coating or layer, the pH protective coating or layer being
effective to increase the calculated shelf life of the vessel
(total Si/Si dissolution rate), in which the degree of retention of
the composite barrier coating or layer on the substrate is at least
95%, by the Coated Article Cross-Scratch Tape Test Method.
2-71. (canceled)
72. The vessel of claim 1, in which the vessel has a rated volume
between 0.5 and 5 ml and/or a fill volume between 0.8 and 9 ml.
73.-81. (canceled)
82. The vessel of claim 1, in which the vessel is a vial, a
syringe, a prefilled syringe, or a cartridge.
83.-87. (canceled)
88. The vessel of claim 1, in which the the SiO.sub.x composite
barrier coating or layer is formed at an initial RF power level of
from 3 to 1 W/mL.
89. The vessel of claim 88, in which the the SiO.sub.x composite
barrier coating or layer is formed at a highest RF power level of
from 60 to 4 W/mL.
90. The vessel of claim 1, in which the the SiO.sub.x composite
barrier coating or layer is formed by PECVD from an organosilicon
monomer and oxidizing gas, and the organosilicon monomer is an
organosiloxane having from 2 to 6 silicon atoms per molecule.
91-93. (canceled)
94. The vessel of claim 1, in which the lumen contains a
pharmaceutical agent.
95. The vessel of claim 94, in which the pharmaceutical agent has a
pH between 5 and 9.
96. The vessel of claim 1, further comprising an opening between
the lumen and the exterior of the vessel and a closure seated in
the opening.
97-128. (canceled)
129. The vessel of claim 1, in which at least a portion of the wall
of the vessel comprises a cyclic olefin polymer, polypropylene, or
a polyester.
130-140. (canceled)
141. The vessel of claim 1, in which the vessel comprises a blister
package.
142-155. (canceled)
156. The vessel of claim 1, in which the pH protective coating or
layer comprises SiO.sub.xC.sub.y.
157-172. (canceled)
173. The vessel of claim 1, in which the pH protective coating or
layer as applied is between 100 and 700 nm thick.
174-175. (canceled)
176. The vessel of claim 95, in which the pH protective coating or
layer contacting the pharmaceutical agent is between 20 and 700 nm
thick two years after the invention is assembled.
177-183. (canceled)
184. The vessel of claim 1, in which the rate of erosion of the pH
protective coating or layer, if directly contacted by a fluid
composition having a pH of 8, is from 5% to 20% of the rate of
erosion of the composite barrier coating or layer, if directly
contacted by the same fluid composition under the same
conditions.
185-189. (canceled)
190. The vessel of claim 95, having a shelf life of at least two
years and at most ten years.
191-198. (canceled)
199. The vessel of claim 190, in which the shelf life is determined
at 3.degree. C.
200-205. (canceled)
206. The vessel of claim 199, in which the pH of the fluid
composition is between 7 and 8 and the thickness of the pH
protective coating or layer is at least 80 nm at the end of the
shelf life.
207-211. (canceled)
212. The vessel of claim 95, in which the fluid composition removes
the pH protective coating or layer at a rate of 1 nm or less of pH
protective coating or layer thickness per 44 or 250 hours of
contact with the fluid composition.
213-229. (canceled)
230. The vessel of claim 1, in which an FTIR absorbance spectrum of
the pH protective coating or layer has a ratio greater than 0.75
and at most 1.7 between: the maximum amplitude of the Si--O--Si
symmetrical stretch peak between about 1000 and 1040 cm.sup.-1, and
the maximum amplitude of the Si--O--Si assymmetric stretch peak
between about 1060 and about 1100 cm.sup.-1.
231-241. (canceled)
242. The vessel of claim 1, in which the silicon dissolution rate
by a 50 mM potassium phosphate buffer diluted in water for
injection, adjusted to pH 8 with concentrated nitric acid, and
containing 0.2 wt. % polysorbate-80 surfactant from the vessel is
less than 170 ppb/day.
243.-254. (canceled)
255. The vessel of claim 1, in which the calculated shelf life
(total Si/Si dissolution rate) is more than 1 year and less than 5
years.
256-311. (canceled)
312. The vessel of claim 1, wherein the pH protective layer shows
an O-Parameter measured with attenuated total reflection (ATR) from
0.1 to 0.39, measured as: O - Parameter = Intensity at 1253 cm - 1
Maximum intensity in the range 1000 to 1100 cm - 1 .
##EQU00005##
313-1663. (canceled)
1664. The vessel of claim 1, in which the lumen contains a fluid
composition comprising a member selected from the group consisting
of: INHALATION ANESTHETICS Aliflurane; Chloroform; Cyclopropane;
Desflurane (Suprane); Diethyl Ether; Enflurane (Ethrane); Ethyl
Chloride; Ethylene; Halothane (Fluothane); Isoflurane (Forane,
Isoflo); Isopropenyl vinyl ether; Methoxyflurane; Methoxypropane;
Nitrous Oxide; Roflurane; Sevoflurane (Sevorane, Ultane, Sevoflo;
Teflurane; Trichloroethylene; Vinyl Ether; Xenon; INJECTABLE DRUGS
Ablavar (Gadofosveset Trisodium Injection); Abarelix Depot;
Abobotulinumtoxin A Injection (Dysport); ABT-263; ABT-869; ABX-EFG;
Accretropin (Somatropin Injection); Acetadote (Acetylcysteine
Injection); Acetazolamide Injection (Acetazolamide Injection);
Acetylcysteine Injection (Acetadote); Actemra (Tocilizumab
Injection); Acthrel (Corticorelin Ovine Triflutate for Injection);
Actummune; Activase; Acyclovir for Injection (Zovirax Injection);
Adacel; Adalimumab; Adenoscan (Adenosine Injection); Adenosine
Injection (Adenoscan); Adrenaclick; AdreView (lobenguane I 123
Injection for Intravenous Use); Afluria; Ak-Fluor (Fluorescein
Injection); Aldurazyme (Laronidase); Alglucerase Injection
(Ceredase); Alkeran Injection (Melphalan Hcl Injection);
Allopurinol Sodium for Injection (Aloprim); Aloprim (Allopurinol
Sodium for Injection); Alprostadil; Alsuma (Sumatriptan Injection);
ALTU-238; Amino Acid Injections; Aminosyn; Apidra; Apremilast;
Alprostadil Dual Chamber System for Injection (Caverject Impulse);
AMG 009; AMG 076; AMG 102; AMG 108; AMG 114; AMG 162; AMG 220; AMG
221; AMG 222; AMG 223; AMG 317; AMG 379; AMG 386; AMG 403; AMG 477;
AMG 479; AMG 517; AMG 531; AMG 557; AMG 623; AMG 655; AMG 706; AMG
714; AMG 745; AMG 785; AMG 811; AMG 827; AMG 837; AMG 853; AMG 951;
Amiodarone HCl Injection (Amiodarone HCl Injection); Amobarbital
Sodium Injection (Amytal Sodium); Amytal Sodium (Amobarbital Sodium
Injection); Anakinra; Anti-Abeta; Anti-Beta7; Anti-Beta20;
Anti-CD4; Anti-CD20; Anti-CD40; Anti-IFNalpha; Anti-IL13;
Anti-OX40L; Anti-oxLDS; Anti-NGF; Anti-NRP1; Arixtra; Amphadase
(Hyaluronidase Inj); Ammonul (Sodium Phenylacetate and Sodium
Benzoate Injection); Anaprox; Anzemet Injection (Dolasetron
Mesylate Injection); Apidra (Insulin Glulisine [rDNA origin] Inj);
Apomab; Aranesp (darbepoetin alfa); Argatroban (Argatroban
Injection); Arginine Hydrochloride Injection (R-Gene 10);
Aristocort; Aristospan; Arsenic Trioxide Injection (Trisenox);
Articane HCl and Epinephrine Injection (Septocaine); Arzerra
(Ofatumumab Injection); Asclera (Polidocanol Injection); Ataluren;
Ataluren-DMD; Atenolol Inj (Tenormin I.V. Injection); Atracurium
Besylate Injection (Atracurium Besylate Injection); Avastin;
Azactam Injection (Aztreonam Injection); Azithromycin (Zithromax
Injection); Aztreonam Injection (Azactam Injection); Baclofen
Injection (Lioresal Intrathecal); Bacteriostatic Water
(Bacteriostatic Water for Injection); Baclofen Injection (Lioresal
Intrathecal); Bal in Oil Ampules (Dimercarprol Injection); BayHepB;
BayTet; Benadryl; Bendamustine Hydrochloride Injection (Treanda);
Benztropine Mesylate Injection (Cogentin); Betamethasone Injectable
Suspension (Celestone Soluspan); Bexxar; Bicillin C-R 900/300
(Penicillin G Benzathine and Penicillin G Procaine Injection);
Blenoxane (Bleomycin Sulfate Injection); Bleomycin Sulfate
Injection (Blenoxane); Boniva Injection (Ibandronate Sodium
Injection); Botox Cosmetic (OnabotulinumtoxinA for Injection);
BR3-FC; Bravelle (Urofollitropin Injection); Bretylium (Bretylium
Tosylate Injection); Brevital Sodium (Methohexital Sodium for
Injection); Brethine; Briobacept; BTT-1023; Bupivacaine HCl;
Byetta; Ca-DTPA (Pentetate Calcium Trisodium Inj); Cabazitaxel
Injection (Jevtana); Caffeine Alkaloid (Caffeine and Sodium
Benzoate Injection); Calcijex Injection (Calcitrol); Calcitrol
(Calcijex Injection); Calcium Chloride (Calcium Chloride Injection
10%); Calcium Disodium Versenate (Edetate Calcium Disodium
Injection); Campath (Altemtuzunab); Camptosar Injection (Irinotecan
Hydrochloride); Canakinumab Injection (Ilaris); Capastat Sulfate
(Capreomycin for Injection); Capreomycin for Injection (Capastat
Sulfate); Cardiolite (Prep kit for Technetium Tc99 Sestamibi for
Injection); Carticel; Cathflo; Cefazolin and Dextrose for Injection
(Cefazolin Injection); Cefepime Hydrochloride; Cefotaxime;
Ceftriaxone; Cerezyme; Carnitor Injection; Caverject; Celestone
Soluspan; Celsior; Cerebyx (Fosphenytoin Sodium Injection);
Ceredase (Alglucerase Injection); Ceretec (Technetium Tc99m
Exametazime Injection); Certolizumab; CF-101; Chloramphenicol
Sodium Succinate (Chloramphenicol Sodium Succinate Injection);
Chloramphenicol Sodium Succinate Injection (Chloramphenicol Sodium
Succinate); Cholestagel (Colesevelam HCL); Choriogonadotropin Alfa
Injection (Ovidrel); Cimzia; Cisplatin (Cisplatin Injection);
Clolar (Clofarabine Injection); Clomiphine Citrate; Clonidine
Injection (Duraclon); Cogentin (Benztropine Mesylate Injection);
Colistimethate Injection (Coly-Mycin M); Coly-Mycin M
(Colistimethate Injection); Compath; Conivaptan Hcl Injection
(Vaprisol); Conjugated Estrogens for Injection (Premarin
Injection); Copaxone; Corticorelin Ovine Triflutate for Injection
(Acthrel); Corvert (Ibutilide Fumarate Injection); Cubicin
(Daptomycin Injection); CF-101; Cyanokit (Hydroxocobalamin for
Injection); Cytarabine Liposome Injection (DepoCyt);
Cyanocobalamin; Cytovene (ganciclovir); D.H.E. 45; Dacetuzumab;
Dacogen (Decitabine Injection); Dalteparin; Dantrium IV (Dantrolene
Sodium for Injection); Dantrolene Sodium for Injection (Dantrium
IV); Daptomycin Injection (Cubicin); Darbepoietin Alfa; DDAVP
Injection (Desmopressin Acetate Injection); Decavax; Decitabine
Injection (Dacogen); Dehydrated Alcohol (Dehydrated Alcohol
Injection); Denosumab Injection (Prolia); Delatestryl; Delestrogen;
Delteparin Sodium; Depacon (Valproate Sodium Injection); Depo
Medrol (Methylprednisolone Acetate Injectable Suspension); DepoCyt
(Cytarabine Liposome Injection); DepoDur (Morphine Sulfate XR
Liposome Injection); Desmopressin Acetate Injection (DDAVP
Injection); Depo-Estradiol; Depo-Provera 104 mg/ml; Depo-Provera
150 mg/ml; Depo-Testosterone; Dexrazoxane for Injection,
Intravenous Infusion Only (Totect); Dextrose/Electrolytes; Dextrose
and Sodium Chloride Inj (Dextrose 5% in 0.9% Sodium Chloride);
Dextrose; Diazepam Injection (Diazepam Injection); Digoxin
Injection (Lanoxin Injection); Dilaudid-HP (Hydromorphone
Hydrochloride Injection) Dimercarprol Injection (Bal in Oil
Ampules); Diphenhydramine Injection (Benadryl Injection);
Dipyridamole Injection (Dipyridamole Injection); DMOAD; Docetaxel
for Injection (Taxotere); Dolasetron Mesylate Injection (Anzemet
Injection); Doribax (Doripenem for Injection); Doripenem for
Injection (Doribax); Doxercalciferol Injection (Hectorol
Injection); Doxil (Doxorubicin Hcl Liposome Injection); Doxorubicin
Hcl Liposome Injection (Doxil); Duraclon (Clonidine Injection);
Duramorph (Morphine Injection); Dysport (Abobotulinumtoxin A
Injection); Ecallantide Injection (Kalbitor); EC-Naprosyn
(naproxen); Edetate Calcium Disodium Injection (Calcium Disodium
Versenate); Edex (Alprostadil for Injection); Engerix; Edrophonium
Injection (Enlon); Eliglustat Tartate; Eloxatin (Oxaliplatin
Injection); Emend Injection (Fosaprepitant Dimeglumine Injection);
Enalaprilat Injection (Enalaprilat Injection); Enlon (Edrophonium
Injection); Enoxaparin Sodium Injection (Lovenox); Eovist
(Gadoxetate Disodium Injection); Enbrel (etanercept); Enoxaparin;
Epicel; Epinepherine; Epipen; Epipen Jr.; Epratuzumab; Erbitux;
Ertapenem Injection (Invanz); Erythropoieten; Essential Amino Acid
Injection (Nephramine); Estradiol Cypionate; Estradiol Valerate;
Etanercept; Exenatide Injection (Byetta); Evlotra; Fabrazyme
(Adalsidase beta); Famotidine Injection; FDG (Fludeoxyglucose F 18
Injection); Feraheme (Ferumoxytol Injection); Feridex I.V.
(Ferumoxides Injectable Solution); Fertinex; Ferumoxides Injectable
Solution (Feridex I.V.); Ferumoxytol Injection (Feraheme); Flagyl
Injection (Metronidazole Injection); Fluarix; Fludara (Fludarabine
Phosphate); Fludeoxyglucose F 18 Injection (FDG); Fluorescein
Injection (Ak-Fluor); Follistim AQ Cartridge (Follitropin Beta
Injection); Follitropin Alfa Injection (Gonal-f RFF); Follitropin
Beta Injection (Follistim AQ Cartridge); Folotyn (Pralatrexate
Solution for Intravenous Injection); Fondaparinux; Forteo
(Teriparatide (rDNA origin) Injection); Fostamatinib; Fosaprepitant
Dimeglumine Injection (Emend Injection); Foscarnet Sodium Injection
(Foscavir); Foscavir (Foscarnet Sodium Injection); Fosphenytoin
Sodium Injection (Cerebyx); Fospropofol Disodium Injection
(Lusedra); Fragmin; Fuzeon (enfuvirtide); GA101; Gadobenate
Dimeglumine Injection (Multihance); Gadofosveset Trisodium
Injection (Ablavar); Gadoteridol Injection Solution (ProHance);
Gadoversetamide Injection (OptiMARK); Gadoxetate Disodium Injection
(Eovist); Ganirelix (Ganirelix Acetate Injection); Gardasil;
GC1008; GDFD; Gemtuzumab Ozogamicin for Injection (Mylotarg);
Genotropin; Gentamicin Injection; GENZ-112638; Golimumab Injection
(Simponi Injection); Gonal-f RFF (Follitropin Alfa Injection);
Granisetron Hydrochloride (Kytril Injection); Gentamicin Sulfate;
Glatiramer Acetate; Glucagen; Glucagon; HAE1; Haldol (Haloperidol
Injection); Havrix; Hectorol Injection (Doxercalciferol Injection);
Hedgehog Pathway Inhibitor; Heparin; Herceptin; hG-CSF; Humalog;
Human Growth Hormone; Humatrope; HuMax; Humegon; Humira; Humulin;
Ibandronate Sodium Injection (Boniva Injection); Ibuprofen Lysine
Injection (NeoProfen); Ibutilide Fumarate Injection (Corvert);
Idamycin PFS (Idarubicin Hydrochloride Injection); Idarubicin
Hydrochloride Injection (Idamycin PFS); Ilaris (Canakinumab
Injection); Imipenem and Cilastatin for Injection (Primaxin I.V.);
Imitrex; Incobotulinumtoxin A for Injection (Xeomin); Increlex
(Mecasermin [rDNA origin] Injection); Indocin IV (Indomethacin
Inj); Indomethacin Inj (Indocin IV); Infanrix; Innohep; Insulin;
Insulin Aspart [rDNA origin] Inj (NovoLog); Insulin Glargine [rDNA
origin] Injection (Lantus); Insulin Glulisine [rDNA origin] Inj
(Apidra); Interferon alfa-2b, Recombinant for Injection (Intron A);
Intron A (Interferon alfa-2b, Recombinant for Injection); Invanz
(Ertapenem Injection); Invega Sustenna (Paliperidone Palmitate
Extended-Release Injectable Suspension); Invirase (saquinavir
mesylate); Iobenguane I 123 Injection for Intravenous Use
(AdreView); Iopromide Injection (Ultravist) Ioversol Injection
(Optiray Injection); Iplex (Mecasermin Rinfabate [rDNA origin]
Injection); Iprivask; Irinotecan Hydrochloride (Camptosar
Injection); Iron Sucrose Injection (Venofer); Istodax (Romidepsin
for Injection); Itraconazole Injection (Sporanox Injection);
Jevtana (Cabazitaxel Injection); Jonexa; Kalbitor (Ecallantide
Injection); KCL in D5NS (Potassium Chloride in 5% Dextrose and
Sodium Chloride Injection); KCL in D5W; KCL in NS; Kenalog 10
Injection (Triamcinolone Acetonide Injectable Suspension);
Kepivance (Palifermin); Keppra Injection (Levetiracetam);
Keratinocyte; KFG; Kinase Inhibitor; Kineret (Anakinra); Kinlytic
(Urokinase Injection); Kinrix; Kionopin (clonazepam); Kytril
Injection (Granisetron Hydrochloride); lacosamide Tablet and
Injection (Vimpat); Lactated Ringer's; Lanoxin Injection (Digoxin
Injection); Lansoprazole for Injection (Prevacid I.V.); Lantus;
Leucovorin Calcium (Leucovorin Calcium Injection); Lente (L);
Leptin; Levemir; Leukine Sargramostim; Leuprolide Acetate;
Levothyroxine; Levetiracetam (Keppra Injection); Lovenox;
Levocarnitine Injection (Carnitor Injection); Lexiscan (Regadenoson
Injection); Lioresal Intrathecal (Baclofen Injection); Liraglutide
[rDNA] Injection (Victoza); Lovenox (Enoxaparin Sodium Injection);
Lucentis (Ranibizumab Injection); Lumizyme; Lupron (Leuprolide
Acetate Injection); Lusedra (Fospropofol Disodium Injection); Maci;
Magnesium Sulfate (Magnesium Sulfate Injection); Mannitol Injection
(Mannitol IV); Marcaine (Bupivacaine Hydrochloride and Epinephrine
Injection); Maxipime (Cefepime Hydrochloride for Injection); MDP
Multidose Kit of Technetium Injection (Technetium Tc99m Medronate
Injection); Mecasermin [rDNA origin] Injection (Increlex);
Mecasermin Rinfabate [rDNA origin] Injection (Iplex); Melphalan Hcl
Injection (Alkeran Injection); Methotrexate; Menactra; Menopur
(Menotropins Injection); Menotropins for Injection (Repronex);
Methohexital Sodium for Injection (Brevital Sodium); Methyldopate
Hydrochloride Injection, Solution (Methyldopate Hcl); Methylene
Blue (Methylene Blue Injection); Methylprednisolone Acetate
Injectable Suspension (Depo Medrol); MetMab; Metoclopramide
Injection (Reglan Injection); Metrodin (Urofollitropin for
Injection); Metronidazole Injection (Flagyl Injection); Miacalcin;
Midazolam (Midazolam Injection); Mimpara (Cinacalet); Minocin
Injection (Minocycline Inj); Minocycline Inj (Minocin Injection);
Mipomersen; Mitoxantrone for Injection Concentrate (Novantrone);
Morphine Injection (Duramorph); Morphine Sulfate XR Liposome
Injection (DepoDur); Morrhuate Sodium (Morrhuate Sodium Injection);
Motesanib; Mozobil (Plerixafor Injection); Multihance (Gadobenate
Dimeglumine Injection); Multiple Electrolytes and Dextrose
Injection; Multiple Electrolytes Injection; Mylotarg (Gemtuzumab
Ozogamicin for Injection); Myozyme (Alglucosidase alfa); Nafcillin
Injection (Nafcillin Sodium); Nafcillin Sodium (Nafcillin
Injection); Naltrexone XR Inj (Vivitrol); Naprosyn (naproxen);
NeoProfen (Ibuprofen Lysine Injection); Nandrol Decanoate;
Neostigmine Methylsulfate (Neostigmine Methylsulfate Injection);
NEO-GAA; NeoTect (Technetium Tc 99m Depreotide Injection);
Nephramine (Essential Amino Acid Injection); Neulasta
(pegfilgrastim); Neupogen (Filgrastim); Novolin; Novolog;
NeoRecormon; Neutrexin (Trimetrexate Glucuronate Inj); NPH (N);
Nexterone (Amiodarone HCl Injection); Norditropin (Somatropin
Injection); Normal Saline (Sodium Chloride Injection); Novantrone
(Mitoxantrone for Injection Concentrate); Novolin 70/30 Innolet
(70% NPH, Human Insulin Isophane Suspension and 30% Regular, Human
Insulin Injection); NovoLog (Insulin Aspart [rDNA origin] Inj);
Nplate (romiplostim); Nutropin (Somatropin (rDNA origin) for Inj);
Nutropin AQ; Nutropin Depot (Somatropin (rDNA origin) for Inj);
Octreotide Acetate Injection (Sandostatin LAR); Ocrelizumab;
Ofatumumab Injection (Arzerra); Olanzapine Extended Release
Injectable Suspension (Zyprexa Relprevv); Omnitarg; Omnitrope
(Somatropin [rDNA origin] Injection); Ondansetron Hydrochloride
Injection (Zofran Injection); OptiMARK (Gadoversetamide Injection);
Optiray Injection (Ioversol Injection); Orencia; Osmitrol Injection
in Aviva (Mannitol Injection in Aviva Plastic Vessel); Osmitrol
Injection in Viaflex (Mannitol Injection in Viaflex Plastic
Vessel); Osteoprotegrin; Ovidrel (Choriogonadotropin Alfa
Injection); Oxacillin (Oxacillin for Injection); Oxaliplatin
Injection (Eloxatin); Oxytocin Injection (Pitocin); Paliperidone
Palmitate Extended-Release Injectable Suspension (Invega Sustenna);
Pamidronate Disodium Injection (Pamidronate Disodium Injection);
Panitumumab Injection for Intravenous Use (Vectibix); Papaverine
Hydrochloride Injection (Papaverine Injection); Papaverine
Injection (Papaverine Hydrochloride Injection); Parathyroid
Hormone; Paricalcitol Injection Fliptop Vial (Zemplar Injection);
PARP Inhibitor; Pediarix; PEGIntron; Peginterferon; Pegfilgrastim;
Penicillin G Benzathine and Penicillin G Procaine; Pentetate
Calcium Trisodium Inj (Ca-DTPA); Pentetate Zinc Trisodium Injection
(Zn-DTPA); Pepcid Injection (Famotidine Injection); Pergonal;
Pertuzumab; Phentolamine Mesylate (Phentolamine Mesylate for
Injection); Physostigmine Salicylate (Physostigmine Salicylate
(injection)); Physostigmine Salicylate (injection) (Physostigmine
Salicylate); Piperacillin and Tazobactam Injection (Zosyn); Pitocin
(Oxytocin Injection); Plasma-Lyte 148 (Multiple Electrolytes Inj);
Plasma-Lyte 56 and Dextrose (Multiple Electrolytes and Dextrose
Injection in Viaflex Plastic Vessel); PlasmaLyte; Plerixafor
Injection (Mozobil); Polidocanol Injection (Asclera); Potassium
Chloride; Pralatrexate Solution for Intravenous Injection
(Folotyn); Pramlintide Acetate Injection (Symlin); Premarin
Injection (Conjugated Estrogens for Injection); Prep kit for
Technetium Tc99 Sestamibi for Injection (Cardiolite); Prevacid I.V.
(Lansoprazole for Injection); Primaxin I.V. (Imipenem and
Cilastatin for Injection); Prochymal; Procrit; Progesterone;
ProHance (Gadoteridol Injection Solution); Prolia (Denosumab
Injection); Promethazine HCl Injection (Promethazine Hydrochloride
Injection); Propranolol Hydrochloride Injection (Propranolol
Hydrochloride Injection); Quinidine Gluconate Injection (Quinidine
Injection); Quinidine Injection (Quinidine Gluconate Injection);
R-Gene 10 (Arginine Hydrochloride Injection); Ranibizumab Injection
(Lucentis); Ranitidine Hydrochloride Injection (Zantac Injection);
Raptiva; Reclast (Zoledronic Acid Injection); Recombivarix HB;
Regadenoson Injection (Lexiscan); Reglan Injection (Metoclopramide
Injection); Remicade; Renagel; Renvela (Sevelamer Carbonate);
Repronex (Menotropins for Injection); Retrovir IV (Zidovudine
Injection);
rhApo2L/TRAIL; Ringer's and 5% Dextrose Injection (Ringers in
Dextrose); Ringer's Injection (Ringers Injection); Rituxan;
Rituximab; Rocephin (ceftriaxone); Rocuronium Bromide Injection
(Zemuron); Roferon-A (interferon alfa-2a); Romazicon (flumazenil);
Romidepsin for Injection (Istodax); Saizen (Somatropin Injection);
Sandostatin LAR (Octreotide Acetate Injection); Sclerostin Ab;
Sensipar (cinacalcet); Sensorcaine (Bupivacaine HCl Injections);
Septocaine (Articane HCl and Epinephrine Injection); Serostim LQ
(Somatropin (rDNA origin) Injection); Simponi Injection (Golimumab
Injection); Sodium Acetate (Sodium Acetate Injection); Sodium
Bicarbonate (Sodium Bicarbonate 5% Injection); Sodium Lactate
(Sodium Lactate Injection in AVIVA); Sodium Phenylacetate and
Sodium Benzoate Injection (Ammonul); Somatropin (rDNA origin) for
Inj (Nutropin); Sporanox Injection (Itraconazole Injection);
Stelara Injection (Ustekinumab); Stemgen; Sufenta (Sufentanil
Citrate Injection); Sufentanil Citrate Injection (Sufenta);
Sumavel; Sumatriptan Injection (Alsuma); Symlin; Symlin Pen;
Systemic Hedgehog Antagonist; Synvise-One (Hylan G-F 20 Single
Intra-articular Injection); Tarceva; Taxotere (Docetaxel for
Injection); Technetium Tc 99m; Telavancin for Injection (Vibativ);
Temsirolimus Injection (Torisel); Tenormin I.V. Injection (Atenolol
Inj); Teriparatide (rDNA origin) Injection (Forteo); Testosterone
Cypionate; Testosterone Enanthate; Testosterone Propionate;
Tev-Tropin (Somatropin, rDNA Origin, for Injection); tgAAC94;
Thallous Chloride; Theophylline; Thiotepa (Thiotepa Injection);
Thymoglobulin (Anti-Thymocyte Globulin (Rabbit); Thyrogen
(Thyrotropin Alfa for Injection); Ticarcillin Disodium and
Clavulanate Potassium Galaxy (Timentin Injection); Tigan Injection
(Trimethobenzamide Hydrochloride Injectable); Timentin Injection
(Ticarcillin Disodium and Clavulanate Potassium Galaxy); TNKase;
Tobramycin Injection (Tobramycin Injection); Tocilizumab Injection
(Actemra); Torisel (Temsirolimus Injection); Totect (Dexrazoxane
for Injection, Intravenous Infusion Only); Trastuzumab-DM1;
Travasol (Amino Acids (Injection)); Treanda (Bendamustine
Hydrochloride Injection); Trelstar (Triptorelin Pamoate for
Injectable Suspension); Triamcinolone Acetonide; Triamcinolone
Diacetate; Triamcinolone Hexacetonide Injectable Suspension
(Aristospan Injection 20 mg); Triesence (Triamcinolone Acetonide
Injectable Suspension); Trimethobenzamide Hydrochloride Injectable
(Tigan Injection); Trimetrexate Glucuronate Inj (Neutrexin);
Triptorelin Pamoate for Injectable Suspension (Trelstar); Twinject;
Trivaris (Triamcinolone Acetonide Injectable Suspension); Trisenox
(Arsenic Trioxide Injection); Twinrix; Typhoid Vi; Ultravist
(lopromide Injection); Urofollitropin for Injection (Metrodin);
Urokinase Injection (Kinlytic); Ustekinumab (Stelara Injection);
Ultralente (U); Valium (diazepam); Valproate Sodium Injection
(Depacon); Valtropin (Somatropin Injection); Vancomycin
Hydrochloride (Vancomycin Hydrochloride Injection); Vancomycin
Hydrochloride Injection (Vancomycin Hydrochloride); Vaprisol
(Conivaptan Hcl Injection); VAQTA; Vasovist (Gadofosveset Trisodium
Injection for Intravenous Use); Vectibix (Panitumumab Injection for
Intravenous Use); Venofer (Iron Sucrose Injection); Verteporfin Inj
(Visudyne); Vibativ (Telavancin for Injection); Victoza
(Liraglutide [rDNA] Injection); Vimpat (lacosamide Tablet and
Injection); Vinblastine Sulfate (Vinblastine Sulfate Injection);
Vincasar PFS (Vincristine Sulfate Injection); Victoza; Vincristine
Sulfate (Vincristine Sulfate Injection); Visudyne (Verteporfin
Inj); Vitamin B-12; Vivitrol (Naltrexone XR Inj); Voluven
(Hydroxyethyl Starch in Sodium Chloride Injection); Xeloda; Xenical
(orlistat); Xeomin (Incobotulinumtoxin A for Injection); Xolair;
Zantac Injection (Ranitidine Hydrochloride Injection); Zemplar
Injection (Paricalcitol Injection Fliptop Vial); Zemuron
(Rocuronium Bromide Injection); Zenapax (daclizumab); Zevalin;
Zidovudine Injection (Retrovir IV); Zithromax Injection
(Azithromycin); Zn-DTPA (Pentetate Zinc Trisodium Injection);
Zofran Injection (Ondansetron Hydrochloride Injection); Zingo;
Zoledronic Acid for Inj (Zometa); Zoledronic Acid Injection
(Reclast); Zometa (Zoledronic Acid for Inj); Zosyn (Piperacillin
and Tazobactam Injection); Zyprexa Relprevv (Olanzapine Extended
Release Injectable Suspension)
LIQUID DRUGS (NON-INJECTABLE) Abilify; AccuNeb (Albuterol Sulfate
Inhalation Solution); Actidose Aqua (Activated Charcoal
Suspension); Activated Charcoal Suspension (Actidose Aqua); Advair;
Agenerase Oral Solution (Amprenavir Oral Solution); Akten
(Lidocaine Hydrochloride Ophthalmic Gel); Alamast (Pemirolast
Potassium Ophthalmic Solution); Albumin (Human) 5% Solution
(Buminate 5%); Albuterol Sulfate Inhalation Solution; Alinia;
Alocril; Alphagan; Alrex; Alvesco; Amprenavir Oral Solution;
Analpram-HC; Arformoterol Tartrate Inhalation Solution (Brovana);
Aristospan Injection 20 mg (Triamcinolone Hexacetonide Injectable
Suspension); Asacol; Asmanex; Astepro; Astepro (Azelastine
Hydrochloride Nasal Spray); Atrovent Nasal Spray (Ipratropium
Bromide Nasal Spray); Atrovent Nasal Spray 0.06; Augmentin ES-600;
Azasite (Azithromycin Ophthalmic Solution); Azelaic Acid (Finacea
Gel); Azelastine Hydrochloride Nasal Spray (Astepro); Azelex
(Azelaic Acid Cream); Azopt (Brinzolamide Ophthalmic Suspension);
Bacteriostatic Saline; Balanced Salt; Bepotastine; Bactroban Nasal;
Bactroban; Beclovent; Benzac W; Betimol; Betoptic S; Bepreve;
Bimatoprost Ophthalmic Solution; Bleph 10 (Sulfacetamide Sodium
Ophthalmic Solution 10%); Brinzolamide Ophthalmic Suspension
(Azopt); Bromfenac Ophthalmic Solution (Xibrom); Bromhist; Brovana
(Arformoterol Tartrate Inhalation Solution); Budesonide Inhalation
Suspension (Pulmicort Respules); Cambia (Diclofenac Potassium for
Oral Solution); Capex; Carac; Carboxine-PSE; Carnitor; Cayston
(Aztreonam for Inhalation Solution); Cellcept; Centany; Cerumenex;
Ciloxan Ophthalmic Solution (Ciprofloxacin HCL Ophthalmic
Solution); Ciprodex; Ciprofloxacin HCL Ophthalmic Solution (Ciloxan
Ophthalmic Solution); Clemastine Fumarate Syrup (Clemastine
Fumarate Syrup); CoLyte (PEG Electrolytes Solution); Combiven;
Comtan; Condylox; Cordran; Cortisporin Ophthalmic Suspension;
Cortisporin Otic Suspension; Cromolyn Sodium Inhalation Solution
(Intal Nebulizer Solution); Cromolyn Sodium Ophthalmic Solution
(Opticrom); Crystalline Amino Acid Solution with Electrolytes
(Aminosyn Electrolytes); Cutivate; Cuvposa (Glycopyrrolate Oral
Solution); Cyanocobalamin (CaloMist Nasal Spray); Cyclosporine Oral
Solution (Gengraf Oral Solution); Cyclogyl; Cysview
(Hexaminolevulinate Hydrochloride Intravesical Solution); DermOtic
Oil (Fluocinolone Acetonide Oil Ear Drops); Desmopressin Acetate
Nasal Spray; DDAVP; Derma-Smoothe/FS; Dexamethasone Intensol;
Dianeal Low Calcium; Dianeal PD; Diclofenac Potassium for Oral
Solution (Cambia); Didanosine Pediatric Powder for Oral Solution
(Videx); Differin; Dilantin 125 (Phenytoin Oral Suspension);
Ditropan; Dorzolamide Hydrochloride Ophthalmic Solution (Trusopt);
Dorzolamide Hydrochloride-Timolol Maleate Ophthalmic Solution
(Cosopt); Dovonex Scalp (Calcipotriene Solution); Doxycycline
Calcium Oral Suspension (Vibramycin Oral); Efudex; Elaprase
(Idursulfase Solution); Elestat (Epinastine HCl Ophthalmic
Solution); Elocon; Epinastine HCl Ophthalmic Solution (Elestat);
Epivir HBV; Epogen (Epoetin alfa); Erythromycin Topical Solution
1.5% (Staticin); Ethiodol (Ethiodized Oil); Ethosuximide Oral
Solution (Zarontin Oral Solution); Eurax; Extraneal (Icodextrin
Peritoneal Dialysis Solution); Felbatol; Feridex I.V. (Ferumoxides
Injectable Solution); Flovent; Floxin Otic (Ofloxacin Otic
Solution); Flo-Pred (Prednisolone Acetate Oral Suspension);
Fluoroplex; Flunisolide Nasal Solution (Flunisolide Nasal Spray
0.025%); Fluorometholone Ophthalmic Suspension (FML); Flurbiprofen
Sodium Ophthalmic Solution (Ocufen); FML; Foradil; Formoterol
Fumarate Inhalation Solution (Perforomist); Fosamax; Furadantin
(Nitrofurantoin Oral Suspension); Furoxone; Gammagard Liquid
(Immune Globulin Intravenous (Human) 10%); Gantrisin (Acetyl
Sulfisoxazole Pediatric Suspension); Gatifloxacin Ophthalmic
Solution (Zymar); Gengraf Oral Solution (Cyclosporine Oral
Solution); Glycopyrrolate Oral Solution (Cuvposa); Halcinonide
Topical Solution (Halog Solution); Halog Solution (Halcinonide
Topical Solution); HEP-LOCK U/P (Preservative-Free Heparin Lock
Flush Solution); Heparin Lock Flush Solution (Hepflush 10);
Hexaminolevulinate Hydrochloride Intravesical Solution (Cysview);
Hydrocodone Bitartrate and Acetaminophen Oral Solution (Lortab
Elixir); Hydroquinone 3% Topical Solution (Melquin-3 Topical
Solution); IAP Antagonist; Isopto; Ipratropium Bromide Nasal Spray
(Atrovent Nasal Spray); Itraconazole Oral Solution (Sporanox Oral
Solution); Ketorolac Tromethamine Ophthalmic Solution (Acular LS);
Kaletra; Lanoxin; Lexiva; Leuprolide Acetate for Depot Suspension
(Lupron Depot 11.25 mg); Levobetaxolol Hydrochloride Ophthalmic
Suspension (Betaxon); Levocarnitine Tablets, Oral Solution,
Sugar-Free (Carnitor); Levofloxacin Ophthalmic Solution 0.5%
(Quixin); Lidocaine HCl Sterile Solution (Xylocaine MPF Sterile
Solution); Lok Pak (Heparin Lock Flush Solution); Lorazepam
Intensol; Lortab Elixir (Hydrocodone Bitartrate and Acetaminophen
Oral Solution); Lotemax (Loteprednol Etabonate Ophthalmic
Suspension); Loteprednol Etabonate Ophthalmic Suspension (Alrex);
Low Calcium Peritoneal Dialysis Solutions (Dianeal Low Calcium);
Lumigan (Bimatoprost Ophthalmic Solution 0.03% for Glaucoma);
Lupron Depot 11.25 mg (Leuprolide Acetate for Depot Suspension);
Megestrol Acetate Oral Suspension (Megestrol Acetate Oral
Suspension); MEK Inhibitor; Mepron; Mesnex; Mestinon; Mesalamine
Rectal Suspension Enema (Rowasa); Melquin-3 Topical Solution
(Hydroquinone 3% Topical Solution); MetMab; Methyldopate Hcl
(Methyldopate Hydrochloride Injection, Solution); Methylin Oral
Solution (Methylphenidate HCl Oral Solution 5 mg/5 mL and 10 mg/5
mL); Methylprednisolone Acetate Injectable Suspension (Depo
Medrol); Methylphenidate HCl Oral Solution 5 mg/5 mL and 10 mg/5 mL
(Methylin Oral Solution); Methylprednisolone sodium succinate (Solu
Medrol); Metipranolol Ophthalmic Solution (Optipranolol); Migranal;
Miochol-E (Acetylcholine Chloride Intraocular Solution); Micro-K
for Liquid Suspension (Potassium Chloride Extended Release
Formulation for Liquid Suspension); Minocin (Minocycline
Hydrochloride Oral Suspension); Nasacort; Neomycin and Polymyxin B
Sulfates and Hydrocortisone; Nepafenac Ophthalmic Suspension
(Nevanac); Nevanac (Nepafenac Ophthalmic Suspension);
Nitrofurantoin Oral Suspension (Furadantin); Noxafil (Posaconazole
Oral Suspension); Nystatin (oral) (Nystatin Oral Suspension);
Nystatin Oral Suspension (Nystatin (oral)); Ocufen (Flurbiprofen
Sodium Ophthalmic Solution); Ofloxacin Ophthalmic Solution
(Ofloxacin Ophthalmic Solution); Ofloxacin Otic Solution (Floxin
Otic); Olopatadine Hydrochloride Ophthalmic Solution (Pataday);
Opticrom (Cromolyn Sodium Ophthalmic Solution); Optipranolol
(Metipranolol Ophthalmic Solution); Patanol; Pediapred; PerioGard;
Phenytoin Oral Suspension (Dilantin 125); Phisohex; Posaconazole
Oral Suspension (Noxafil); Potassium Chloride Extended Release
Formulation for Liquid Suspension (Micro-K for Liquid Suspension);
Pataday (Olopatadine Hydrochloride Ophthalmic Solution); Patanase
Nasal Spray (Olopatadine Hydrochloride Nasal Spray); PEG
Electrolytes Solution (CoLyte); Pemirolast Potassium Ophthalmic
Solution (Alamast); Penlac (Ciclopirox Topical Solution); PENNSAID
(Diclofenac Sodium Topical Solution); Perloromist (Formoterol
Fumarate Inhalation Solution); Peritoneal Dialysis Solution;
Phenylephrine Hydrochloride Ophthalmic Solution (Neo-Synephrine);
Phospholine Iodide (Echothiophate Iodide for Ophthalmic Solution);
Podofilox (Podofilox Topical Solution); Pred Forte (Prednisolone
Acetate Ophthalmic Suspension); Pralatrexate Solution for
Intravenous Injection (Folotyn); Pred Mild; Prednisone Intensol;
Prednisolone Acetate Ophthalmic Suspension (Pred Forte); Prevacid;
PrismaSol Solution (Sterile Hemofiltration Hemodiafiltration
Solution); ProAir; Proglycem; ProHance (Gadoteridol Injection
Solution); Proparacaine Hydrochloride Ophthalmic Solution
(Alcaine); Propine; Pulmicort; Pulmozyme; Quixin (Levofloxacin
Ophthalmic Solution 0.5%); QVAR; Rapamune; Rebetol; Relacon-HC;
Rotarix (Rotavirus Vaccine, Live, Oral Suspension); Rotavirus
Vaccine, Live, Oral Suspension (Rotarix); Rowasa (Mesalamine Rectal
Suspension Enema); Sabril (Vigabatrin Oral Solution); Sacrosidase
Oral Solution (Sucraid); Sandimmune; Sepra; Serevent Diskus; Solu
Cortef (Hydrocortisone Sodium Succinate); Solu Medrol
(Methylprednisolone sodium succinate); Spiriva; Sporanox Oral
Solution (Itraconazole Oral Solution); Staticin (Erythromycin
Topical Solution 1.5%); Stalevo; Starlix; Sterile Hemofiltration
Hemodiafiltration Solution (PrismaSol Solution); Stimate;
Sucralfate (Carafate Suspension); Sulfacetamide Sodium Ophthalmic
Solution 10% (Bleph 10); Synarel Nasal Solution (Nafarelin Acetate
Nasal Solution for Endometriosis); Taclonex Scalp (Calcipotriene
and Betamethasone Dipropionate Topical Suspension); Tamiflu; Tobi;
TobraDex; Tobradex ST (Tobramycin/Dexamethasone Ophthalmic
Suspension 0.3%/0.05%); Tobramycin/Dexamethasone Ophthalmic
Suspension 0.3%/0.05% (Tobradex ST); Timolol; Timoptic; Travatan Z;
Treprostinil Inhalation Solution (Tyvaso); Trusopt (Dorzolamide
Hydrochloride Ophthalmic Solution); Tyvaso (Treprostinil Inhalation
Solution); Ventolin; Vfend; Vibramycin Oral (Doxycycline Calcium
Oral Suspension); Videx (Didanosine Pediatric Powder for Oral
Solution); Vigabatrin Oral Solution (Sabril); Viokase; Viracept;
Viramune; Vitamin K1 (Fluid Colloidal Solution of Vitamin K1);
Voltaren Ophthalmic (Diclofenac Sodium Ophthalmic Solution);
Zarontin Oral Solution (Ethosuximide Oral Solution); Ziagen; Zyvox;
Zymar (Gatifloxacin Ophthalmic Solution); Zymaxid (Gatifloxacin
Ophthalmic Solution) DRUG CLASSES 5-alpha-reductase inhibitors;
5-aminosalicylates; 5HT3 receptor antagonists; adamantane
antivirals; adrenal cortical steroids; adrenal corticosteroid
inhibitors; adrenergic bronchodilators; agents for hypertensive
emergencies; agents for pulmonary hypertension; aldosterone
receptor antagonists; alkylating agents; alpha-adrenoreceptor
antagonists; alpha-glucosidase inhibitors; alternative medicines;
amebicides; aminoglycosides; aminopenicillins; aminosalicylates;
amylin analogs; Analgesic Combinations; Analgesics; androgens and
anabolic steroids; angiotensin converting enzyme inhibitors;
angiotensin II inhibitors; anorectal preparations; anorexiants;
antacids; anthelmintics; anti-angiogenic ophthalmic agents;
anti-CTLA-4 monoclonal antibodies; anti-infectives; antiadrenergic
agents, centrally acting; antiadrenergic agents, peripherally
acting; antiandrogens; antianginal agents; antiarrhythmic agents;
antiasthmatic combinations; antibiotics/antineoplastics;
anticholinergic antiemetics; anticholinergic antiparkinson agents;
anticholinergic bronchodilators; anticholinergic chronotropic
agents; anticholinergics/antispasmodics; anticoagulants;
anticonvulsants; antidepressants; antidiabetic agents; antidiabetic
combinations; antidiarrheals; antidiuretic hormones; antidotes;
antiemetic/antivertigo agents; antifungals; antigonadotropic
agents; antigout agents; antihistamines; antihyperlipidemic agents;
antihyperlipidemic combinations; antihypertensive combinations;
antihyperuricemic agents; antimalarial agents; antimalarial
combinations; antimalarial quinolines; antimetabolites;
antimigraine agents; antineoplastic detoxifying agents;
antineoplastic interferons; antineoplastic monoclonal antibodies;
antineoplastics; antiparkinson agents; antiplatelet agents;
antipseudomonal penicillins; antipsoriatics; antipsychotics;
antirheumatics; antiseptic and germicides; antithyroid agents;
antitoxins and antivenins; antituberculosis agents;
antituberculosis combinations; antitussives; antiviral agents;
antiviral combinations; antiviral interferons anxiolytics,
sedatives, and hypnotics; aromatase inhibitors; atypical
antipsychotics; azole antifungals; bacterial vaccines; barbiturate
anticonvulsants; barbiturates; BCR-ABL tyrosine kinase inhibitors;
benzodiazepine anticonvulsants; benzodiazepines; beta-adrenergic
blocking agents; beta-lactamase inhibitors; bile acid sequestrants;
biologicals; bisphosphonates; bone resorption inhibitors;
bronchodilator combinations; bronchodilators; calcitonin; calcium
channel blocking agents; carbamate anticonvulsants; carbapenems;
carbonic anhydrase inhibitor anticonvulsants; carbonic anhydrase
inhibitors; cardiac stressing agents; cardioselective beta
blockers; cardiovascular agents; catecholamines; CD20 monoclonal
antibodies; CD33 monoclonal antibodies; CD52 monoclonal antibodies;
central nervous system agents; cephalosporins; cerumenolytics;
chelating agents; chemokine receptor antagonist; chloride channel
activators; cholesterol absorption inhibitors; cholinergic
agonists; cholinergic muscle stimulants; cholinesterase inhibitors;
CNS stimulants; coagulation modifiers; colony stimulating factors;
contraceptives; corticotropin; coumarins and indandiones; cox-2
inhibitors; decongestants; dermatological agents; diagnostic
radiopharmaceuticals; dibenzazepine anticonvulsants; digestive
enzymes; dipeptidyl peptidase 4 inhibitors; diuretics; dopaminergic
antiparkinsonism agents; drugs used in alcohol dependence;
echinocandins; EGFR inhibitors; estrogen receptor antagonists;
estrogens; expectorants; factor Xa inhibitors; fatty acid
derivative anticonvulsants; fibric acid derivatives; first
generation cephalosporins; fourth generation cephalosporins;
functional bowel disorder agents; gallstone solubilizing agents;
gamma-aminobutyric acid analogs; gamma-aminobutyric acid reuptake
inhibitors; gamma-aminobutyric acid transaminase inhibitors;
gastrointestinal agents; general anesthetics; genitourinary tract
agents; GI stimulants; glucocorticoids; glucose elevating agents;
glycopeptide antibiotics; glycoprotein platelet inhibitors;
glycylcyclines; gonadotropin releasing hormones;
gonadotropin-releasing hormone antagonists; gonadotropins; group I
antiarrhythmics; group II antiarrhythmics; group III
antiarrhythmics; group IV antiarrhythmics; group V antiarrhythmics;
growth hormone receptor blockers; growth hormones; H. pylori
eradication agents; H2 antagonists; hematopoietic stem cell
mobilizer; heparin antagonists; heparins; HER2 inhibitors; herbal
products; histone deacetylase inhibitors; hormone replacement
therapy; hormones; hormones/antineoplastics; hydantoin
anticonvulsants; illicit (street) drugs; immune globulins;
immunologic agents; immunosuppressive agents; impotence agents; in
vivo diagnostic biologicals; incretin mimetics; inhaled
anti-infectives; inhaled corticosteroids; inotropic agents;
insulin; insulin-like growth factor; integrase strand transfer
inhibitor; interferons; intravenous nutritional products; iodinated
contrast media; ionic iodinated contrast media; iron products;
ketolides; laxatives; leprostatics; leukotriene modifiers;
lincomycin derivatives; lipoglycopeptides; local injectable
anesthetics; loop diuretics; lung surfactants; lymphatic staining
agents; lysosomal enzymes; macrolide derivatives; macrolides;
magnetic resonance imaging contrast media; mast cell stabilizers;
medical gas; meglitinides; metabolic agents; methylxanthines;
mineralocorticoids; minerals and electrolytes; miscellaneous
agents; miscellaneous analgesics; miscellaneous antibiotics;
miscellaneous anticonvulsants; miscellaneous antidepressants;
miscellaneous antidiabetic agents; miscellaneous antiemetics;
miscellaneous antifungals; miscellaneous antihyperlipidemic agents;
miscellaneous antimalarials; miscellaneous antineoplastics;
miscellaneous antiparkinson agents; miscellaneous antipsychotic
agents; miscellaneous antituberculosis agents; miscellaneous
antivirals; miscellaneous anxiolytics, sedatives and hypnotics;
miscellaneous biologicals; miscellaneous bone resorption
inhibitors; miscellaneous cardiovascular agents; miscellaneous
central nervous system agents; miscellaneous coagulation modifiers;
miscellaneous diuretics; miscellaneous genitourinary tract agents;
miscellaneous GI agents; miscellaneous hormones; miscellaneous
metabolic agents; miscellaneous ophthalmic agents; miscellaneous
otic agents; miscellaneous respiratory agents; miscellaneous sex
hormones; miscellaneous topical agents; miscellaneous uncategorized
agents; miscellaneous vaginal agents; mitotic inhibitors; monoamine
oxidase inhibitors; monoclonal antibodies; mouth and throat
products; mTOR inhibitors; mTOR kinase inhibitors; mucolytics;
multikinase inhibitors; muscle relaxants; mydriatics; narcotic
analgesic combinations; narcotic analgesics; nasal anti-infectives;
nasal antihistamines and decongestants; nasal lubricants and
irrigations; nasal preparations; nasal steroids; natural
penicillins; neuraminidase inhibitors; neuromuscular blocking
agents; next generation cephalosporins; nicotinic acid derivatives;
nitrates; NNRTIs; non-cardioselective beta blockers; non-iodinated
contrast media; non-ionic iodinated contrast media;
non-sulfonylureas; nonsteroidal anti-inflammatory agents;
norepinephrine reuptake inhibitors; norepinephrine-dopamine
reuptake inhibitors; nucleoside reverse transcriptase inhibitors
(NRTIs); nutraceutical products; nutritional
products; ophthalmic anesthetics; ophthalmic anti-infectives;
ophthalmic anti-inflammatory agents; ophthalmic antihistamines and
decongestants; ophthalmic diagnostic agents; ophthalmic glaucoma
agents; ophthalmic lubricants and irrigations; ophthalmic
preparations; ophthalmic steroids; ophthalmic steroids with
anti-infectives; ophthalmic surgical agents; oral nutritional
supplements; otic anesthetics; otic anti-infectives; otic
preparations; otic steroids; otic steroids with anti-infectives;
oxazolidinedione anticonvulsants; parathyroid hormone and analogs;
penicillinase resistant penicillins; penicillins; peripheral opioid
receptor antagonists; peripheral vasodilators; peripherally acting
antiobesity agents; phenothiazine antiemetics; phenothiazine
antipsychotics; phenylpiperazine antidepressants; plasma expanders;
platelet aggregation inhibitors; platelet-stimulating agents;
polyenes potassium-sparing diuretics; probiotics; progesterone
receptor modulators; progestins; prolactin inhibitors;
prostaglandin D2 antagonists; protease inhibitors; proton pump
inhibitors; psoralens; psychotherapeutic agents; psychotherapeutic
combinations; purine nucleosides; pyrrolidine anticonvulsants;
quinolones; radiocontrast agents; radiologic adjuncts; radiologic
agents; radiologic conjugating agents; radiopharmaceuticals; RANK
ligand inhibitors; recombinant human erythropoietins; renin
inhibitors; respiratory agents; respiratory inhalant products;
rifamycin derivatives; salicylates; sclerosing agents; second
generation cephalosporins; selective estrogen receptor modulators;
selective serotonin reuptake inhibitors; serotonin-norepinephrine;
reuptake inhibitors; serotoninergic neuroenteric modulators; sex
hormone combinations; sex hormones; skeletal muscle relaxant
combinations; skeletal muscle relaxants; smoking cessation agents;
somatostatin and somatostatin analogs; spermicides; statins;
sterile irrigating solutions; streptomyces derivatives; succinimide
anticonvulsants; sulfonamides; sulfonylureas; synthetic ovulation
stimulants; tetracyclic antidepressants; tetracyclines; therapeutic
radiopharmaceuticals; thiazide diuretics; thiazolidinediones;
thioxanthenes; third generation cephalosporins; thrombin
inhibitors; thrombolytics; thyroid drugs; tocolytic agents; topical
acne agents; topical agents; topical anesthetics; topical
anti-infectives; topical antibiotics; topical antifungals; topical
antihistamines; topical antipsoriatics; topical antivirals; topical
astringents; topical debriding agents; topical depigmenting agents;
topical emollients; topical keratolytics; topical steroids; topical
steroids with anti-infectives; toxoids; triazine anticonvulsants;
tricyclic antidepressants; trifunctional monoclonal antibodies;
tumor necrosis factor (TNF) inhibitors; tyrosine kinase inhibitors;
ultrasound contrast media; upper respiratory combinations; urea
anticonvulsants; urinary anti-infectives; urinary antispasmodics;
urinary pH modifiers; uterotonic agents; vaccine; vaccine
combinations; vaginal anti-infectives; vaginal preparations;
vasodilators; vasopressin antagonists; vasopressors; VEGF/VEGFR
inhibitors; viral vaccines; viscosupplementation agents; vitamin
and mineral combinations; vitamins
DIAGNOSTIC TESTS 17-Hydroxyprogesterone; ACE (Angiotensin I
converting enzyme); Acetaminophen; Acid phosphatase; ACTH;
Activated clotting time; Activated protein C resistance;
Adrenocorticotropic hormone (ACTH); Alanine aminotransferase (ALT);
Albumin; Aldolase; Aldosterone; Alkaline phosphatase; Alkaline
phosphatase (ALP); Alpha1-antitrypsin; Alpha-fetoprotein;
Alpha-fetoprotien; Ammonia levels; Amylase; ANA (antinuclear
antbodies); ANA (antinuclear antibodies); Angiotensin-converting
enzyme (ACE); Anion gap; Anticardiolipin antibody; Anticardiolipin
antivbodies (ACA); Anti-centromere antibody; Antidiuretic hormone;
Anti-DNA; Anti-Dnase-B; Anti-Gliadin antibody; Anti-glomerular
basement membrane antibody; Anti-HBc (Hepatitis B core antibodies;
Anti-HBs (Hepatitis B surface antibody; Antiphospholipid antibody;
Anti-RNA polymerase; Anti-Smith (Sm) antibodies; Anti-Smooth Muscle
antibody; Antistreptolysin O (ASO); Antithrombin III; Anti-Xa
activity; Anti-Xa assay; Apolipoproteins; Arsenic; Aspartate
aminotransferase (AST); B12; Basophil; Beta-2-Microglobulin;
Beta-hydroxybutyrate; B-HCG; Bilirubin; Bilirubin, direct;
Bilirubin, indirect; Bilirubin, total; Bleeding time; Blood gases
(arterial); Blood urea nitrogen (BUN); BUN; BUN (blood urea
nitrogen); CA 125; CA 15-3; CA 19-9; Calcitonin; Calcium; Calcium
(ionized); Carbon monoxide (CO); Carcinoembryonic antigen (CEA);
CBC; CEA; CEA (carcinoembryonic antigen); Ceruloplasmin;
CH50Chloride; Cholesterol; Cholesterol, HDL; Clot lysis time; Clot
retraction time; CMP; CO2; Cold agglutinins; Complement C3; Copper;
Corticotrophin releasing hormone (CRH) stimulation test; Cortisol;
Cortrosyn stimulation test; C-peptide; CPK (Total); CPK-MB;
C-reactive protein; Creatinine; Creatinine kinase (CK);
Cryoglobulins; DAT (Direct antiglobulin test); D-Dimer;
Dexamethasone suppression test; DHEA-S; Dilute Russell viper venom;
Elliptocytes; Eosinophil; Erythrocyte sedimentation rate (ESR);
Estradiol; Estriol; Ethanol; Ethylene glycol; Euglobulin lysis;
Factor V Leiden; Factor VIII inhibitor; Factor VIII level;
Ferritin; Fibrin split products; Fibrinogen; Folate; Folate (serum;
Fractional excretion of sodium (FENA); FSH (follicle stimulating
factor); FTA-ABS; Gamma glutamyl transferase (GGT); Gastrin; GGTP
(Gamma glutamyl transferase); Glucose; Growth hormone; Haptoglobin;
HBeAg (Hepatitis Be antigen); HBs-Ag (Hepatitis B surface antigen);
Helicobacter pylori; Hematocrit; Hematocrit (HCT); Hemoglobin;
Hemoglobin A1C; Hemoglobin electrophoresis; Hepatitis A antibodies;
Hepatitis C antibodies; IAT (Indirect antiglobulin test);
Immunofixation (IFE); Iron; Lactate dehydrogenase (LDH); Lactic
acid (lactate); LDH; LH (Leutinizing hormone; Lipase; Lupus
anticoagulant; Lymphocyte; Magnesium; MCH (mean corpuscular
hemoglobin; MCHC (mean corpuscular hemoglobin concentration); MCV
(mean corpuscular volume); Methylmalonate; Monocyte; MPV (mean
platelet volume); Myoglobin; Neutrophil; Parathyroid hormone (PTH);
Phosphorus; Platelets (plt); Potassium; Prealbumin; Prolactin;
Prostate specific antigen (PSA); Protein C; Protein S; PSA
(prostate specific antigen); PT (Prothrombin time); PTT (Partial
thromboplastin time); RDW (red cell distribution width); Renin;
Rennin; Reticulocyte count; reticulocytes; Rheumatoid factor (RF);
Sed Rate; Serum glutamic-pyruvic transaminase (SGPT; Serum protein
electrophoresis (SPEP); Sodium; T3-resin uptake (T3RU); T4, Free;
Thrombin time; Thyroid stimulating hormone (TSH); Thyroxine (T4);
Total iron binding capacity (TIBC); Total protein; Transferrin;
Transferrin saturation; Triglyceride (TG); Troponin; Uric acid;
Vitamin B12; White blood cells (WBC); Widal test.
Description
[0001] Priority is claimed from U.S. Ser. Nos. 61/667,871, filed
Jul. 3, 2012, and 61/800,746, filed Mar. 15, 2013, and this
application is a continuation-in-part of U.S. Ser. No. 13/169,811,
filed Jun. 27, 2011, now pending, which is a divisional of U.S.
Ser. No. 12/779,007, filed May 12, 2010, now U.S. Pat. No.
7,985,188, which claims priority to U.S. Provisional Ser. Nos.
61/222,727, filed Jul. 2, 2009; 61/213,904, filed Jul. 24, 2009;
61/234,505, filed Aug. 17, 2009; 61/261,321, filed Nov. 14, 2009;
61/263,289, filed Nov. 20, 2009; 61/285,813, filed Dec. 11, 2009;
61/298,159, filed Jan. 25, 2010; 61/299,888, filed Jan. 29, 2010;
61/318,197, filed Mar. 26, 2010, and 61/333,625, filed May 11,
2010. The above patent and applications are incorporated here by
reference in their entirety.
[0002] U.S. Pat. No. 7,985,188; International Application
PCT/US11/36097, filed May 11, 2011; U.S. Ser. No. 61/558,885, filed
Nov. 11, 2011; and U.S. Ser. No. 61/636,377, filed Apr. 20, 2012,
are all incorporated here by reference in their entirety.
[0003] Also incorporated by reference in their entirety are the
following European patent applications: EP10162755.2 filed May 12,
2010; EP10162760.2 filed May 12, 2010; EP10162756.0 filed May 12,
2010; EP10162758.6 filed May 12, 2010; EP10162761.0 filed May 12,
2010; and EP10162757.8 filed May 12, 2010. These European patent
applications describe apparatus, vessels, precursors, coatings or
layers and methods (in particular coating methods and test methods
for examining the coatings or layers) which can generally be used
in performing the present invention, unless stated otherwise
herein.
FIELD OF THE INVENTION
[0004] The present invention relates to the technical field of
coated surfaces, for example interior surfaces of pharmaceutical
packages or other vessels for storing or other contact with fluids.
Examples of suitable fluids include foods, biologically active
compounds or body fluids, for example pharmaceutical materials,
blood, and many others. The present invention also relates to a
pharmaceutical package or other vessel and to a method for coating
an inner or interior surface of a pharmaceutical package or other
vessel. The present invention also relates more generally to
medical devices, including devices other than packages or vessels,
for example catheters.
[0005] The present disclosure also relates to improved methods for
processing pharmaceutical packages or other vessels, for example
multiple identical pharmaceutical packages or other vessels used
for pharmaceutical preparation storage and delivery, venipuncture
and other medical sample collection, and other purposes. Such
pharmaceutical packages or other vessels are used in large numbers
for these purposes, and must be relatively economical to
manufacture and yet highly reliable in storage and use.
BACKGROUND OF THE INVENTION
[0006] One important consideration in manufacturing pharmaceutical
packages or other vessels for storing or other contact with fluids,
for example vials and pre-filled syringes, is that the contents of
the pharmaceutical package or other vessel desirably will have a
substantial shelf life. During this shelf life, it is important to
isolate the material filling the pharmaceutical package or other
vessel from atmospheric gases such as oxygen. It is also important
to isolate such material from the vessel wall containing it, or
from barrier layers or other functional layers applied to the
pharmaceutical package or other vessel wall to avoid leaching
material from the pharmaceutical package or other vessel wall,
barrier layer, or other functional layers into the prefilled
contents or vice versa.
[0007] Since many of these pharmaceutical packages or other vessels
are inexpensive and used in large quantities, for certain
applications it will be useful to reliably obtain the necessary
shelf life without increasing the manufacturing cost to a
prohibitive level.
[0008] For decades, most parenteral therapeutics have been
delivered to end users in Type I medical grade borosilicate glass
vessels such as vials or pre-filled syringes. The relatively
strong, impermeable and inert surface of borosilicate glass has
performed adequately for most drug products. However, the recent
advent of costly, complex and sensitive biologies as well as such
advanced delivery systems as auto injectors has exposed the
physical and chemical shortcomings of glass pharmaceutical packages
or other vessels, including possible contamination from metals,
flaking, and breakage, among other problems. Moreover, glass
contains several components which can leach out during storage and
cause damage to the stored material. In more detail, borosilicate
pharmaceutical packages or other vessels exhibit a number of
drawbacks.
[0009] Glass is manufactured from sand containing a heterogeneous
mixture of many elements (silicon, oxygen, boron, aluminum, sodium,
calcium) with trace levels of other alkali metals and alkaline
earth metals. Type I borosilicate glass consists of approximately
76% SiO.sub.2, 10.5% B.sub.2O.sub.3, 5% Al.sub.2O.sub.3, 7%
Na.sub.2O and 1.5% CaO and often contains trace metals such as
iron, magnesium, zinc, copper and others. The heterogeneous nature
of borosilicate glass creates a non-uniform surface chemistry at
the molecular level. Glass forming processes used to create glass
vessels expose some portions of the vessels to temperatures as
great as 1200.degree. C. Under such high temperatures alkali ions
migrate to the local surface and form oxides. The presence of ions
extracted from borosilicate glass devices may be involved in
degradation, aggregation and denaturation of some biologies. Many
proteins and other biologies must be lyophilized (freeze dried),
because they are not sufficiently stable in solution in glass vials
or syringes.
[0010] Glass pharmaceutical packages or other vessels are prone to
breakage or degradation during manufacture, filling operations,
shipping and use, which means that glass particulates may enter the
drug. The presence of glass particles has led to many FDA Warning
Letters and to product recalls.
[0011] Glass-forming processes do not yield the tight dimensional
tolerances required for some of the newer auto-injectors and
delivery systems.
[0012] As a result, some companies have turned to plastic
pharmaceutical packages or other vessels, which provide greater
dimensional tolerance and less breakage than glass but lack its
impermeability.
[0013] Although plastic is superior to glass with respect to
breakage, dimensional tolerances and surface uniformity, its use
for primary pharmaceutical packaging remains limited due to the
following shortcomings: [0014] Gas (oxygen) permeability: Plastic
allows small molecule gases to permeate into (or out of) the
device. The permeability of plastics to gases is significantly
greater than that of glass and, in many cases (as with
oxygen-sensitive drugs such as epinephrine), plastics have been
unacceptable for that reason. [0015] Water vapor transmission:
Plastics allow water vapors to pass through devices to a greater
degree than glass. This can be detrimental to the shelf life of a
solid (lyophilized) drug. Alternatively, a liquid product may lose
water in an arid environment. [0016] Leachables and extractables:
Plastic pharmaceutical packages or other vessels contain organic
compounds that can leach out or be extracted into the drug product.
These compounds can contaminate the drug and/or negatively impact
the drug's stability.
[0017] Clearly, while plastic and glass pharmaceutical packages or
other vessels each offer certain advantages in pharmaceutical
primary packaging, neither is optimal for all drugs, biologies or
other therapeutics. Thus, there is a desire for plastic
pharmaceutical packages or other vessels, for example vials, sample
collection tubes, and syringes, with gas and solute barrier
properties which approach the properties of glass.
[0018] A non-exhaustive list of documents of possible relevance
includes U.S. Pat. Nos. 7,488,683; 7,901,783; 6,068,884; 4,844,986;
and 8,067,070 and U.S. Publ. Appl. Nos. 2008/0090039, 2011/0152820,
2006/0046006 and 2004/0267194. These documents are all incorporated
by reference.
SUMMARY OF THE INVENTION
[0019] A non-limiting aspect of the invention is a vessel including
a thermoplastic wall enclosing a lumen. The wall supports an
SiO.sub.x composite barrier coating or layer, for which x is from
1.8 to 2.4, between the wall and the lumen. The SiO.sub.x composite
barrier coating or layer is formed by PECVD from an organosilicon
monomer and an oxidizing gas. The SiO.sub.x composite barrier
coating or layer is formed in at least bonding and build-up stages,
under the following conditions. During the bonding stage, the feed
ratio of organosilicon monomer to oxidizing gas, in seem, is from
2.5 to 10. During the build-up stage, the feed ratio of
organosilicon monomer to oxidizing gas is from 0.1 to 0.05.
[0020] A non-limiting aspect of the invention is a vessel including
a thermoplastic wall enclosing a lumen. The wall supports an
SiO.sub.x composite barrier coating or layer, for which x is from
1.8 to 2.4, between the wall and the lumen. The SiO.sub.x composite
barrier coating or layer is formed by PECVD from an organosilicon
monomer and an oxidizing gas. The SiO.sub.x composite barrier
coating or layer is formed at an initial RF power level from 20 to
4 W and a highest RF power level of from 300 to 30 W.
[0021] A non-limiting aspect of the invention is a vessel including
a thermoplastic wall enclosing a lumen. The wall supports an
SiO.sub.x composite barrier coating or layer, for which x is from
1.8 to 2.4, between the wall and the lumen. The degree of retention
of the composite barrier coating or layer on the substrate is at
least 95% by the Article Deformation/Tape Test Method described in
this specification.
[0022] A non-limiting aspect of the invention is a vessel including
a thermoplastic wall enclosing a lumen. The wall supports an
SiO.sub.x composite barrier coating or layer, for which x is from
1.8 to 2.4, between the wall and the lumen. The degree of retention
of the composite barrier coating or layer on the substrate is at
least 90% by the Coated Article Cross-Scratch Tape Test Method.
[0023] A non-limiting aspect of the invention is a vessel including
a thermoplastic wall enclosing a lumen. The wall supports an
SiO.sub.x composite barrier coating or layer, for which x is from
1.8 to 2.4, between the wall and the lumen. High Resolution X-ray
Photoelectron Spectroscopy (XPS) shows the presence of an interface
between the composite barrier coating or layer and the wall or
substrate. The interface has at least 1 mol.% O.sub.3--Si--C
covalent bonding, as a proportion of the O.sub.3--Si--C covalent
bonding plus SiO.sub.4 bonding.
[0024] A non-limiting aspect of the invention is a vessel including
a thermoplastic wall enclosing a lumen. The wall supports an
SiO.sub.x composite barrier coating or layer, for which x is from
1.8 to 2.4, between the wall and the lumen. High Resolution X-ray
Photoelectron Spectroscopy (XPS) shows the presence of an interface
between the composite barrier coating or layer and the wall or
substrate. The interface has an Si 2p chemical shift to lower
binding energy (eV), compared to the binding energy of SiO.sub.4
bonding.
[0025] A non-limiting aspect of the invention is a method of making
a vessel. A thermoplastic wall enclosing a lumen is provided. An
SiO.sub.x composite barrier coating or layer, for which x is from
1.8 to 2.4, is applied to the thermoplastic wall. The composite
barrier coating or layer is supported by the wall between the wall
and the lumen. The composite barrier coating or layer is applied by
PECVD from an organosilicon monomer and oxidizing gas. The
composite barrier coating or layer is applied in at least bonding
and build-up stages, under the following conditions. During the
bonding stage, the feed ratio of organosilicon monomer to oxidizing
gas, in seem, is from 2.5 to 10. During the build-up stage, the
feed ratio of organosilicon monomer to oxidizing gas is from 0.1 to
0.05.
[0026] A non-limiting aspect of the invention is a method of making
a vessel. A thermoplastic wall enclosing a lumen is provided. An
SiO.sub.x composite barrier coating or layer, for which x is from
1.8 to 2.4, is applied to the thermoplastic wall. The composite
barrier coating or layer is supported by the wall between the wall
and the lumen. The composite barrier coating or layer is applied by
PECVD from an organosilicon monomer and oxidizing gas. The
composite barrier coating or layer is applied at an initial RF
power level from 20 to 4 W and a highest RF power level of from 300
to 30 W.
[0027] A non-limiting aspect of the invention is a method of making
a vessel. A thermoplastic wall enclosing a lumen is provided. An
SiO.sub.x composite barrier coating or layer, for which x is from
1.8 to 2.4, is applied to the thermoplastic wall. The composite
barrier coating or layer is supported by the wall between the wall
and the lumen. The composite barrier coating or layer is applied by
PECVD from an organosilicon monomer and oxidizing gas. The
composite barrier coating or layer is applied in at least bonding
and build-up stages. The degree of retention of the composite
barrier coating or layer on the substrate is at least 95% by the
Article Deformation/Tape Test Method.
[0028] A non-limiting aspect of the invention is a method of making
a vessel. A thermoplastic wall enclosing a lumen is provided. An
SiO.sub.x composite barrier coating or layer, for which x is from
1.8 to 2.4, is applied to the thermoplastic wall. The composite
barrier coating or layer is supported by the wall between the wall
and the lumen. The composite barrier coating or layer is applied by
PECVD from an organosilicon monomer and oxidizing gas. The
composite barrier coating or layer is applied in at least bonding
and build-up stages. The degree of retention of the composite
barrier coating or layer on the substrate is at least 90% by the
Coated Article Cross-Scratch Tape Test Method.
[0029] A non-limiting aspect of the invention is a method of making
a vessel. A thermoplastic wall enclosing a lumen is provided. An
SiO.sub.x composite barrier coating or layer, for which x is from
1.8 to 2.4, is applied to the thermoplastic wall. The composite
barrier coating or layer is supported by the wall between the wall
and the lumen. The composite barrier coating or layer is applied by
PECVD from an organosilicon monomer and oxidizing gas. The
composite barrier coating or layer is applied in at least bonding
and build-up stages. High Resolution X-ray Photoelectron
Spectroscopy (XPS) shows the presence of an interface between the
composite barrier coating or layer and the substrate having at
least 1 mol.% O.sub.3--Si--C covalent bonding, as a proportion of
the O.sub.3--Si--C covalent bonding plus SiO.sub.4 bonding.
[0030] A non-limiting aspect of the invention is a method of making
a vessel. A thermoplastic wall enclosing a lumen is provided. An
SiO.sub.x composite barrier coating or layer, for which x is from
1.8 to 2.4, is applied to the thermoplastic wall. The composite
barrier coating or layer is supported by the wall between the wall
and the lumen. The composite barrier coating or layer is applied by
PECVD from an organosilicon monomer and oxidizing gas. The
composite barrier coating or layer is applied in at least bonding
and build-up stages. High Resolution X-ray Photoelectron
Spectroscopy (XPS) shows the presence of an Si 2p chemical shift to
lower binding energy (eV), compared to the binding energy of
SiO.sub.4 bonding.
[0031] A non-limiting aspect of the invention is a filled package
comprising a vessel having a lumen defined at least in part by a
wall. The wall has an interior surface facing the lumen, an outer
surface, and a coating set on the interior surface comprising a tie
coating or layer, a barrier coating or layer, and a pH protective
coating or layer. Optionally in any embodiment, the tie coating or
layer and the barrier coating or layer together are provided in the
form of a composite barrier as previously defined.
[0032] The tie coating or layer comprises SiO.sub.xC.sub.y or
SiN.sub.xC.sub.y wherein x is from about 0.5 to about 2.4 and y is
from about 0.6 to about 3. The tie coating or layer has an interior
surface facing the lumen and an outer surface facing the wall
interior surface.
[0033] The barrier coating or layer comprises SiO.sub.x, wherein x
is from 1.5 to 2.9, from 2 to 1000 nm thick, the barrier coating or
layer of SiO.sub.x having an interior surface facing the lumen and
an outer surface facing the interior surface of the tie coating or
layer, the barrier coating or layer being effective to reduce the
ingress of atmospheric gas into the lumen compared to an vessel
without a barrier coating or layer;
[0034] The pH protective coating or layer comprises
SiO.sub.xC.sub.y or SiN.sub.xC.sub.y wherein x is from about 0.5 to
about 2.4 and y is from about 0.6 to about 3, the pH protective
coating or layer having an interior surface facing the lumen and an
outer surface facing the interior surface of the composite barrier
coating or layer,
[0035] The combination of the tie coating or layer and the pH
protective coating or layer is effective to increase the calculated
shelf life of the package (total Si/Si dissolution rate).
[0036] The package also includes a fluid composition contained in
the lumen and having a pH between 5 and 9. The calculated shelf
life of the package is more than six months at a storage
temperature of 4.degree. C.
[0037] A non-limiting aspect of the invention is an article
including a wall having a surface and a coating set on the surface
comprising a tie coating or layer, a barrier coating or layer, and
a pH protective coating or layer.
[0038] The tie coating or layer comprises SiO.sub.xC.sub.y or
SiN.sub.xC.sub.y wherein x is from about 0.5 to about 2.4 and y is
from about 0.6 to about 3. The tie coating or layer has an outer
surface facing the wall surface and an interior surface;
[0039] The barrier coating or layer comprises SiO.sub.x, wherein x
is from 1.5 to 2.9, from 2 to 1000 nm thick. The composite barrier
coating or layer of SiO.sub.x has an outer surface facing the
interior surface of the tie coating or layer and the composite
barrier coating or layer of SiO.sub.x has an interior surface. The
composite barrier coating or layer is effective to reduce the
ingress of atmospheric gas through the wall compared to an uncoated
wall.
[0040] Optionally in any embodiment, the tie coating or layer and
the barrier coating or layer together are provided in the form of a
composite barrier coating or layer as previously defined.
[0041] The pH protective coating or layer comprises
SiO.sub.xC.sub.y or SiN.sub.xC.sub.y wherein x is from about 0.5 to
about 2.4 and y is from about 0.6 to about 3. The pH protective
coating or layer is deposited on the composite barrier coating or
layer. The pH protective coating or layer is formed by chemical
vapor deposition of a precursor selected from an acyclic siloxane,
a monocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane,
a monocyclic silazane, a polycyclic silazane, a polysilsesquiazane,
a silatrane, a silquasilatrane, a silproatrane, an azasilatrane, an
azasilquasiatrane, an azasilproatrane, or a combination of any two
or more of these precursors; and
[0042] The rate of erosion of the pH protective coating or layer,
if directly contacted by a fluid composition having a pH at some
point between 5 and 9, is less than the rate of erosion of the
composite barrier coating or layer, if directly contacted by the
fluid composition.
[0043] A non-limiting aspect of the invention is a vessel
comprising a thermoplastic wall having an interior surface
enclosing a lumen. The interior surface has a tie coating or layer,
a barrier coating or layer, and a pH protective coating or layer. A
fluid is contained in the lumen having a pH greater than 5.
[0044] The tie coating or layer comprises SiO.sub.xC.sub.y or
SiN.sub.xC.sub.y wherein x is from about 0.5 to about 2.4 and y is
from about 0.6 to about 3, the tie coating or layer having an outer
surface facing the wall surface and the tie coating or layer having
an interior surface.
[0045] The barrier coating or layer comprises SiO.sub.x, in which x
is between 1.5 and 2.9. The barrier coating or layer is applied by
PECVD, is positioned between the interior surface of the tie
coating or layer and the fluid, and is supported by the
thermoplastic wall. The barrier coating or layer has the
characteristic of being subject to being measurably diminished in
barrier improvement factor in less than six months as a result of
attack by the fluid.
[0046] Optionally in any embodiment, the tie coating or layer and
the barrier coating or layer together are provided in the form of a
composite barrier as previously defined.
[0047] The vessel has a pH protective coating or layer of
SiO.sub.xC.sub.y, in which x is between 0.5 and 2.4 and y is
between 0.6 and 3. The pH protective coating or layer is applied by
PECVD, is positioned between the composite barrier coating or layer
and the fluid and is supported by the thermoplastic wall. The pH
protective coating or layer and tie coating or layer together are
effective to keep the composite barrier coating or layer at least
substantially undissolved as a result of attack by the fluid for a
period of at least six months.
BRIEF DESCRIPTION OF THE DRAWINGS
[0048] FIG. 1 is a schematic sectional view of a vessel holder in a
coating station according to an embodiment of the disclosure.
[0049] FIG. 2 is a section taken along section lines A-A of FIG.
1.
[0050] FIG. 3 is a view similar to FIG. 1 of another embodiment for
processing syringe barrels and other pharmaceutical packages or
other vessels.
[0051] FIG. 4 is an enlarged detail view of the processing vessel
of FIG. 3.
[0052] FIG. 5 is a schematic view of an assembly for treating
pharmaceutical packages or other vessels. The assembly is usable
with the apparatus in any of the preceding figures.
[0053] FIG. 6 shows a TEM image of a lubricity and/or pH protective
coating or layer according to the invention coated on a composite
barrier coating or layer, which in turn is coated on a COC
substrate.
[0054] FIG. 7 shows a TEM image of a composite barrier coating or
layer which is coated on a COC substrate.
[0055] FIG. 8 is an assembly view of a prefilled syringe provided
with a composite barrier layer, a pH protective coating or layer,
and a lubricity layer and filled and closed to provide a
pharmaceutical package.
[0056] FIG. 9 is a schematic view of a pharmaceutical package in
the form of a vial provided with a composite barrier layer, a pH
protective coating or layer, and optionally a lubricity layer.
[0057] FIG. 10 is a schematic view of a pharmaceutical package in
the form of a blister package provided with a composite barrier
layer and a pH protective coating or layer.
[0058] FIGS. 11-14 are FTIR absorbance spectra showing absorbance
at the symmetric stretching mode (1000-1040 cm.sup.-1) and the
asymmetric stretching mode (1060-1100 cm.sup.-1) of the Si--O--Si
bond.
[0059] FIG. 15 is a FTIR amplitude versus wave number plot marked
up from FIG. 5 of U.S. Pat. No. 8,067,070.
[0060] The following reference characters are used in the drawing
figures:
TABLE-US-00001 28 coating station 38 Vessel holder 50 Vessel holder
80 Vessel 82 Opening 84 Closed end 86 Wall 88 Inner or interior
surface 90 Composite barrier layer 92 Vessel port 94 Vacuum duct 96
Vacuum port 98 Vacuum source 100 O-ring (of 92) 102 O-ring (of 96)
104 Gas inlet port 106 O-ring (of 100) 108 Probe (counter
electrode) 110 Gas delivery port (of 108) 114 Housing (of 50 or
112) 116 Collar 118 Exterior surface (of 80) 144 PECVD gas source
152 Pressure gauge 160 Electrode 162 Power supply 164 Sidewall (of
160) 166 Sidewall (of 160) 168 Closed end (of 160) 210
Pharmaceutical package 212 Lumen 214 Wall 216 Outer surface 218
Fluid composition 220 Interior surface (of 288) 222 Outer surface
(of 288) 224 Interior surface (of 286) 226 Outer surface (of 286)
250 Syringe barrel 254 Inner or interior surface (of 250) 256 Back
end (of 250) 258 Plunger (of 252) (relatively sliding part) 260
Front end (of 250) 262 Cap 286 pH protective coating 287 Lubricity
layer (FIGS. 8-9) 288 Composite barrier layer 290 Apparatus for
coating, for example, 250 292 Inner or interior surface (of 294)
294 Restricted opening (of 250) 296 Processing vessel 298 Outer
surface (of 250) 300 Lumen (of 250) 302 Larger opening (of 250) 304
Processing vessel lumen 306 Processing vessel opening 308 Inner
electrode 310 Interior passage (of 308) 312 Proximal end (of 308)
314 Distal end (of 308) 316 Distal opening (of 308) 318 Plasma 332
First fitting (male Luer taper) 334 Second fitting (female Luer
taper) 336 Locking collar (of 332) 338 First abutment (of 332) 340
Second abutment (of 332) 342 O-ring 344 Dog 404 Vent (FIG. 5) 574
Main vacuum valve 576 Vacuum line 578 Manual bypass valve 580
Bypass line 582 Vent valve 584 Main reactant gas valve 586 Main
reactant feed line 588 Organosilicon liquid reservoir 590
Organosilicon feed line (capillary) 592 Organosilicon shut-off
valve 594 Oxygen tank 596 Oxygen feed line 598 Mass flow controller
600 Oxygen shut-off valve 602 Source of carrier gas (FIG. 5) 604
Conduit (FIG. 5) 606 Carrier gas shut-off valve (FIG. 5) 614
Headspace 616 Pressure source 618 Pressure line 620 Capillary
connection
DETAILED DESCRIPTION
[0061] The present invention will now be described more fully, with
reference to the accompanying drawings, in which several
embodiments are shown. This invention can, however, be embodied in
many different forms and should not be construed as limited to the
embodiments set forth here. Rather, these embodiments are examples
of the invention, which has the full scope indicated by the
language of the claims. Like numbers refer to like or corresponding
elements throughout. The following disclosure relates to all
embodiments unless specifically limited to a certain
embodiment.
DEFINITION SECTION
[0062] In the context of the present invention, the following
definitions and abbreviations are used:
[0063] RF is radio frequency.
[0064] The term "at least" in the context of the present invention
means "equal or more" than the integer following the term. The word
"comprising" does not exclude other elements or steps, and the
indefinite article "a" or "an" does not exclude a plurality unless
indicated otherwise. Whenever a parameter range is indicated, it is
intended to disclose the parameter values given as limits of the
range and all values of the parameter falling within said
range.
[0065] "First" and "second" or similar references to, for example,
processing stations or processing devices refer to the minimum
number of processing stations or devices that are present, but do
not necessarily represent the order or total number of processing
stations and devices. These terms do not limit the number of
processing stations or the particular processing carried out at the
respective stations.
[0066] For purposes of the present invention, an "organosilicon
precursor" is a compound having at least one of the linkages:
##STR00001##
which is a tetravalent silicon atom connected to an oxygen or
nitrogen atom and an organic carbon atom (an organic carbon atom
being a carbon atom bonded to at least one hydrogen atom). A
volatile organosilicon precursor, defined as such a precursor that
can be supplied as a vapor in a PECVD apparatus, is an optional
organosilicon precursor. Optionally, the organosilicon precursor is
selected from the group consisting of a linear siloxane, a
monocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane,
an alkyl trimethoxysilane, a linear silazane, a monocyclic
silazane, a polycyclic silazane, a polysilsesquiazane, and a
combination of any two or more of these precursors.
[0067] The feed amounts of PECVD precursors, gaseous reactant or
process gases, and carrier gas are sometimes expressed in "standard
volumes" in the specification and claims. The standard volume of a
charge or other fixed amount of gas is the volume the fixed amount
of the gas would occupy at a standard temperature and pressure
(without regard to the actual temperature and pressure of
delivery). Standard volumes can be measured using different units
of volume, and still be within the scope of the present disclosure
and claims. For example, the same fixed amount of gas could be
expressed as the number of standard cubic centimeters, the number
of standard cubic meters, or the number of standard cubic feet.
Standard volumes can also be defined using different standard
temperatures and pressures, and still be within the scope of the
present disclosure and claims. For example, the standard
temperature might be 0.degree. C. and the standard pressure might
be 760 Torr (as is conventional), or the standard temperature might
be 20.degree. C. and the standard pressure might be 1 Torr. But
whatever standard is used in a given case, when comparing relative
amounts of two or more different gases without specifying
particular parameters, the same units of volume, standard
temperature, and standard pressure are to be used relative to each
gas, unless otherwise indicated.
[0068] The corresponding feed rates of PECVD precursors, gaseous
reactant or process gases, and carrier gas are expressed in
standard volumes per unit of time in the specification. For
example, in the working examples the flow rates are expressed as
standard cubic centimeters per minute, abbreviated as seem. As with
the other parameters, other units of time can be used, such as
seconds or hours, but consistent parameters are to be used when
comparing the flow rates of two or more gases, unless otherwise
indicated.
[0069] A "vessel" in the context of the present invention can be
any type of vessel with at least one opening and a wall defining an
inner or interior surface. The substrate can be the inside wall of
a vessel having a lumen. Though the invention is not necessarily
limited to pharmaceutical packages or other vessels of a particular
volume, pharmaceutical packages or other vessels are contemplated
in which the lumen has a void volume of from 0.5 to 50 ml,
optionally from 1 to 10 ml, optionally from 0.5 to 5 ml, optionally
from 1 to 3 ml. The substrate surface can be part or all of the
inner or interior surface of a vessel having at least one opening
and an inner or interior surface.
[0070] The term "at least" in the context of the present invention
means "equal or more" than the integer following the term. Thus, a
vessel in the context of the present invention has one or more
openings. One or two openings, like the openings of a sample tube
(one opening) or a syringe barrel (two openings) are preferred. If
the vessel has two openings, they can be of same or different size.
If there is more than one opening, one opening can be used for the
gas inlet for a PECVD coating method according to the present
invention, while the other openings are either capped or open. A
vessel according to the present invention can be a sample tube, for
example for collecting or storing biological fluids like blood or
urine, a syringe (or a part thereof, for example a syringe barrel)
for storing or delivering a biologically active compound or
composition, for example a medicament or pharmaceutical
composition, a vial for storing biological materials or
biologically active compounds or compositions, a pipe, for example
a catheter for transporting biological materials or biologically
active compounds or compositions, or a cuvette for holding fluids,
for example for holding biological materials or biologically active
compounds or compositions.
[0071] A vessel can be of any shape, a vessel having a
substantially cylindrical wall adjacent to at least one of its open
ends being preferred. Generally, the interior wall of the vessel is
cylindrically shaped, like, for example in a sample tube or a
syringe barrel. Sample tubes and syringes or their parts (for
example syringe barrels) are contemplated.
[0072] A "hydrophobic layer" in the context of the present
invention means that the coating or layer lowers the wetting
tension of a surface coated with the coating or layer, compared to
the corresponding uncoated surface. Hydrophobicity is thus a
function of both the uncoated substrate and the coating or layer.
The same applies with appropriate alterations for other contexts
wherein the term "hydrophobic" is used. The term "hydrophilic"
means the opposite, i.e. that the wetting tension is increased
compared to reference sample. The present hydrophobic layers are
primarily defined by their hydrophobicity and the process
conditions providing hydrophobicity
[0073] The values of w, x, y, and z used throughout this
specification, as in the formula Si.sub.wO.sub.xC.sub.yH.sub.z or
its equivalent in this specification, SiO.sub.xC.sub.y, should be
understood as ratios or an empirical formula (for example for a
coating or layer), rather than as a limit on the number or type of
atoms in a molecule. For example, octamethylcyclotetrasiloxane,
which has the molecular composition Si.sub.4O.sub.4C.sub.8H.sub.24,
can be described by the following empirical formula, arrived at by
dividing each of w, x, y, and z in the molecular formula by 4, the
largest common factor: Si.sub.1O.sub.1C.sub.2H.sub.6. The values of
w, x, y, and z are also not limited to integers. For example,
(acyclic) octamethyltrisiloxane, molecular composition
Si.sub.3O.sub.2C.sub.8H.sub.24, is reducible to
Si.sub.1O.sub.0.67C.sub.2.67H.sub.8. Also, in this specification
SiO.sub.xC.sub.yH.sub.z is equivalent to SiO.sub.xC.sub.y (i.e. w
is set equal to 1 and the amount of hydrogen, if any, is not
reported). It is not necessary to show the presence of hydrogen in
any proportion to show the presence of SiO.sub.xC.sub.y.
[0074] "Wetting tension" is a specific measure for the
hydrophobicity or hydrophilicity of a surface. An optional wetting
tension measurement method in the context of the present invention
is ASTM D 2578 or a modification of the method described in ASTM D
2578. This method uses standard wetting tension solutions (called
dyne solutions) to determine the solution that comes nearest to
wetting a plastic film surface for exactly two seconds. This is the
film's wetting tension. The procedure utilized is varied herein
from ASTM D 2578 in that the substrates are not flat plastic films,
but are tubes made according to the Protocol for Forming PET Tube
and (except for controls) coated according to the Protocol for
coating Tube Interior with Hydrophobic Coating or Layer (see
Example 9 of EP2251671 A2).
[0075] A "lubricity and/or pH protective coating" according to the
present invention is a coating or layer which has a lower
frictional resistance than the uncoated surface, which is a
lubricity layer, and/or protects an underlying surface or layer
from a fluid composition contacting the layer, which is a pH
protective coating or layer (as more extensively defined elsewhere
in this specification). In other words, respecting a lubricity
layer, it reduces the frictional resistance of the coated surface
in comparison to a reference surface that is uncoated. The present
lubricity and/or pH protective coatings are primarily defined as
lubricity layers by their lower frictional resistance than the
uncoated surface and the process conditions providing lower
frictional resistance than the uncoated surface, and optionally can
have a composition according to the empirical composition
Si.sub.wO.sub.xC.sub.yH.sub.z, (or its equivalent SiO.sub.xC.sub.y)
as defined herein. It generally has an atomic ratio
Si.sub.wO.sub.xC.sub.y (or its equivalent SiO.sub.xC.sub.y) wherein
w is 1, x is from about 0.5 to about 2.4, y is from about 0.6 to
about 3.
[0076] Typically, expressed as the formula Si.sub.wO.sub.xC.sub.y,
the atomic ratios of Si, O, and C
[0077] in the "lubricity and/or pH protective coating" are, as
several options: [0078] Si 100: O 50-150: C 90-200 (i.e. w=1, x=0.5
to 1.5, y=0.9 to 2); [0079] Si 100: O 70-130: C 90-200 (i.e. w=1,
x=0.7 to 1.3, y=0.9 to 2) [0080] Si 100: O 80-120: C 90-150 (i.e.
w=1, x=0.8 to 1.2, y=0.9 to 1.5) [0081] Si 100: O 90-120: C 90-140
(i.e. w=1, x=0.9 to 1.2, y=0.9 to 1.4), or [0082] Si 100: O 92-107:
C 116-133 (i.e. w=1, x=0.92 to 1.07, y=1.16 to 1.33)
[0083] The atomic ratio can be determined by XPS (X-ray
photoelectron spectroscopy). Taking into account the H atoms, which
are not measured by XPS, the coating or layer may thus in one
aspect have the formula Si.sub.wO.sub.xC.sub.yH.sub.z (or its
equivalent SiO.sub.xC.sub.y), for example where w is 1, x is from
about 0.5 to about 2.4, y is from about 0.6 to about 3, and z is
from about 2 to about 9. Typically, such coating or layer would
hence contain 36% to 41% carbon normalized to 100% carbon plus
oxygen plus silicon.
[0084] "Frictional resistance" can be static frictional resistance
and/or kinetic frictional resistance.
[0085] One of the optional embodiments of the present invention is
a syringe part, for example a syringe barrel or plunger, coated
with a lubricity and/or pH protective coating. In this contemplated
embodiment, the relevant static frictional resistance in the
context of the present invention is the breakout force as defined
herein, and the relevant kinetic frictional resistance in the
context of the present invention is the plunger sliding force as
defined herein. For example, the plunger sliding force as defined
and determined herein is suitable to determine the presence or
absence and the lubricity and/or pH protective characteristics of a
lubricity and/or pH protective coating or layer in the context of
the present invention whenever the coating or layer is applied to
any syringe or syringe part, for example to the inner wall of a
syringe barrel. The breakout force is of particular relevance for
evaluation of the coating or layer effect on a prefilled syringe,
i.e. a syringe which is filled after coating and can be stored for
some time, for example several months or even years, before the
plunger is moved again (has to be "broken out").
[0086] The "plunger sliding force" (synonym to "glide force,"
"maintenance force", or Fm, also used in this description) in the
context of the present invention is the force required to maintain
movement of a plunger in a syringe barrel, for example during
aspiration or dispense. It can advantageously be determined using
the ISO 7886-1:1993 test described herein and known in the art. A
synonym for "plunger sliding force" often used in the art is
"plunger force" or "pushing force".
[0087] The "plunger breakout force" (synonym to "breakout force",
"break loose force", "initiation force", Fi, also used in this
description) in the context of the present invention is the initial
force required to move the plunger in a syringe, for example in a
prefilled syringe.
[0088] Both "plunger sliding force" and "plunger breakout force"
and methods for their measurement are described in more detail in
subsequent parts of this description. These two forces can be
expressed in N, lbs or kg and all three units are used herein.
These units correlate as follows: 1 N=0.102 kg=0.2248 lbs
(pounds).
[0089] Sliding force and breakout force are sometimes used herein
to describe the forces required to advance a stopper or other
closure into a pharmaceutical package or other vessel, such as a
medical sample tube or a vial, to seat the stopper in a vessel to
close the vessel. Its use is analogous to use in the context of a
syringe and its plunger, and the measurement of these forces for a
vessel and its closure are contemplated to be analogous to the
measurement of these forces for a syringe, except that at least in
most cases no liquid is ejected from a vessel when advancing the
closure to a seated position.
[0090] "Slidably" means that the plunger, closure, or other
removable part is permitted to slide in a syringe barrel or other
vessel.
[0091] Coatings of SiO.sub.x are deposited by plasma enhanced
chemical vapor deposition (PECVD) or other chemical vapor
deposition processes on the vessel of a pharmaceutical package, in
particular a thermoplastic package, to serve as a composite barrier
coating or layer preventing oxygen, carbon dioxide, or other gases
from entering the vessel and/or to prevent leaching of the
pharmaceutical material into or through the package wall.
[0092] Referring to the Figures, in any embodiment of the vessel or
method, the vessel can be provided in any configuration, for
example a tube 80, a vial 228, a blister package 230, a syringe
252, a syringe barrel 250, a prefilled syringe (FIG. 8), a
cartridge, a sample tube 80, or an evacuated blood sample tube, as
several non-limiting examples. Any of these types of vessels is
alternatively 288 referred to as a vessel 80 in this
disclosure.
[0093] In any embodiment of the vessel 80 or method, the vessel 80
optionally can have a rated volume (the maximum volume of fluid it
is routinely used to contain and deliver, as reported by the
manufacturer) between 0.2 and 50 ml., optionally between 2 and 50
ml., optionally between 2 and 20 ml., optionally between 2 and 6
ml., optionally between 3 and 5 ml., optionally between 0.25 and 20
ml., optionally between 0.5 and 5 ml., optionally between 1 and 2
ml.
[0094] In any embodiment of the vessel 80 or method, the vessel 80
optionally has a fill volume (the entire volume of the stoppered
vessel 80, including headspace) between 0.3 and 75 ml., optionally
between 3 and 75 ml., optionally between 3 and 30 ml., optionally
between 4 and 9 ml., optionally between 4 and 8 ml., optionally
between 0.4 and 35 ml., optionally between 0.8 and 9 ml.,
optionally between 1.7 and 3.5 ml.
[0095] In any embodiment of the vessel 80 or method, the vessel 80
optionally includes a thermoplastic wall 214 enclosing a lumen 212.
"Thermoplastic" is explicitly defined to include glass or quartz
materials, one example of which is borosilicate glass, as well as
organic thermoplastic resins and resin compositions. The wall
supports an SiO.sub.x composite barrier coating or layer 288, for
which x is from 1.8 to 2.4, between the wall and the lumen. The
SiO.sub.x composite barrier coating or layer 288 is formed by PECVD
from an organosilicon monomer and an oxidizing gas.
[0096] In any embodiment of the vessel 80, the SiO.sub.x composite
barrier coating or layer 288 can optionally be formed in at least
bonding and build-up stages.
[0097] In any embodiment of the vessel 80 or method, the substrate
optionally is ablated by the plasma before the SiO.sub.x bonding
and build-up stages. Ablation roughens the substrate surface and
introduces organic material into the plasma which participates in
coating formation, adding to the carbon and hydrogen in the plasma.
The ablation is contemplated to subside as the composite barrier
coating or layer 288 begins to bond and build up, leaving a surface
that is not as readily ablated under deposition conditions.
[0098] In any embodiment of the vessel 80 or method, the SiO.sub.x
composite barrier coating or layer 288 can be formed by PECVD from
a gas feed including an organosilicon monomer, an oxidizing gas,
and a carrier gas. (As used in this specification, "carrier gas" is
also inclusive of a diluent gas.)
[0099] In any embodiment of the vessel 80 or method, the
organosilicon monomer, also known as a precursor feed, can include
an organosiloxane, an organosilane, an organosiloxazane, an
organosilazane, or a combination of two or more of these. In any
embodiment of the vessel 80 or method, gas feed optionally can
contain a linear or branched siloxane having from 1 to 6 silicon
atoms, a monocyclic siloxane, a polycyclic siloxane, a
polysilsesquioxane, a monocyclic silazane, a polycyclic silazane, a
polysilsesquiazane, a silatrane, a silquasilatrane, a silproatrane,
an azasilatrane, an azasilquasiatrane, an azasilproatrane, or a
combination of any two or more of these precursors. The composite
barrier coating or layer 288 optionally can be applied by PECVD of
a precursor feed comprising a monocyclic siloxane, a polycyclic
siloxane, a polysilsesquioxane, a silatrane, a silquasilatrane, a
silproatrane, or a combination of any two or more of these
precursors.
[0100] In any embodiment of the vessel 80 or method, the oxidizing
gas can include diatomic oxygen, O.sub.2. Optionally, the oxidizing
gas comprises hydrogen peroxide, H.sub.2O.sub.2. Optionally, the
oxidizing gas comprises ozone, O.sub.3. Optionally, the oxidizing
gas comprises water, H.sub.2O.
[0101] In any embodiment of the vessel 80 or method, a carrier gas
can either be used or not. If used, the carrier gas optionally
includes an inert gas under the PECVD conditions employed. In any
embodiment of the vessel 80 or method, the carrier gas optionally
comprises a noble gas. In any embodiment of the vessel 80 or
method, the carrier gas optionally comprises helium. In any
embodiment of the vessel 80 or method, the carrier gas optionally
comprises neon. In any embodiment of the vessel 80 or method, the
carrier gas optionally comprises argon. In any embodiment of the
vessel 80 or method, the carrier gas optionally comprises krypton.
In any embodiment of the vessel 80 or method, the carrier gas
optionally comprises xenon. Mixtures of any two or more of these
gases can also be employed.
[0102] In any embodiment of the vessel 80 or method, during the
bonding stage the feed ratio of organosilicon monomer to oxidizing
gas, in seem, can be from 2.5 to 10. During the build-up stage, the
feed ratio of organosilicon monomer to oxidizing gas can be from
0.1 to 0.05.
[0103] The plasma used in PECVD according to the present disclosure
can be generated conventionally, as by using radio frequency (RF)
energy or microwave energy. The SiO.sub.x composite barrier coating
or layer 288 optionally can be formed at an initial power level
(for example, an RF power level) from 20 to 4 W and a highest RF
power level of from 300 to 30 W. In any embodiment of the vessel 80
or method, the power density at the initial RF power level
optionally can be from 3 to 1 W/ml. In any embodiment of the vessel
80 or method, the power density at the highest RF power level is
from 30 to 4 W/ml.
[0104] In any embodiment of the vessel such as a tube 80, a vial
228, a blister package 230, a syringe 252, a syringe barrel 250 or
a cartridge, the degree of retention of the composite barrier
coating or layer 288 on the substrate optionally can be at least
95% by the Article Deformation/Tape Test Method described in this
specification.
[0105] In any embodiment of the vessel 80 such as a tube 80, a vial
228, a blister package 230, a syringe 252, a syringe barrel 250 or
a cartridge, the degree of retention of the composite barrier
coating or layer 288 on the substrate optionally can be at least
90% by the Coated Article Cross-Scratch Tape Test Method described
in this specification.
[0106] In any embodiment of the vessel such as a tube 80, a vial
228, a blister package 230, a syringe 252, a syringe barrel 250 or
a cartridge, High Resolution X-ray Photoelectron Spectroscopy (XPS)
optionally shows the presence of an interface between the composite
barrier coating or layer 288 and the wall or substrate. The
interface optionally has at least 1 mol.% O.sub.3--Si--C covalent
bonding, as a proportion of the O.sub.3--Si--C covalent bonding
plus SiO.sub.4 bonding.
[0107] In any embodiment of the vessel 80 such as a tube 80, a vial
228, a blister package 230, a syringe 252, a syringe barrel 250 or
a cartridge, the interface optionally has an Si 2p chemical shift
to lower binding energy (eV), compared to the binding energy of
SiO.sub.4 bonding.
[0108] Another embodiment is a method of making a vessel 80. In any
embodiment of the method, a thermoplastic wall enclosing a lumen
can be provided. An SiO.sub.x composite barrier coating or layer
288, for which x is from 1.8 to 2.4, is applied to the
thermoplastic wall. The composite barrier coating or layer 288 is
supported by the wall between the wall and the lumen. The composite
barrier coating or layer 288 is applied by PECVD from an
organosilicon monomer and oxidizing gas.
[0109] In any embodiment of the method, the composite barrier
coating or layer 288 optionally can be applied in at least bonding
and build-up stages, under the following conditions. During the
bonding stage, the feed ratio of organosilicon monomer to oxidizing
gas, in seem, optionally can be from 2.5 to 10. During the build-up
stage, the feed ratio of organosilicon monomer to oxidizing gas
optionally can be from 0.1 to 0.05.
[0110] In any embodiment of the method, the composite barrier
coating or layer 288 optionally can be applied at an initial RF
power level from 20 to 4 W and a highest RF power level of from 300
to 30 W. In any embodiment of the vessel 80 or method, the RF power
level optionally can be increased uniformly from the initial RF
power level to the highest RF power level. Optionally, the RF power
level can be increased in one or more steps from the initial RF
power level to the highest RF power level.
[0111] In any embodiment of the vessel 80 or method, the RF power
level optionally is not pulsed, meaning that it is applied without
interruption from the beginning to the end of the deposition. As
another option, however, the RF power level can be pulsed or turned
on and off periodically during the deposition of a single composite
barrier coating or layer 288 on a single vessel 80. This type of
deposition using a pulsed RF power level is sometimes known as
plasma impulse chemical vapor deposition.
[0112] In any embodiment of the method, the composite barrier
coating or layer 288 optionally can have a degree of retention on
the substrate of at least 95% by volume, as measured by the Article
Deformation/Tape Test Method. In any embodiment of the vessel 80 or
method, the degree of retention of the composite barrier coating or
layer 288 on the substrate optionally is at least 96% by volume,
optionally at least 97% by volume, optionally at least 98% by
volume, optionally at least 99% by volume, optionally 100% by
volume, according to the Article Deformation/Tape Test Method. In
any embodiment of the vessel 80 or method, the Article
Deformation/Tape Test Method optionally is carried out using axial
deformation, but optionally can be carried out using diametric
deformation instead.
[0113] In any embodiment of the method, the composite barrier
coating or layer 288 optionally can have a degree of retention on
the substrate of at least 90% by the Coated Article Cross-Scratch
Tape Test Method. The degree of retention of the composite barrier
coating or layer 288 on the substrate optionally is at least 91% by
volume, optionally at least 92% by volume, optionally at least 93%
by volume, optionally at least 94% by volume, optionally at least
95% by volume, optionally at least 96% by volume, optionally at
least 97% by volume, optionally at least 98% by volume, optionally
at least 99% by volume, optionally 100% by volume, according to the
Coated Article Cross-Scratch Tape Test Method. As one option in any
embodiment, the Coated Article Cross-Scratch Tape Test Method can
be carried out using an X scratch pattern. As another option in any
embodiment, the Coated Article Cross-Scratch Tape Test Method can
be carried out using a rectangular scratch pattern.
[0114] In any embodiment of the method, the composite barrier
coating or layer 288 optionally can have an interface between the
composite barrier coating or layer 288 and the substrate having at
least 1 mol.% O.sub.3--Si--C covalent bonding, as a proportion of
the O.sub.3--Si--C covalent bonding plus SiO.sub.4 bonding.
[0115] High Resolution X-ray Photoelectron Spectroscopy (XPS)
optionally shows the presence of an interface between the composite
barrier coating or layer 288 and the substrate having at least 2
mol.% O.sub.3--Si--C covalent bonding, optionally at least 3 mol.%
O.sub.3--Si--C covalent bonding, optionally at least 4 mol.%
O.sub.3--Si--C covalent bonding, optionally at least 5 mol.%
O.sub.3--Si--C covalent bonding, optionally at least 6 mol.%
O.sub.3--Si--C covalent bonding, optionally at least 7 mol.%
O.sub.3--Si--C covalent bonding, optionally at least 8 mol.%
O.sub.3--Si--C covalent bonding, optionally at least 9 mol.%
O.sub.3--Si--C covalent bonding, optionally at least 10 mol.%
O.sub.3--Si--C covalent bonding, optionally at least 11 mol.%
O.sub.3--Si--C covalent bonding, optionally at least at least 12
mol.% O.sub.3--Si--C covalent bonding, optionally at least 13 mol.%
O.sub.3--Si--C covalent bonding, optionally at least 14 mol.%
O.sub.3--Si--C covalent bonding, optionally at least 15 mol.%
O.sub.3--Si--C covalent bonding, optionally at least 16 mol.%
O.sub.3--Si--C covalent bonding, optionally at least 17 mol.%
O.sub.3--Si--C covalent bonding, optionally at least 18 mol.%
O.sub.3--Si--C covalent bonding, optionally at least 19 mol.%
O.sub.3--Si--C covalent bonding, optionally at least 20 mol.%
O.sub.3--Si--C covalent bonding, as a proportion of the
O.sub.3--Si--C covalent bonding plus SiO.sub.4 bonding. The
interface for any embodiment of the vessel 80 or method optionally
has at most 25 mol.% O.sub.3--Si--C covalent bonding, alternatively
at most 20 mol.% O.sub.3--Si--C covalent bonding, alternatively at
most 15 mol.% O.sub.3--Si--C covalent bonding, alternatively at
most 10 mol.% O.sub.3--Si--C covalent bonding, as a proportion of
the O.sub.3--Si--C covalent bonding plus SiO.sub.4 bonding.
[0116] In any embodiment of the method, the composite barrier
coating or layer 288 optionally can have an Si 2p chemical shift to
lower binding energy (eV), compared to the binding energy of
SiO.sub.4 bonding, when studied using High Resolution X-ray
Photoelectron Spectroscopy (XPS). In any embodiment of the vessel
80 or method, High Resolution X-ray Photoelectron Spectroscopy
(XPS) optionally shows the presence of an interface between the
composite barrier coating or layer 288 and the substrate having Si
2p peak broadening of at least 0.2 eV, compared to the binding
energy of SiO.sub.4 bonding.
[0117] In any embodiment of the vessel 80 or method, the lumen
optionally can contain a pharmaceutical agent. The pharmaceutical
agent optionally can have a pH between 5 and 9. An opening
optionally can be provided in the vessel 80 between the lumen and
the exterior of the vessel 80. A closure optionally can be seated
in the opening.
Tie Coating or Layer
[0118] As an alternative to the above description of a composite
barrier coating or layer having bonding and build-up portions, in
other aspects of the invention a separate tie coating or layer and
composite barrier coating or layer can be described, in which the
properties of the respective layers are separately defined. The tie
coating or layer can be defined as follows.
[0119] The tie coating or layer 289 has at least two functions. One
function of the tie coating or layer 289 is to improve adhesion of
a composite barrier coating or layer to a substrate, in particular
a thermoplastic substrate, although a tie layer can be used to
improve adhesion to a glass substrate or to another coating or
layer. For example, a tie coating or layer, also referred to as an
adhesion layer or coating can be applied to the substrate and the
barrier layer can be applied to the adhesion layer to improve
adhesion of the barrier layer or coating to the substrate.
[0120] Another function of the tie coating or layer 289 has been
discovered: a tie coating or layer 289 applied under a composite
barrier coating or layer 288 can improve the function of a pH
protective coating or layer 286 applied over the composite barrier
coating or layer 288.
[0121] The tie coating or layer 289 can be composed of, comprise,
or consist essentially of SiO.sub.xC.sub.y, in which x is between
0.5 and 2.4 and y is between 0.6 and 3. Alternatively, the atomic
ratio can be expressed as the formula Si.sub.wO.sub.xC.sub.y, The
atomic ratios of Si, O, and C in the tie coating or layer 289 are,
as several options: [0122] Si 100: O 50-150: C 90-200 (i.e. w=1,
x=0.5 to 1.5, y=0.9 to 2); [0123] Si 100: O 70-130: C 90-200 (i.e.
w=1, x=0.7 to 1.3, y=0.9 to 2) [0124] Si 100: O 80-120: C 90-150
(i.e. w=1, x=0.8 to 1.2, y=0.9 to 1.5) [0125] Si 100: O 90-120: C
90-140 (i.e. w=1, x=0.9 to 1.2, y=0.9 to 1.4), or [0126] Si 100: O
92-107: C 116-133 (i.e. w=1, x=0.92 to 1.07, y=1.16 to 1.33)
[0127] The atomic ratio can be determined by XPS. Taking into
account the H atoms, which are not measured by XPS, the tie coating
or layer 289 may thus in one aspect have the formula
Si.sub.wO.sub.xC.sub.yH.sub.z (or its equivalent SiO.sub.xC.sub.y),
for example where w is 1, x is from about 0.5 to about 2.4, y is
from about 0.6 to about 3, and z is from about 2 to about 9.
Typically, tie coating or layer 289 would hence contain 36% to 41%
carbon normalized to 100% carbon plus oxygen plus silicon.
[0128] Optionally, the tie coating or layer can be similar or
identical in composition with the pH protective coating or layer
286 described elsewhere in this specification, although this is not
a requirement.
[0129] The tie coating or layer 289 is contemplated generally to be
from 5 nm to 100 nm thick, preferably from 5 to 20 nm thick,
particularly if applied by chemical vapor deposition. These
thicknesses are not critical. Commonly but not necessarily, the tie
coating or layer 289 will be relatively thin, since its function is
to change the surface properties of the substrate.
Barrier Coating or Layer
[0130] In the instance in which a separate tie coating or layer and
composite barrier coating or layer are described, the composite
barrier coating or layer can be described as follows.
[0131] A composite barrier coating or layer 288 optionally can be
deposited by plasma enhanced chemical vapor deposition (PECVD) or
other chemical vapor deposition processes on the vessel of a
pharmaceutical package, in particular a thermoplastic package, to
prevent oxygen, carbon dioxide, or other gases from entering the
vessel and/or to prevent leaching of the pharmaceutical material
into or through the package wall.
[0132] The composite barrier coating or layer for any embodiment
defined in this specification (unless otherwise specified in a
particular instance) is a coating or layer, optionally applied by
PECVD as indicated in U.S. Pat. No. 7,985,188. The barrier layer
optionally is characterized as an "SiO.sub.x" coating, and contains
silicon, oxygen, and optionally other elements, in which x, the
ratio of oxygen to silicon atoms, is from about 1.5 to about 2.4,
or 1.5 to about 2.3, or about 2. These alternative definitions of x
apply to any use of the term SiO.sub.x in this specification to
define a composite barrier coating or layer (though a composite
barrier coating or layer has a different definition of x). The
composite barrier coating or layer is applied, for example to the
interior of a pharmaceutical package or other vessel, for example a
sample collection tube, a syringe barrel, a vial, or another type
of vessel.
[0133] The composite barrier coating or layer 288 comprises or
consists essentially of SiO.sub.x, wherein x is from 1.5 to 2.4,
from 2 to 1000 nm thick, the composite barrier coating or layer 288
of SiO.sub.x having an interior surface 220 facing the lumen 212
and an outer surface 222 facing the wall 214 article surface 254,
the composite barrier coating or layer 288 being effective to
reduce the ingress of atmospheric gas into the lumen 212 compared
to an uncoated vessel 250. One suitable barrier composition is one
where x is 2.3, for example. For example, the composite barrier
coating or layer such as 288 of any embodiment can be applied at a
thickness of at least 2 nm, or at least 4 nm, or at least 7 nm, or
at least 10 nm, or at least 20 nm, or at least 30 nm, or at least
40 nm, or at least 50 nm, or at least 100 nm, or at least 150 nm,
or at least 200 nm, or at least 300 nm, or at least 400 nm, or at
least 500 nm, or at least 600 nm, or at least 700 nm, or at least
800 nm, or at least 900 nm. The composite barrier coating or layer
can be up to 1000 nm, or at most 900 nm, or at most 800 nm, or at
most 700 nm, or at most 600 nm, or at most 500 nm, or at most 400
nm, or at most 300 nm, or at most 200 nm, or at most 100 nm, or at
most 90 nm, or at most 80 nm, or at most 70 nm, or at most 60 nm,
or at most 50 nm, or at most 40 nm, or at most 30 nm, or at most 20
nm, or at most 10 nm, or at most 5 nm thick. Ranges of 20-200 nm,
optionally 20-30 nm, are contemplated. Specific thickness ranges
composed of any one of the minimum thicknesses expressed above,
plus any equal or greater one of the maximum thicknesses expressed
above, are expressly contemplated.
[0134] The thickness of the SiO.sub.x or other composite barrier
coating or layer can be measured, for example, by transmission
electron microscopy (TEM), and its composition can be measured by
X-ray photoelectron spectroscopy (XPS). The primer coating or layer
described herein can be applied to a variety of pharmaceutical
packages or other vessels made from plastic or glass, for example
to plastic tubes, vials, and syringes.
[0135] A composite barrier coating or layer 288 of SiO.sub.x, in
which x is between 1.5 and 2.9, is applied by plasma enhanced
chemical vapor deposition (PECVD) directly or indirectly to the
thermoplastic wall 214 so that in the filled pharmaceutical package
or other vessel 210 the composite barrier coating or layer 286 is
located between the inner or interior surface 220 of the
thermoplastic wall 214 and the fluid 218.
[0136] The composite barrier coating or layer 286 of SiO.sub.x is
supported by the thermoplastic wall 214. The composite barrier
coating or layer 286 as described elsewhere in this specification,
or in U.S. Pat. No. 7,985,188, can be used in any embodiment.
[0137] Certain barrier coatings or layers such as SiO.sub.x as
defined here have been found to have the characteristic of being
subject to being measurably diminished in barrier improvement
factor in less than six months as a result of attack by certain
relatively high pH contents of the coated vessel as described
elsewhere in this specification, particularly where the composite
barrier coating or layer directly contacts the contents. This issue
can be addressed using a pH protective coating or layer as
discussed in this specification.
pH Protective Coating or Layer
[0138] The inventors have found that some barrier layers or
coatings of SiO.sub.x are eroded or dissolved by some fluid
compositions, for example aqueous compositions having a pH above
about 5. Since coatings applied by chemical vapor deposition can be
very thin--tens to hundreds of nanometers thick--even a relatively
slow rate of erosion can remove or reduce the effectiveness of the
barrier layer in less time than the desired shelf life of a product
package. This is particularly a problem for fluid pharmaceutical
compositions, since many of them have a pH of roughly 7, or more
broadly in the range of 5 to 9, similar to the pH of blood and
other human or animal fluids. The higher the pH of the
pharmaceutical preparation, the more quickly it erodes or dissolves
the SiO.sub.x coating.
[0139] The inventors have further found that certain pH protective
coatings of SiO.sub.xC.sub.y or SiN.sub.xC.sub.y formed from cyclic
or acyclic siloxane precursors, which pH protective coatings have a
substantial organic component, do not erode quickly when exposed to
fluid compositions, and in fact erode or dissolve more slowly when
the fluid compositions have higher pHs within the range of 5 to 9.
For example, at pH 8, the dissolution rate of a pH protective
coating made from the precursor octamethylcyclotetrasiloxane, or
OMCTS, is quite slow. These pH protective coatings of
SiO.sub.xC.sub.y or SiN.sub.xC.sub.y can therefore be used to cover
a barrier layer of SiO.sub.x, retaining the benefits of the barrier
layer by protecting it from the fluid composition in the
pharmaceutical package.
[0140] Although the present invention does not depend upon the
accuracy of the following theory, it is believed that the material
properties of an effective SiO.sub.xC.sub.y pH protective coating
and those of an effective lubricity layer as described in U.S. Pat.
No. 7,985,188 and in International Application PCT/US11/36097 are
similar in some instances, such that a coating having the
characteristics of a lubricity layer as described in certain
working examples of this specification, U.S. Pat. No. 7,985,188, or
International Application PCT/US11/36097 will also in certain cases
serve as well as a pH protective coating to protect the barrier
layer of the package and vice versa.
[0141] One specific type of lubricity and/or pH protective coatings
contemplated here is made from one or more cyclic siloxanes and
silazanes as described in this disclosure. Although the present
invention does not depend upon the accuracy of the following
theory, SiO.sub.xC.sub.y or SiN.sub.xC.sub.y coatings deposited
from linear siloxane or linear silazane precursors, for example
hexamethyldisiloxane (HMDSO), are believed to contain fragments of
the original precursor to a large degree and low organic content.
Such SiO.sub.xC.sub.y or SiN.sub.xC.sub.y coatings have a degree of
water miscibility or swellability, allowing them to be attacked by
aqueous solutions. SiO.sub.xC.sub.y or SiN.sub.xC.sub.y coatings
deposited from cyclic siloxane or linear silazane precursors, for
example octamethylcyclotetrasiloxane (OMCTS), are believed to
include more intact cyclic siloxane rings and longer series of
repeating units of the precursor structure. These coatings are
believed to be nanoporous but structured and hydrophobic, and these
properties are believed to contribute to their success as pH
protective coatings. This is shown, for example, in U.S. Pat. No.
7,901,783.
[0142] Optionally, the pH protective coating or layer 286 can be
composed of, comprise, or consist essentially of
Si.sub.wO.sub.xC.sub.yH.sub.z (or its equivalent SiO.sub.xC.sub.y)
or Si.sub.wN.sub.xC.sub.yH.sub.z or its equivalent
SiN.sub.xC.sub.y), each as defined previously. The atomic ratio of
Si:O:C or Si:N:C can be determined by XPS (X-ray photoelectron
spectroscopy). Taking into account the H atoms, the pH protective
coating or layer may thus in one aspect have the formula
Si.sub.wO.sub.xC.sub.yH.sub.z, or its equivalent SiO.sub.xC.sub.y,
for example where w is 1, x is from about 0.5 to about 2.4, y is
from about 0.6 to about 3, and z is from about 2 to about 9.
[0143] Typically, expressed as the formula SiwOxCy, the atomic
ratios of Si, O, and C are, as several options: [0144] Si 100: O
50-150: C 90-200 (i.e. w=1, x=0.5 to 1.5, y=0.9 to 2); [0145] Si
100: O 70-130: C 90-200 (i.e. w=1, x=0.7 to 1.3, y=0.9 to 2) [0146]
Si 100: O 80-120: C 90-150 (i.e. w=1, x=0.8 to 1.2, y=0.9 to 1.5)
[0147] Si 100: O 90-120: C 90-140 (i.e. w=1, x=0.9 to 1.2, y=0.9 to
1.4) [0148] Si 100: O 92-107: C 116-133 (i.e. w=1, x=0.92 to 1.07,
y=1.16 to 1.33), or [0149] Si 100: O 80-130: C 90-150.
[0150] Alternatively, the pH protective coating or layer can have
atomic concentrations normalized to 100% carbon, oxygen, and
silicon, as determined by X-ray photoelectron spectroscopy (XPS) of
less than 50% carbon and more than 25% silicon. Alternatively, the
atomic concentrations are from 25 to 45% carbon, 25 to 65% silicon,
and 10 to 35% oxygen. Alternatively, the atomic concentrations are
from 30 to 40% carbon, 32 to 52% silicon, and 20 to 27% oxygen.
Alternatively, the atomic concentrations are from 33 to 37% carbon,
37 to 47% silicon, and 22 to 26% oxygen.
[0151] The thickness of the pH protective coating or layer can be,
for example:
[0152] from 10 nm to 1000 nm;
[0153] alternatively from 10 nm to 1000 nm;
[0154] alternatively from 10 nm to 900 nm;
[0155] alternatively from 10 nm to 800 nm;
[0156] alternatively from 10 nm to 700 nm;
[0157] alternatively from 10 nm to 600 nm;
[0158] alternatively from 10 nm to 500 nm;
[0159] alternatively from 10 nm to 400 nm;
[0160] alternatively from 10 nm to 300 nm;
[0161] alternatively from 10 nm to 200 nm;
[0162] alternatively from 10 nm to 100 nm;
[0163] alternatively from 10 nm to 50 nm;
[0164] alternatively from 20 nm to 1000 nm;
[0165] alternatively from 50 nm to 1000 nm;
[0166] alternatively from 10 nm to 1000 nm;
[0167] alternatively from 50 nm to 800 nm;
[0168] alternatively from 100 nm to 700 nm;
[0169] alternatively from 300 to 600 nm.
[0170] Optionally, the atomic concentration of carbon in the pH
protective layer, normalized to 100% of carbon, oxygen, and
silicon, as determined by X-ray photoelectron spectroscopy (XPS),
can be greater than the atomic concentration of carbon in the
atomic formula for the organosilicon precursor. For example,
embodiments are contemplated in which the atomic concentration of
carbon increases by from 1 to 80 atomic percent, alternatively from
10 to 70 atomic percent, alternatively from 20 to 60 atomic
percent, alternatively from 30 to 50 atomic percent, alternatively
from 35 to 45 atomic percent, alternatively from 37 to 41 atomic
percent.
[0171] Optionally, the atomic ratio of carbon to oxygen in the pH
protective coating or layer can be increased in comparison to the
organosilicon precursor, and/or the atomic ratio of oxygen to
silicon can be decreased in comparison to the organosilicon
precursor.
[0172] Optionally, the pH protective coating or layer can have an
atomic concentration of silicon, normalized to 100% of carbon,
oxygen, and silicon, as determined by X-ray photoelectron
spectroscopy (XPS), less than the atomic concentration of silicon
in the atomic formula for the feed gas. For example, embodiments
are contemplated in which the atomic concentration of silicon
decreases by from 1 to 80 atomic percent, alternatively by from 10
to 70 atomic percent, alternatively by from 20 to 60 atomic
percent, alternatively by from 30 to 55 atomic percent,
alternatively by from 40 to 50 atomic percent, alternatively by
from 42 to 46 atomic percent.
[0173] As another option, a pH protective coating or layer is
contemplated that can be characterized by a sum formula wherein the
atomic ratio C:O can be increased and/or the atomic ratio Si:O can
be decreased in comparison to the sum formula of the organosilicon
precursor.
[0174] The pH protective coating or layer 286 commonly is located
between the composite barrier coating or layer 288 and the fluid
218 in the finished article. The pH protective coating or layer 286
is supported by the thermoplastic wall 214.
[0175] The pH protective coating or layer 286 optionally is
effective to keep the composite barrier coating or layer 288 at
least substantially undissolved as a result of attack by the fluid
218 for a period of at least six months.
[0176] The pH protective coating or layer can have a density
between 1.25 and 1.65 g/cm.sup.3, alternatively between 1.35 and
1.55 g/cm.sup.3, alternatively between 1.4 and 1.5 g/cm.sup.3,
alternatively between 1.4 and 1.5 g/cm.sup.3, alternatively between
1.44 and 1.48 g/cm.sup.3, as determined by X-ray reflectivity
(XRR). Optionally, the organosilicon compound can be
octamethylcyclotetrasiloxane and the pH protective coating or layer
can have a density which can be higher than the density of a pH
protective coating or layer made from HMDSO as the organosilicon
compound under the same PECVD reaction conditions.
[0177] The pH protective coating or layer optionally can prevent or
reduce the precipitation of a compound or component of a
composition in contact with the pH protective coating or layer, in
particular can prevent or reduce insulin precipitation or blood
clotting, in comparison to the uncoated surface and/or to a barrier
coated surface using HMDSO as precursor.
[0178] The pH protective coating or layer optionally can have an
RMS surface roughness value (measured by AFM) of from about 5 to
about 9, optionally from about 6 to about 8, optionally from about
6.4 to about 7.8. The Ra surface roughness value of the pH
protective coating or layer, measured by AFM, can be from about 4
to about 6, optionally from about 4.6 to about 5.8. The Rmax
surface roughness value of the pH protective coating or layer,
measured by AFM, can be from about 70 to about 160, optionally from
about 84 to about 142, optionally from about 90 to about 130.
[0179] The interior surface of the pH protective optionally can
have a contact angle (with distilled water) of from 90.degree. to
110.degree., optionally from 80.degree. to 120.degree., optionally
from 70.degree. to 130.degree., as measured by Goniometer Angle
measurement of a water droplet on the pH protective surface, per
ASTM D7334-08 "Standard Practice for Surface Wettability of
Coatings, Substrates and Pigments by Advancing Contact Angle
Measurement."
[0180] The passivation layer or pH protective coating or layer 286
optionally shows an O-Parameter measured with attenuated total
reflection (ATR) of less than 0.4, measured as:
O - Parameter = Intensity at 1253 cm - 1 Maximum intensity in the
range 1000 to 1100 cm - 1 ##EQU00001##
[0181] The O-Parameter is defined in U.S. Pat. No. 8,067,070, which
claims an O-parameter value of most broadly from 0.4 to 0.9. It can
be measured from physical analysis of an FTIR amplitude versus wave
number plot to find the numerator and denominator of the above
expression, as shown in FIG. 22, which is the same as FIG. 5 of
U.S. Pat. No. 8,067,070, except annotated to show interpolation of
the wave number and absorbance scales to arrive at an absorbance at
1253 cm.sup.-1 of 0.0424 and a maximum absorbance at 1000 to 1100
cm.sup.-1 of 0.08, resulting in a calculated O-parameter of 0.53.
The O-Parameter can also be measured from digital wave number
versus absorbance data.
[0182] U.S. Pat. No. 8,067,070 asserts that the claimed O-parameter
range provides a superior pH protective coating or layer, relying
on experiments only with HMDSO and HMDSN, which are both non-cyclic
siloxanes. Surprisingly, it has been found by the present inventors
that if the PECVD precursor is a cyclic siloxane, for example
OMCTS, O-parameters outside the ranges claimed in U.S. Pat. No.
8,067,070, using OMCTS, provide even better results than are
obtained in U.S. Pat. No. 8,067,070 with HMDSO.
[0183] Alternatively in the embodiment of FIGS. 19-21, the
O-parameter has a value of from 0.1 to 0.39, or from 0.15 to 0.37,
or from 0.17 to 0.35.
[0184] Even another aspect of the invention is a composite material
as just described, exemplified in FIGS. 19-21, wherein the
passivation layer shows an N-Parameter measured with attenuated
total reflection (ATR) of less than 0.7, measured as:
N - Parameter = Intensity at 840 cm - 1 Intensity at 799 cm - 1 .
##EQU00002##
[0185] The N-Parameter is is also described in U.S. Pat. No.
8,067,070, and is measured analogously to the O-Parameter except
that intensities at two specific wave numbers are used--neither of
these wave numbers is a range. U.S. Pat. No. 8,067,070 claims a
passivation layer with an N-Parameter of 0.7 to 1.6. Again, the
present inventors have made better coatings employing a pH
protective coating or layer 286 having an N-Parameter lower than
0.7, as described above. Alternatively, the N-parameter has a value
of at least 0.3, or from 0.4 to 0.6, or at least 0.53.
[0186] The rate of erosion, dissolution, or leaching (different
names for related concepts) of the pH protective coating or layer
286, if directly contacted by the fluid 218, is less than the rate
of erosion of the composite barrier coating or layer 288, if
directly contacted by the fluid 218.
[0187] The thickness of the pH protective coating or layer is
contemplated to be from 50-500 nm, with a preferred range of
100-200 nm.
[0188] The pH protective coating or layer 286 is effective to
isolate the fluid 218 from the composite barrier coating or layer
288, at least for sufficient time to allow the barrier coating to
act as a barrier during the shelf life of the pharmaceutical
package or other vessel 210.
[0189] The inventors have further found that certain pH protective
coatings or layers of SiO.sub.xC.sub.y or SiN.sub.xC.sub.y formed
from cyclic polysiloxane precursors, which pH protective coatings
or layers have a substantial organic component, do not erode
quickly when exposed to fluids, and in fact erode or dissolve more
slowly when the fluids have higher pHs within the range of 5 to 9.
For example, at pH 8, the dissolution rate of a pH protective
coating or layer made from the precursor
octamethylcyclotetrasiloxane, or OMCTS, is quite slow. These pH
protective coatings or layers of SiO.sub.xC.sub.y or
SiN.sub.xC.sub.y can therefore be used to cover a barrier layer of
SiOx, retaining the benefits of the barrier layer by protecting it
from the fluid in the pharmaceutical package. The pH protective
layer is applied over at least a portion of the SiOx layer to
protect the SiOx layer from contents stored in a vessel, where the
contents otherwise would be in contact with the SiOx layer.
[0190] Although the present invention does not depend upon the
accuracy of the following theory, it is further believed that
effective pH protective coatings or layers for avoiding erosion can
be made from cyclic siloxanes and silazanes as described in this
disclosure. SiO.sub.xC.sub.y or SiN.sub.xC.sub.y coatings deposited
from cyclic siloxane or linear silazane precursors, for example
octamethylcyclotetrasiloxane (OMCTS), are believed to include
intact cyclic siloxane rings and longer series of repeating units
of the precursor structure. These coatings are believed to be
nanoporous but structured and hydrophobic, and these properties are
believed to contribute to their success as pH protective coatings
or layers. This is shown, for example, in U.S. Pat. No.
7,901,783.
[0191] SiO.sub.xC.sub.y or SiN.sub.xC.sub.y coatings also can be
deposited from linear siloxane or linear silazane precursors, for
example hexamethyldisiloxane (HMDSO) or tetramethyldisiloxane
(TMDSO).
[0192] Optionally an FTIR absorbance spectrum of the pH protective
coating or layer 286 of any embodiment has a ratio greater than
0.75 between the maximum amplitude of the Si--O--Si symmetrical
stretch peak normally located between about 1000 and 1040
cm.sup.-1, and the maximum amplitude of the Si--O--Si asymmetric
stretch peak normally located between about 1060 and about 1100
cm.sup.-1. Alternatively in any embodiment, this ratio can be at
least 0.8, or at least 0.9, or at least 1.0, or at least 1.1, or at
least 1.2. Alternatively in any embodiment, this ratio can be at
most 1.7, or at most 1.6, or at most 1.5, or at most 1.4, or at
most 1.3. Any minimum ratio stated here can be combined with any
maximum ratio stated here, as an alternative embodiment of the
invention of FIGS. 19-21.
[0193] Optionally, in any embodiment the pH protective coating or
layer 286, in the absence of the medicament, has a non-oily
appearance. This appearance has been observed in some instances to
distinguish an effective pH protective coating or layer from a
lubricity layer, which in some instances has been observed to have
an oily (i.e. shiny) appearance.
[0194] Optionally, for the pH protective coating or layer 286 in
any embodiment, the silicon dissolution rate by a 50 mM potassium
phosphate buffer diluted in water for injection, adjusted to pH 8
with concentrated nitric acid, and containing 0.2 wt. %
polysorbate-80 surfactant, (measured in the absence of the
medicament, to avoid changing the dissolution reagent), at
40.degree. C., is less than 170 ppb/day. (Polysorbate-80 is a
common ingredient of pharmaceutical preparations, available for
example as Tween.RTM.-80 from Uniqema Americas LLC, Wilmington
Del.)
[0195] Optionally, for the pH protective coating or layer 286 in
any embodiment, the silicon dissolution rate is less than 160
ppb/day, or less than 140 ppb/day, or less than 120 ppb/day, or
less than 100 ppb/day, or less than 90 ppb/day, or less than 80
ppb/day. Optionally, in any embodiment of FIGS. 24-26 the silicon
dissolution rate is more than 10 ppb/day, or more than 20 ppb/day,
or more than 30 ppb/day, or more than 40 ppb/day, or more than 50
ppb/day, or more than 60 ppb/day. Any minimum rate stated here can
be combined with any maximum rate stated here for the pH protective
coating or layer 286 in any embodiment.
[0196] Optionally, for the pH protective coating or layer 286 in
any embodiment the total silicon content of the pH protective
coating or layer and barrier coating, upon dissolution into a test
composition with a pH of 8 from the vessel, is less than 66 ppm, or
less than 60 ppm, or less than 50 ppm, or less than 40 ppm, or less
than 30 ppm, or less than 20 ppm.
[0197] The inventors offer the following theory of operation of the
pH protective coating or layer described here. The invention is not
limited by the accuracy of this theory or to the embodiments
predictable by use of this theory.
[0198] The dissolution rate of the SiO.sub.x barrier layer is
believed to be dependent on SiO bonding within the layer. Oxygen
bonding sites (silanols) are believed to increase the dissolution
rate.
[0199] It is believed that the OMCTS-based pH protective coating or
layer bonds with the silanol sites on the SiO.sub.x barrier layer
to "heal" or passivate the SiO.sub.x surface and thus dramatically
reduces the dissolution rate. In this hypothesis, the thickness of
the OMCTS layer is not the primary means of protection--the primary
means is passivation of the SiO.sub.x surface. It is contemplated
that a pH protective coating or layer as described in this
specification can be improved by increasing the crosslink density
of the pH protective coating or layer.
Hydrophobic Layer
[0200] The pH protective or lubricity coating or layer of
SiO.sub.xC.sub.y also can have utility as a hydrophobic layer,
independent of whether it also functions as a pH protective coating
or layer. Suitable hydrophobic coatings or layers and their
application, properties, and use are described in U.S. Pat. No.
7,985,188. Dual functional pH protective/hydrophobic coatings or
layers having the properties of both types of coatings or layers
can be provided for any embodiment of the present invention.
[0201] An embodiment can be carried out under conditions effective
to form a hydrophobic pH protective coating or layer on the
substrate. Optionally, the hydrophobic characteristics of the pH
protective coating or layer can be set by setting the ratio of the
O.sub.2 to the organosilicon precursor in the gaseous reactant,
and/or by setting the electric power used for generating the
plasma. Optionally, the pH protective coating or layer can have a
lower wetting tension than the uncoated surface, optionally a
wetting tension of from 20 to 72 dyne/cm, optionally from 30 to 60
dynes/cm, optionally from 30 to 40 dynes/cm, optionally 34 dyne/cm.
Optionally, the pH protective coating or layer can be more
hydrophobic than the uncoated surface.
[0202] Use of a coating or layer according to any described
embodiment is contemplated as (i) a lubricity coating having a
lower frictional resistance than the uncoated surface; and/or (ii)
a pH protective coating or layer preventing dissolution of the
barrier coating in contact with a fluid, and/or (iii) a hydrophobic
layer that is more hydrophobic than the uncoated surface.
Pharmaceutical Packages
[0203] Three embodiments of the invention having many common
features are those of FIGS. 8-10. Some of their common features are
the following, indicated in many cases by common reference
characters or names. The nature of the features of each embodiment
can be as described later in the specification.
[0204] The pharmaceutical packages 210 of FIGS. 8-10 each include a
vessel, a fluid composition 218, a composite barrier coating or
layer 288 (alternatively described as a tie coating or layer plus a
composite barrier coating or layer), and a pH protective coating
286. The vessel 250 has a lumen 212 defined at least in part by a
wall 214 made of thermoplastic material.
[0205] The wall 214 has an interior surface 254 facing the lumen
212 and an outer surface 216.
[0206] The fluid composition 218 is contained in the lumen 212 and
has a pH between 5 and 9.
[0207] The composite barrier coating or layer 288 comprises or
consists essentially of SiOx, wherein x is from 1.5 to 2.4, from 2
to 1000 nm thick, the composite barrier coating or layer 288 of
SiO.sub.x having an interior surface 220 facing the lumen 212 and
an outer surface 222 facing the wall 214 interior surface 254, the
composite barrier coating or layer 288 being effective to reduce
the ingress of atmospheric gas into the lumen 212 compared to an
uncoated vessel 250. One suitable barrier composition is one where
x is 2.3, for example.
[0208] The pH protective coating 286 is made of SiO.sub.xC.sub.y or
SiN.sub.xC.sub.y wherein x is from about 0.5 to about 2.4 and y is
from about 0.6 to about 3. The pH protective coating 286 has an
interior surface 224 facing the lumen 212 and an outer surface 226
facing the interior surface 220 of the composite barrier coating or
layer 288. The pH protective coating 286 is formed by chemical
vapor deposition of a precursor selected from a monocyclic
siloxane, a polycyclic siloxane, a polysilsesquioxane, a monocyclic
silazane, a polycyclic silazane, a polysilsesquiazane, a Silatrane,
a Silquasilatrane, a Silproatrane, an azasilatrane, an
azasilquasiatrane, an azasilproatrane, or a combination of any two
or more of these precursors. This process is described in more
detail throughout this specification.
[0209] The rate of erosion of the pH protective coating 286, if
directly contacted by the fluid composition 218, is less than the
rate of erosion of the composite barrier coating or layer 288, if
directly contacted by the fluid composition 218.
[0210] The pH protective coating 286 is effective to isolate the
fluid composition 218 from the composite barrier coating or layer
288.
[0211] The embodiments of FIGS. 8-9 also share as a common feature
a lubricity layer 287, which serves in the syringe of FIG. 8 to
reduce the friction of the plunger 258 sliding in the syringe
barrel 250 and in the vial of FIG. 9 to ease the insertion of a
stopper cap (not shown) into the mouth of the vial to close it.
[0212] Optionally any of the embodiments of FIGS. 8-10 have as a
common feature that at least a portion of the wall 214 of the
vessel 250 comprises or consists essentially of a polymer, for
example a polyolefin (for example a cyclic olefin polymer, a cyclic
olefin copolymer, or polypropylene), a polyester, for example
polyethylene terephthalate, a polycarbonate, or any combination or
copolymer of any of these. Optionally for any of the embodiments of
FIGS. 8-10, at least a portion of the wall 214 of the vessel 250
comprises or consists essentially of glass, for example
borosilicate glass. A combination of any two or more of the
materials in this paragraph can also be used.
[0213] Optionally for the embodiments of FIG. 8, the vessel 250
comprises a syringe barrel 250.
[0214] Optionally for the embodiments of FIG. 9, the vessel 250
comprises a vial.
[0215] Optionally for the embodiments of FIG. 10, the vessel 250
comprises a blister package.
[0216] Optionally for any of the embodiments of FIGS. 8-10, the
fluid composition 218 has a pH between 5 and 6, optionally between
6 and 7, optionally between 7 and 8, optionally between 8 and 9,
optionally between 6.5 and 7.5, optionally between 7.5 and 8.5,
optionally between 8.5 and 9.
[0217] Optionally for any of the embodiments of FIGS. 8-10, the
fluid composition 218 is a liquid at 20.degree. C. and ambient
pressure at sea level, which is defined as a pressure of 760 mm
Hg.
[0218] Optionally for any of the embodiments of FIGS. 8-10, the
fluid composition 218 is an aqueous liquid.
[0219] Optionally for any of the embodiments of FIGS. 8-10, the
composite barrier coating or layer 288 is from 4 nm to 500 nm
thick, optionally from 7 nm to 400 nm thick, optionally from 10 nm
to 300 nm thick, optionally from 20 nm to 200 nm thick, optionally
from 30 nm to 100 nm thick.
[0220] Optionally for any of the embodiments of FIGS. 8-10, the pH
protective coating 286 comprises or consists essentially of
SiO.sub.xC.sub.y. Optionally for any of the embodiments of FIGS.
8-10, the pH protective coating 286 comprises or consists
essentially of SiN.sub.xC.sub.y.
[0221] Optionally for any of the embodiments of FIGS. 8-10, the
precursor comprises a monocyclic siloxane, a polycyclic siloxane, a
polysilsesquioxane, a monocyclic silazane, a polycyclic silazane, a
polysilsesquiazane, a silatrane, a silquasilatrane, a silproatrane,
an azasilatrane, an azasilquasiatrane, an azasilproatrane, or a
combination of any two or more of these precursors.
[0222] Optionally for any of the embodiments of FIGS. 8-10, the
precursor comprises a monocyclic siloxane, a polycyclic siloxane, a
polysilsesquioxane, a Silatrane, a Silquasilatrane, a Silproatrane,
or a combination of any two or more of these precursors. Optionally
for any of the embodiments of FIGS. 8-10, the precursor comprises
octamethylcyclotetrasiloxane (OMCTS) or consists essentially of
OMCTS. Other precursors described elsewhere in this specification
or known in the art are also contemplated for use according to the
invention.
[0223] Optionally for any of the embodiments of FIGS. 8-10, the
precursor comprises a monocyclic silazane, a polycyclic silazane, a
polysilsesquiazane, an azasilatrane, an azasilquasiatrane, an
azasilproatrane, or a combination of any two or more of these
precursors.
[0224] Optionally for any of the embodiments of FIGS. 8-10, the pH
protective coating 286 as applied is between 10 and 1000 nm thick,
optionally between 50 and 800 nm thick, optionally between 100 and
700 nm thick, optionally between 300 and 600 nm thick. The
thickness does not need to be uniform throughout the vessel, and
will typically vary from the preferred values in portions of a
vessel.
[0225] Optionally for any of the embodiments of FIGS. 8-10, the pH
protective coating 286 contacting the fluid composition 218 is
between 10 and 1000 nm thick, optionally between 50 and 500 nm
thick, optionally between 100 and 400 nm thick, optionally between
150 and 300 nm thick two years after the pharmaceutical package 210
is assembled.
[0226] Optionally for any of the embodiments of FIGS. 8-10, the
rate of erosion of the pH protective coating 286, if directly
contacted by a fluid composition 218 having a pH of 8, is less than
20%, optionally less than 15%, optionally less than 10%, optionally
less than 7%, optionally from 5% to 20%, optionally 5% to 15%,
optionally 5% to 10%, optionally 5% to 7%, of the rate of erosion
of the composite barrier coating or layer 288, if directly
contacted by the same fluid composition 218 under the same
conditions.
[0227] Optionally for any of the embodiments of FIGS. 8-10, the pH
protective coating 286 is at least coextensive with the composite
barrier coating or layer 288. The pH protective coating 286
alternatively can be less extensive than the barrier coating, as
when the fluid composition does not contact or seldom is in contact
with certain parts of the barrier coating absent the pH protective
coating. The pH protective coating 286 alternatively can be more
extensive than the barrier coating, as it can cover areas that are
not provided with a barrier coating.
[0228] Optionally for any of the embodiments of FIGS. 8-10, the
pharmaceutical package 210 can have a shelf life, after the
pharmaceutical package 210 is assembled, of at least one year,
alternatively at least two years.
[0229] Optionally for any of the embodiments of FIGS. 8-10, the
shelf life is measured at 3.degree. C., alternatively at 4.degree.
C. or higher, alternatively at 20.degree. C. or higher,
alternatively at 23.degree. C., alternatively at 40.degree. C.
[0230] Optionally for any of the embodiments of FIGS. 8-10, the pH
of the fluid composition 218 is between 5 and 6 and the thickness
by TEM of the pH protective coating 286 is at least 80 nm at the
end of the shelf life. Alternatively, the pH of the fluid
composition 218 is between 6 and 7 and the thickness by TEM of the
pH protective coating 286 is at least 80 nm at the end of the shelf
life. Alternatively, the pH of the fluid composition 218 is between
7 and 8 and the thickness by TEM of the pH protective coating 286
is at least 80 nm at the end of the shelf life. Alternatively, the
pH of the fluid composition 218 is between 8 and 9 and the
thickness by TEM of the pH protective coating 286 is at least 80 nm
at the end of the shelf life. Alternatively, the pH of the fluid
composition 218 is between 5 and 6 and the thickness by TEM of the
pH protective coating 286 is at least 150 nm at the end of the
shelf life. Alternatively, the pH of the fluid composition 218 is
between 6 and 7 and the thickness by TEM of the pH protective
coating 286 is at least 150 nm at the end of the shelf life.
Alternatively, the pH of the fluid composition 218 is between 7 and
8 and the thickness by TEM of the pH protective coating 286 is at
least 150 nm at the end of the shelf life. Alternatively, the pH of
the fluid composition 218 is between 8 and 9 and the thickness by
TEM of the pH protective coating 286 is at least 150 nm at the end
of the shelf life.
[0231] Optionally for any of the embodiments of FIGS. 8-10, the
fluid composition 218 removes the pH protective coating 286 at a
rate of 1 nm or less of lubricity and/or pH protective coating
thickness per 44 hours of contact with the fluid composition 218
(200 nm per year), alternatively 1 nm or less of lubricity and/or
pH protective coating thickness per 88 hours of contact with the
fluid composition 218 (100 nm per year), alternatively 1 nm or less
of lubricity and/or pH protective coating thickness per 175 hours
of contact with the fluid composition 218 (50 nm per year),
alternatively 1 nm or less of lubricity and/or pH protective
coating thickness per 250 hours of contact with the fluid
composition 218 (35 nm per year), alternatively 1 nm or less of
lubricity and/or pH protective coating thickness per 350 hours of
contact with the fluid composition 218 (25 nm per year). The rate
of removing the pH protective coating can be determined by TEM from
samples exposed to the fluid composition for known periods.
[0232] Optionally for any of the embodiments of FIGS. 8-10, the pH
protective coating 286 is effective to provide a lower frictional
resistance than the uncoated interior surface 254. Preferably the
frictional resistance is reduced by at least 25%, more preferably
by at least 45%, even more preferably by at least 60% in comparison
to the uncoated interior surface 254. For example, the pH
protective coating 286 preferably is effective to reduce the
frictional resistance between a portion of the wall 214 contacted
by the fluid composition 218 and a relatively sliding part 258
after the pharmaceutical package 210 is assembled. Preferably, the
pH protective coating 286 is effective to reduce the frictional
resistance between the wall 214 and a relatively sliding part 258
at least two years after the pharmaceutical package 210 is
assembled.
Fluid Composition
[0233] Optionally for any of the embodiments of FIGS. 8-10, the
fluid composition 218 comprises a member or a combination of two or
more members selected from the group consisting of:
Inhalation Anesthetics
Aliflurane
Chloroform
Cyclopropane
Desflurane (Suprane)
Diethyl Ether
Enflurane (Ethrane)
Ethyl Chloride
Ethylene
Halothane (Fluothane)
Isoflurane (Forane, Isoflo)
[0234] Isopropenyl vinyl ether
Methoxyflurane
[0235] methoxyflurane,
Methoxypropane
Nitrous Oxide
Roflurane
Sevoflurane (Sevorane, Ultane, Sevoflo)
Teflurane
Trichloroethylene
Vinyl Ether
Xenon
Injectable Drugs
Ablavar (Gadofosveset Trisodium Injection)
Abarelix Depot
Abobotulinumtoxin A Injection (Dysport)
ABT-263
ABT-869
ABX-EFG
Accretropin (Somatropin Injection)
Acetadote (Acetylcysteine Injection)
Acetazolamide Injection (Acetazolamide Injection)
Acetylcysteine Injection (Acetadote)
Actemra (Tocilizumab Injection)
Acthrel (Corticorelin Ovine Triflutate for Injection)
Actummune
Activase
Acyclovir for Injection (Zovirax Injection)
Adacel
Adalimumab
Adenoscan (Adenosine Injection)
Adenosine Injection (Adenoscan)
Adrenaclick
[0236] AdreView (lobenguane I 123 Injection for Intravenous
Use)
Afluria
Ak-Fluor (Fluorescein Injection)
Aldurazyme (Laronidase)
Alglucerase Injection (Ceredase)
Alkeran Injection (Melphalan Hcl Injection)
Allopurinol Sodium for Injection (Aloprim)
Aloprim (Allopurinol Sodium for Injection)
Alprostadil
Alsuma (Sumatriptan Injection)
ALTU-238
Amino Acid Injections
Aminosyn
Apidra
Apremilast
Alprostadil Dual Chamber System for Injection (Caverject
Impulse)
AMG 009
AMG 076
AMG 102
AMG 108
AMG 114
AMG 162
AMG 220
AMG 221
AMG 222
AMG 223
AMG 317
AMG 379
AMG 386
AMG 403
AMG 477
AMG 479
AMG 517
AMG 531
AMG 557
AMG 623
AMG 655
AMG 706
AMG 714
AMG 745
AMG 785
AMG 811
AMG 827
AMG 837
AMG 853
AMG 951
Amiodarone HCl Injection (Amiodarone HCl Injection)
Amobarbital Sodium Injection (Amytal Sodium)
Amytal Sodium (Amobarbital Sodium Injection)
Anakinra
Anti-Abeta
Anti-Beta7
Anti-Beta20
Anti-CD4
Anti-CD20
Anti-CD40
Anti-IFNalpha
Anti-IL13
Anti-OX40L
Anti-oxLDS
Anti-NGF
Anti-NRP1
Arixtra
Amphadase (Hyaluronidase Inj)
Ammonul (Sodium Phenylacetate and Sodium Benzoate Injection)
Anaprox
Anzemet Injection (Dolasetron Mesylate Injection)
[0237] Apidra (Insulin Glulisine [rDNA origin] Inj)
Apomab
[0238] Aranesp (darbepoetin alfa)
Argatroban (Argatroban Injection)
Arginine Hydrochloride Injection (R-Gene 10
Aristocort
Aristospan
Arsenic Trioxide Injection (Trisenox)
Articane HCl and Epinephrine Injection (Septocaine)
Arzerra (Ofatumumab Injection)
Asclera (Polidocanol Injection)
Ataluren
Ataluren-DMD
Atenolol Inj (Tenormin I.V. Injection)
Atracurium Besylate Injection (Atracurium Besylate Injection)
Avastin
Azactam Injection (Aztreonam Injection)
Azithromycin (Zithromax Injection)
Aztreonam Injection (Azactam Injection)
Baclofen Injection (Lioresal Intrathecal)
Bacteriostatic Water (Bacteriostatic Water for Injection)
Baclofen Injection (Lioresal Intrathecal)
Bal in Oil Ampules (Dimercarprol Injection)
BayHepB
BayTet
Benadryl
Bendamustine Hydrochloride Injection (Treanda)
Benztropine Mesylate Injection (Cogentin)
Betamethasone Injectable Suspension (Celestone Soluspan)
Bexxar
Bicillin C-R 900/300 (Penicillin G Benzathine and Penicillin G
Procaine Injection)
Blenoxane (Bleomycin Sulfate Injection)
Bleomycin Sulfate Injection (Blenoxane)
Boniva Injection (Ibandronate Sodium Injection)
Botox Cosmetic (OnabotulinumtoxinA for Injection)
BR3-FC
Bravelle (Urofollitropin Injection)
Bretylium (Bretylium Tosylate Injection)
Brevital Sodium (Methohexital Sodium for Injection)
Brethine
Briobacept
BTT-1023
Bupivacaine HCl
Byetta
Ca-DTPA (Pentetate Calcium Trisodium Inj)
Cabazitaxel Injection (Jevtana)
Caffeine Alkaloid (Caffeine and Sodium Benzoate Injection)
Calcijex Injection (Calcitrol)
Calcitrol (Calcijex Injection)
Calcium Chloride (Calcium Chloride Injection 10%)
Calcium Disodium Versenate (Edetate Calcium Disodium Injection)
Campath (Altemtuzumab)
Camptosar Injection (Irinotecan Hydrochloride)
Canakinumab Injection (Llaris)
Capastat Sulfate (Capreomycin for Injection)
Capreomycin for Injection (Capastat Sulfate)
Cardiolite (Prep kit for Technetium Tc99 Sestamibi for
Injection)
Carticel
Cathflo
Cefazolin and Dextrose for Injection (Cefazolin Injection)
Cefepime Hydrochloride
Cefotaxime
Ceftriaxone
Cerezyme
Carnitor Injection
Caverject
Celestone Soluspan
Celsior
Cerebyx (Fosphenytoin Sodium Injection)
Ceredase (Alglucerase Injection)
Ceretec (Technetium Tc99m Exametazime Injection)
Certolizumab
CF-101
Chloramphenicol Sodium Succinate (Chloramphenicol Sodium Succinate
Injection)
Chloramphenicol Sodium Succinate Injection (Chloramphenicol Sodium
Succinate)
Cholestagel (Colesevelam HCL)
Choriogonadotropin Alfa Injection (Ovidrel)
Cimzia
Cisplatin (Cisplatin Injection)
Clolar (Clofarabine Injection)
Clomiphine Citrate
Clonidine Injection (Duraclon)
Cogentin (Benztropine Mesylate Injection)
Colistimethate Injection (Coly-Mycin M)
Coly-Mycin M (Colistimethate Injection)
[0239] Com path
Conivaptan Hcl Injection (Vaprisol)
Conjugated Estrogens for Injection (Premarin Injection)
Copaxone
Corticorelin Ovine Triflutate for Injection (Acthrel)
Corvert (Ibutilide Fumarate Injection)
Cubicin (Daptomycin Injection)
CF-101
Cyanokit (Hydroxocobalamin for Injection)
Cytarabine Liposome Injection (DepoCyt)
Cyanocobalamin
[0240] Cytovene (ganciclovir)
D.H.E. 45
Dacetuzumab
Dacogen (Decitabine Injection)
Dalteparin
Dantrium IV (Dantrolene Sodium for Injection)
Dantrolene Sodium for Injection (Dantrium IV)
Daptomycin Injection (Cubicin)
Darbepoietin Alfa
DDAVP Injection (Desmopressin Acetate Injection)
Decavax
Decitabine Injection (Dacogen)
Dehydrated Alcohol (Dehydrated Alcohol Injection)
Denosumab Injection (Prolia)
Delatestryl
Delestrogen
Delteparin Sodium
Depacon (Valproate Sodium Injection)
Depo Medrol (Methylprednisolone Acetate Injectable Suspension)
DepoCyt (Cytarabine Liposome Injection)
DepoDur (Morphine Sulfate XR Liposome Injection)
Desmopressin Acetate Injection (DDAVP Injection)
Depo-Estradiol
[0241] Depo-Provera 104 mg/ml Depo-Provera 150 mg/ml
Depo-Testosterone
Dexrazoxane for Injection, Intravenous Infusion Only (Totect)
Dextrose/Electrolytes
Dextrose and Sodium Chloride Inj (Dextrose 5% in 0.9% Sodium
Chloride)
Dextrose
Diazepam Injection (Diazepam Injection)
Digoxin Injection (Lanoxin Injection)
Dilaudid-HP (Hydromorphone Hydrochloride Injection)
Dimercarprol Injection (Bal in Oil Ampules)
Diphenhydramine Injection (Benadryl Injection)
Dipyridamole Injection (Dipyridamole Injection)
DMOAD
Docetaxel for Injection (Taxotere)
Dolasetron Mesylate Injection (Anzemet Injection)
Doribax (Doripenem for Injection)
Doripenem for Injection (Doribax)
Doxercalciferol Injection (Hectorol Injection)
Doxil (Doxorubicin Hcl Liposome Injection)
Doxorubicin Hcl Liposome Injection (Doxil)
Duraclon (Clonidine Injection)
Duramorph (Morphine Injection)
Dysport (Abobotulinumtoxin A Injection)
Ecallantide Injection (Kalbitor)
[0242] EC-Naprosyn (naproxen)
Edetate Calcium Disodium Injection (Calcium Disodium Versenate)
Edex (Alprostadil for Injection)
Engerix
Edrophonium Injection (Enlon)
Eliglustat Tartate
Eloxatin (Oxaliplatin Injection)
Emend Injection (Fosaprepitant Dimeglumine Injection)
Enalaprilat Injection (Enalaprilat Injection)
Enlon (Edrophonium Injection)
Enoxaparin Sodium Injection (Lovenox)
Eovist (Gadoxetate Disodium Injection)
[0243] Enbrel (etanercept)
Enoxaparin
Epicel
Epinepherine
Epipen
Epipen Jr.
Epratuzumab
Erbitux
Ertapenem Injection (Invanz)
Erythropoieten
Essential Amino Acid Injection (Nephramine)
Estradiol Cypionate
Estradiol Valerate
Etanercept
Exenatide Injection (Byetta)
Evlotra
[0244] Fabrazyme (Adalsidase beta)
Famotidine Injection
FDG (Fludeoxyglucose F 18 Injection)
Feraheme (Ferumoxytol Injection)
Feridex I.V. (Ferumoxides Injectable Solution)
Fertinex
Ferumoxides Injectable Solution (Feridex I.V.)
Ferumoxytol Injection (Feraheme)
Flagyl Injection (Metronidazole Injection)
Fluarix
Fludara (Fludarabine Phosphate)
Fludeoxyglucose F 18 Injection (FDG)
Fluorescein Injection (Ak-Fluor)
Follistim AQ Cartridge (Follitropin Beta Injection)
Follitropin Alfa Injection (Gonal-f RFF)
Follitropin Beta Injection (Follistim AQ Cartridge)
Folotyn (Pralatrexate Solution for Intravenous Injection)
Fondaparinux
[0245] Forteo (Teriparatide (rDNA origin) Injection)
Fostamatinib
Fosaprepitant Dimeglumine Injection (Emend Injection)
Foscarnet Sodium Injection (Foscavir)
Foscavir (Foscarnet Sodium Injection)
Fosphenytoin Sodium Injection (Cerebyx)
Fospropofol Disodium Injection (Lusedra)
Fragmin
[0246] Fuzeon (enfuvirtide)
GA101
Gadobenate Dimeglumine Injection (Multihance)
Gadofosveset Trisodium Injection (Ablavar)
Gadoteridol Injection Solution (ProHance)
Gadoversetamide Injection (OptiMARK)
Gadoxetate Disodium Injection (Eovist)
Ganirelix (Ganirelix Acetate Injection)
Gardasil
GC1008
GDFD
Gemtuzumab Ozogamicin for Injection (Mylotarg)
Genotropin
Gentamicin Injection
GENZ-112638
Golimumab Injection (Simponi Injection)
Gonal-f RFF (Follitropin Alfa Injection)
Granisetron Hydrochloride (Kytril Injection)
Gentamicin Sulfate
Glatiramer Acetate
Glucagen
Glucagon
HAE1
Haldol (Haloperidol Injection)
Havrix
Hectorol Injection (Doxercalciferol Injection)
Hedgehog Pathway Inhibitor
Heparin
Herceptin
[0247] hG-CSF
Humalog
Human Growth Hormone
Humatrope
HuMax
Humegon
Humira
Humulin
Ibandronate Sodium Injection (Boniva Injection)
Ibuprofen Lysine Injection (NeoProfen)
Ibutilide Fumarate Injection (Corvert)
Idamycin PFS (Idarubicin Hydrochloride Injection)
Idarubicin Hydrochloride Injection (Idamycin PFS)
Ilaris (Canakinumab Injection)
Imipenem and Cilastatin for Injection (Primaxin I.V.)
Imitrex
Incobotulinumtoxin A for Injection (Xeomin)
[0248] Increlex (Mecasermin [rDNA origin] Injection)
Indocin IV (Indomethacin Inj)
Indomethacin Inj (Indocin IV)
Infanrix
Innohep
Insulin
[0249] Insulin Aspart [rDNA origin] Inj (NovoLog) Insulin Glargine
[rDNA origin] Injection (Lantus) Insulin Glulisine [rDNA origin]
Inj (Apidra) Interferon alfa-2b, Recombinant for Injection (Intron
A) Intron A (Interferon alfa-2b, Recombinant for Injection)
Invanz (Ertapenem Injection)
Invega Sustenna (Paliperidone Palmitate Extended-Release Injectable
Suspension)
[0250] Invirase (saquinavir mesylate) lobenguane I 123 Injection
for Intravenous Use (AdreView) lopromide Injection (Ultravist)
loversol Injection (Optiray Injection) Iplex (Mecasermin Rinfabate
[rDNA origin] Injection)
Iprivask
Irinotecan Hydrochloride (Camptosar Injection)
Iron Sucrose Injection (Venofer)
Istodax (Romidepsin for Injection)
Itraconazole Injection (Sporanox Injection)
Jevtana (Cabazitaxel Injection)
Jonexa
Kalbitor (Ecallantide Injection)
KCL in D5NS (Potassium Chloride in 5% Dextrose and Sodium Chloride
Injection)
KCL in D5W
KCL in NS
Kenalog 10 Injection (Triamcinolone Acetonide Injectable
Suspension)
Kepivance (Palifermin)
Keppra Injection (Levetiracetam)
Keratinocyte
KFG
Kinase Inhibitor
Kineret (Anakinra)
Kinlytic (Urokinase Injection)
Kinrix
[0251] Klonopin (clonazepam)
Kytril Injection (Granisetron Hydrochloride)
[0252] lacosamide Tablet and Injection (Vimpat)
Lactated Ringer's
Lanoxin Injection (Digoxin Injection)
Lansoprazole for Injection (Prevacid I.V.)
Lantus
Leucovorin Calcium (Leucovorin Calcium Injection)
Lente (L)
Leptin
Levemir
Leukine Sargramostim
Leuprolide Acetate
Levothyroxine
Levetiracetam (Keppra Injection)
Lovenox
Levocarnitine Injection (Carnitor Injection)
Lexiscan (Regadenoson Injection)
Lioresal Intrathecal (Baclofen Injection)
[0253] Liraglutide [rDNA] Injection (Victoza)
Lovenox (Enoxaparin Sodium Injection)
Lucentis (Ranibizumab Injection)
Lumizyme
Lupron (Leuprolide Acetate Injection)
Lusedra (Fospropofol Disodium Injection)
Maci
Magnesium Sulfate (Magnesium Sulfate Injection)
Mannitol Injection (Mannitol IV)
Marcaine (Bupivacaine Hydrochloride and Epinephrine Injection)
Maxipime (Cefepime Hydrochloride for Injection)
MDP Multidose Kit of Technetium Injection (Technetium Tc99m
Medronate Injection)
[0254] Mecasermin [rDNA origin] Injection (Increlex) Mecasermin
Rinfabate [rDNA origin] Injection (Iplex)
Melphalan Hcl Injection (Alkeran Injection)
Methotrexate
Menactra
Menopur (Menotropins Injection)
Menotropins for Injection (Repronex)
Methohexital Sodium for Injection (Brevital Sodium)
Methyldopate Hydrochloride Injection, Solution (Methyldopate
Hcl)
Methylene Blue (Methylene Blue Injection)
Methylprednisolone Acetate Injectable Suspension (Depo Medrol)
MetMab
Metoclopramide Injection (Reglan Injection)
Metrodin (Urofollitropin for Injection)
Metronidazole Injection (Flagyl Injection)
Miacalcin
Midazolam (Midazolam Injection)
Mimpara (Cinacalet)
Minocin Injection (Minocycline Inj)
Minocycline Inj (Minocin Injection)
Mipomersen
Mitoxantrone for Injection Concentrate (Novantrone)
Morphine Injection (Duramorph)
Morphine Sulfate XR Liposome Injection (DepoDur)
Morrhuate Sodium (Morrhuate Sodium Injection)
Motesanib
Mozobil (Plerixafor Injection)
Multihance (Gadobenate Dimeglumine Injection)
Multiple Electrolytes and Dextrose Injection
Multiple Electrolytes Injection
Mylotarg (Gemtuzumab Ozogamicin for Injection)
[0255] Myozyme (Alglucosidase alfa)
Nafcillin Injection (Nafcillin Sodium)
Nafcillin Sodium (Nafcillin Injection)
Naltrexone XR Inj (Vivitrol)
[0256] Naprosyn (naproxen)
NeoProfen (Ibuprofen Lysine Injection)
Nandrol Decanoate
Neostigmine Methylsulfate (Neostigmine Methylsulfate Injection)
NEO-GAA
NeoTect (Technetium Tc 99m Depreotide Injection)
Nephramine (Essential Amino Acid Injection)
[0257] Neulasta (pegfilgrastim)
Neupogen (Filgrastim)
Novolin
Novolog
NeoRecormon
Neutrexin (Trimetrexate Glucuronate Inj)
NPH (N)
Nexterone (Amiodarone HCl Injection)
Norditropin (Somatropin Injection)
Normal Saline (Sodium Chloride Injection)
Novantrone (Mitoxantrone for Injection Concentrate)
Novolin 70/30 Innolet (70% NPH, Human Insulin Isophane Suspension
and 30%
Regular, Human Insulin Injection)
[0258] NovoLog (Insulin Aspart [rDNA origin] Inj) Nplate
(romiplostim) Nutropin (Somatropin (rDNA origin) for Inj)
Nutropin AQ
[0259] Nutropin Depot (Somatropin (rDNA origin) for Inj)
Octreotide Acetate Injection (Sandostatin LAR)
Ocrelizumab
Ofatumumab Injection (Arzerra)
Olanzapine Extended Release Injectable Suspension (Zyprexa
Relprevv)
Omnitarg
[0260] Omnitrope (Somatropin [rDNA origin] Injection)
Ondansetron Hydrochloride Injection (Zofran Injection)
OptiMARK (Gadoversetamide Injection)
[0261] Optiray Injection (loversol Injection)
Orencia
Osmitrol Injection in Aviva (Mannitol Injection in Aviva Plastic
Vessel 250)
Osmitrol Injection in Viaflex (Mannitol Injection in Viaflex
Plastic Vessel 250)
Osteoprotegrin
Ovidrel (Choriogonadotropin Alfa Injection)
Oxacillin (Oxacillin for Injection)
Oxaliplatin Injection (Eloxatin)
Oxytocin Injection (Pitocin)
Paliperidone Palmitate Extended-Release Injectable Suspension
(Invega Sustenna)
Pamidronate Disodium Injection (Pamidronate Disodium Injection)
Panitumumab Injection for Intravenous Use (Vectibix)
Papaverine Hydrochloride Injection (Papaverine Injection)
Papaverine Injection (Papaverine Hydrochloride Injection)
Parathyroid Hormone
Paricalcitol Injection Fliptop Vial (Zemplar Injection)
PARP Inhibitor
Pediarix
PEGIntron
Peginterferon
Pegfilgrastim
Penicillin G Benzathine and Penicillin G Procaine
Pentetate Calcium Trisodium Inj (Ca-DTPA)
Pentetate Zinc Trisodium Injection (Zn-DTPA)
Pepcid Injection (Famotidine Injection)
Pergonal
Pertuzumab
Phentolamine Mesylate (Phentolamine Mesylate for Injection)
[0262] Physostigmine Salicylate (Physostigmine Salicylate
(injection)) Physostigmine Salicylate (injection) (Physostigmine
Salicylate)
Piperacillin and Tazobactam Injection (Zosyn)
Pitocin (Oxytocin Injection)
Plasma-Lyte 148 (Multiple Electrolytes Inj)
Plasma-Lyte 56 and Dextrose (Multiple Electrolytes and Dextrose
Injection in Viaflex
Plastic Vessel 250)
PlasmaLyte
Plerixafor Injection (Mozobil)
Polidocanol Injection (Asclera)
Potassium Chloride
Pralatrexate Solution for Intravenous Injection (Folotyn)
Pramlintide Acetate Injection (Symlin)
Premarin Injection (Conjugated Estrogens for Injection)
Prep kit for Technetium Tc99 Sestamibi for Injection
(Cardiolite)
Prevacid I.V. (Lansoprazole for Injection)
Primaxin I.V. (Imipenem and Cilastatin for Injection)
Prochymal
Procrit
Progesterone
ProHance (Gadoteridol Injection Solution)
Prolia (Denosumab Injection)
Promethazine HCl Injection (Promethazine Hydrochloride
Injection)
Propranolol Hydrochloride Injection (Propranolol Hydrochloride
Injection)
Quinidine Gluconate Injection (Quinidine Injection)
Quinidine Injection (Quinidine Gluconate Injection)
R-Gene 10 (Arginine Hydrochloride Injection)
Ranibizumab Injection (Lucentis)
Ranitidine Hydrochloride Injection (Zantac Injection)
Raptiva
Reclast (Zoledronic Acid Injection)
Recombivarix HB
Regadenoson Injection (Lexiscan)
Reglan Injection (Metoclopramide Injection)
Remicade
Renagel
Renvela (Sevelamer Carbonate)
Repronex (Menotropins for Injection)
Retrovir IV (Zidovudine Injection)
[0263] rhApo2L/TRAIL
Ringer's and 5% Dextrose Injection (Ringers in Dextrose)
Ringer's Injection (Ringers Injection)
Rituxan
Rituximab
[0264] Rocephin (ceftriaxone)
Rocuronium Bromide Injection (Zemuron)
[0265] Roferon-A (interferon alfa-2a) Romazicon (flumazenil)
Romidepsin for Injection (Istodax)
Saizen (Somatropin Injection)
Sandostatin LAR (Octreotide Acetate Injection)
Sclerostin Ab
[0266] Sensipar (cinacalcet)
Sensorcaine (Bupivacaine HCl Injections)
Septocaine (Articane HCl and Epinephrine Injection)
[0267] Serostim LQ (Somatropin (rDNA origin) Injection)
Simponi Injection (Golimumab Injection)
Sodium Acetate (Sodium Acetate Injection)
Sodium Bicarbonate (Sodium Bicarbonate 5% Injection)
Sodium Lactate (Sodium Lactate Injection in AVIVA)
Sodium Phenylacetate and Sodium Benzoate Injection (Ammonul)
[0268] Somatropin (rDNA origin) for Inj (Nutropin)
Sporanox Injection (Itraconazole Injection)
Stelara Injection (Ustekinumab)
Stemgen
Sufenta (Sufentanil Citrate Injection)
Sufentanil Citrate Injection (Sufenta)
Sumavel
Sumatriptan Injection (Alsuma)
Symlin
Symlin Pen
Systemic Hedgehog Antagonist
Synvisc-One (Hylan G-F 20 Single Intra-articular Injection)
Tarceva
Taxotere (Docetaxel for Injection)
Technetium Tc 99m
Telavancin for Injection (Vibativ)
Temsirolimus Injection (Torisel)
Tenormin I.V. Injection (Atenolol Inj)
[0269] Teriparatide (rDNA origin) Injection (Forteo)
Testosterone Cypionate
Testosterone Enanthate
Testosterone Propionate
[0270] Tev-Tropin (Somatropin, rDNA Origin, for Injection)
tgAAC94
Thallous Chloride
Theophylline
Thiotepa (Thiotepa Injection)
Thymoglobulin (Anti-Thymocyte Globulin (Rabbit)
Thyrogen (Thyrotropin Alfa for Injection)
Ticarcillin Disodium and Clavulanate Potassium Galaxy (Timentin
Injection)
Tigan Injection (Trimethobenzamide Hydrochloride Injectable)
Timentin Injection (Ticarcillin Disodium and Clavulanate Potassium
Galaxy)
TNKase
Tobramycin Injection (Tobramycin Injection)
Tocilizumab Injection (Actemra)
Torisel (Temsirolimus Injection)
Totect (Dexrazoxane for Injection, Intravenous Infusion Only)
Trastuzumab-DM1
Travasol (Amino Acids (Injection))
Treanda (Bendamustine Hydrochloride Injection)
Trelstar (Triptorelin Pamoate for Injectable Suspension)
Triamcinolone Acetonide
Triamcinolone Diacetate
Triamcinolone Hexacetonide Injectable Suspension (Aristospan
Injection 20 mg)
Triesence (Triamcinolone Acetonide Injectable Suspension)
Trimethobenzamide Hydrochloride Injectable (Tigan Injection)
Trimetrexate Glucuronate Inj (Neutrexin)
Triptorelin Pamoate for Injectable Suspension (Trelstar)
Twinject
Trivaris (Triamcinolone Acetonide Injectable Suspension)
Trisenox (Arsenic Trioxide Injection)
Twinrix
Typhoid Vi
[0271] Ultravist (lopromide Injection)
Urofollitropin for Injection (Metrodin)
Urokinase Injection (Kinlytic)
Ustekinumab (Stelara Injection)
Ultralente (U)
[0272] Valium (diazepam)
Valproate Sodium Injection (Depacon)
Valtropin (Somatropin Injection)
Vancomycin Hydrochloride (Vancomycin Hydrochloride Injection)
Vancomycin Hydrochloride Injection (Vancomycin Hydrochloride)
Vaprisol (Conivaptan Hcl Injection)
VAQTA
Vasovist (Gadofosveset Trisodium Injection for Intravenous Use)
Vectibix (Panitumumab Injection for Intravenous Use)
Venofer (Iron Sucrose Injection)
Verteporfin Inj (Visudyne)
Vibativ (Telavancin for Injection)
[0273] Victoza (Liraglutide [rDNA] Injection) Vimpat (lacosamide
Tablet and Injection)
Vinblastine Sulfate (Vinblastine Sulfate Injection)
Vincasar PFS (Vincristine Sulfate Injection)
Victoza
Vincristine Sulfate (Vincristine Sulfate Injection)
Visudyne (Verteporfin Inj)
Vitamin B-12
Vivitrol (Naltrexone XR Inj)
Voluven (Hydroxyethyl Starch in Sodium Chloride Injection)
Xeloda
[0274] Xenical (orlistat)
Xeomin (Incobotulinumtoxin A for Injection)
Xolair
Zantac Injection (Ranitidine Hydrochloride Injection)
Zemplar Injection (Paricalcitol Injection Fliptop Vial)
Zemuron (Rocuronium Bromide Injection)
[0275] Zenapax (daclizumab)
Zevalin
Zidovudine Injection (Retrovir IV)
Zithromax Injection (Azithromycin)
Zn-DTPA (Pentetate Zinc Trisodium Injection)
Zofran Injection (Ondansetron Hydrochloride Injection)
Zingo
Zoledronic Acid for Inj (Zometa)
Zoledronic Acid Injection (Reclast)
Zometa (Zoledronic Acid for Inj)
Zosyn (Piperacillin and Tazobactam Injection)
Zyprexa Relprevv (Olanzapine Extended Release Injectable
Suspension)
Liquid Drugs (Non-Injectable)
Ability
AccuNeb (Albuterol Sulfate Inhalation Solution)
Actidose Aqua (Activated Charcoal Suspension)
Activated Charcoal Suspension (Actidose Aqua)
Advair
Agenerase Oral Solution (Amprenavir Oral Solution)
Akten (Lidocaine Hydrochloride Ophthalmic Gel)
Alamast (Pemirolast Potassium Ophthalmic Solution)
Albumin (Human) 5% Solution (Buminate 5%)
Albuterol Sulfate Inhalation Solution
Alinia
Alocril
Alphagan
Alrex
Alvesco
Amprenavir Oral Solution
Analpram-HC
Arformoterol Tartrate Inhalation Solution (Brovana)
Aristospan Injection 20 mg (Triamcinolone Hexacetonide Injectable
Suspension)
Asacol
Asmanex
Astepro
Astepro (Azelastine Hydrochloride Nasal Spray)
Atrovent Nasal Spray (Ipratropium Bromide Nasal Spray)
Atrovent Nasal Spray 0.06
Augmentin ES-600
Azasite (Azithromycin Ophthalmic Solution)
Azelaic Acid (Finacea Gel)
Azelastine Hydrochloride Nasal Spray (Astepro)
Azelex (Azelaic Acid Cream)
Azopt (Brinzolamide Ophthalmic Suspension)
Bacteriostatic Saline
Balanced Salt
Bepotastine
Bactroban Nasal
Bactroban
Beclovent
Benzac W
Betimol
Betoptic S
Bepreve
Bimatoprost Ophthalmic Solution
Bleph 10 (Sulfacetamide Sodium Ophthalmic Solution 10%)
Brinzolamide Ophthalmic Suspension (Azopt)
Bromfenac Ophthalmic Solution (Xibrom)
Bromhist
Brovana (Arformoterol Tartrate Inhalation Solution)
Budesonide Inhalation Suspension (Pulmicort Respules)
Cambia (Diclofenac Potassium for Oral Solution)
Capex
Carac
Carboxine-PSE
Carnitor
Cayston (Aztreonam for Inhalation Solution)
Cellcept
Centany
Cerumenex
Ciloxan Ophthalmic Solution (Ciprofloxacin HCL Ophthalmic
Solution)
Ciprodex
Ciprofloxacin HCL Ophthalmic Solution (Ciloxan Ophthalmic
Solution)
Clemastine Fumarate Syrup (Clemastine Fumarate Syrup)
CoLyte (PEG Electrolytes Solution)
Combiven
Comtan
Condylox
Cord ran
Cortisporin Ophthalmic Suspension
Cortisporin Otic Suspension
Cromolyn Sodium Inhalation Solution (Intal Nebulizer Solution)
Cromolyn Sodium Ophthalmic Solution (Opticrom)
[0276] Crystalline Amino Acid Solution with Electrolytes (Aminosyn
Electrolytes)
Cutivate
Cuvposa (Glycopyrrolate Oral Solution)
Cyanocobalamin (CaloMist Nasal Spray)
Cyclosporine Oral Solution (Gengraf Oral Solution)
Cyclogyl
Cysview (Hexaminolevulinate Hydrochloride Intravesical
Solution)
DermOtic Oil (Fluocinolone Acetonide Oil Ear Drops)
Desmopressin Acetate Nasal Spray
DDAVP
Derma-Smoothe/FS
Dexamethasone Intensol
Dianeal Low Calcium
Dianeal PD
Diclofenac Potassium for Oral Solution (Cambia)
Didanosine Pediatric Powder for Oral Solution (Videx)
Differin
Dilantin 125 (Phenytoin Oral Suspension)
Ditropan
Dorzolamide Hydrochloride Ophthalmic Solution (Trusopt)
Dorzolamide Hydrochloride-Timolol Maleate Ophthalmic Solution
(Cosopt)
Dovonex Scalp (Calcipotriene Solution)
Doxycycline Calcium Oral Suspension (Vibramycin Oral)
Efudex
Elaprase (Idursulfase Solution)
Elestat (Epinastine HCl Ophthalmic Solution)
Elocon
Epinastine HCl Ophthalmic Solution (Elestat)
Epivir HBV
[0277] Epogen (Epoetin alfa)
Erythromycin Topical Solution 1.5% (Staticin)
Ethiodol (Ethiodized Oil)
Ethosuximide Oral Solution (Zarontin Oral Solution)
Eurax
Extraneal (Icodextrin Peritoneal Dialysis Solution)
Felbatol
Feridex I.V. (Ferumoxides Injectable Solution)
Flovent
Floxin Otic (Ofloxacin Otic Solution)
Flo-Pred (Prednisolone Acetate Oral Suspension)
Fluoroplex
Flunisolide Nasal Solution (Flunisolide Nasal Spray 0.025%)
Fluorometholone Ophthalmic Suspension (FML)
Flurbiprofen Sodium Ophthalmic Solution (Ocufen)
FML
Foradil
Formoterol Fumarate Inhalation Solution (Perforomist)
Fosamax
Furadantin (Nitrofurantoin Oral Suspension)
Furoxone
Gammagard Liquid (Immune Globulin Intravenous (Human) 10%)
Gantrisin (Acetyl Sulfisoxazole Pediatric Suspension)
Gatifloxacin Ophthalmic Solution (Zymar)
Gengraf Oral Solution (Cyclosporine Oral Solution)
Glycopyrrolate Oral Solution (Cuvposa)
Halcinonide Topical Solution (Halog Solution)
Halog Solution (Halcinonide Topical Solution)
HEP-LOCK U/P (Preservative-Free Heparin Lock Flush Solution)
Heparin Lock Flush Solution (Hepflush 10
Hexaminolevulinate Hydrochloride Intravesical Solution
(Cysview)
Hydrocodone Bitartrate and Acetaminophen Oral Solution (Lortab
Elixir)
Hydroquinone 3% Topical Solution (Melquin-3 Topical Solution)
IAP Antagonist
Isopto
Ipratropium Bromide Nasal Spray (Atrovent Nasal Spray)
Itraconazole Oral Solution (Sporanox Oral Solution)
Ketorolac Tromethamine Ophthalmic Solution (Acular LS)
Kaletra
Lanoxin
Lexiva
Leuprolide Acetate for Depot Suspension (Lupron Depot 11.25 mg)
Levobetaxolol Hydrochloride Ophthalmic Suspension (Betaxon)
Levocarnitine Tablets, Oral Solution, Sugar-Free (Carnitor)
Levofloxacin Ophthalmic Solution 0.5% (Quixin)
Lidocaine HCl Sterile Solution (Xylocaine MPF Sterile Solution)
Lok Pak (Heparin Lock Flush Solution)
Lorazepam Intensol
Lortab Elixir (Hydrocodone Bitartrate and Acetaminophen Oral
Solution)
Lotemax (Loteprednol Etabonate Ophthalmic Suspension)
Loteprednol Etabonate Ophthalmic Suspension (Alrex)
Low Calcium Peritoneal Dialysis Solutions (Dianeal Low Calcium)
Lumigan (Bimatoprost Ophthalmic Solution 0.03% for Glaucoma)
Lupron Depot 11.25 mg (Leuprolide Acetate for Depot Suspension)
Megestrol Acetate Oral Suspension (Megestrol Acetate Oral
Suspension)
MEK Inhibitor
Mepron
Mesnex
Mestinon
Mesalamine Rectal Suspension Enema (Rowasa)
Melquin-3 Topical Solution (Hydroquinone 3% Topical Solution)
MetMab
Methyldopate Hcl (Methyldopate Hydrochloride Injection,
Solution)
[0278] Methylin Oral Solution (Methylphenidate HCl Oral Solution 5
mg/5 mL and 10 mg/5 mL)
Methylprednisolone Acetate Injectable Suspension (Depo Medrol)
[0279] Methylphenidate HCl Oral Solution 5 mg/5 mL and 10 mg/5 mL
(Methylin Oral Solution) Methylprednisolone sodium succinate (Solu
Medrol)
Metipranolol Ophthalmic Solution (Optipranolol)
Migranal
Miochol-E (Acetylcholine Chloride Intraocular Solution)
Micro-K for Liquid Suspension (Potassium Chloride Extended Release
Formulation for
Liquid Suspension)
Minocin (Minocycline Hydrochloride Oral Suspension)
Nasacort
Neomycin and Polymyxin B Sulfates and Hydrocortisone
Nepafenac Ophthalmic Suspension (Nevanac)
Nevanac (Nepafenac Ophthalmic Suspension)
Nitrofurantoin Oral Suspension (Furadantin)
Noxafil (Posaconazole Oral Suspension)
[0280] Nystatin (oral) (Nystatin Oral Suspension) Nystatin Oral
Suspension (Nystatin (oral))
Ocufen (Flurbiprofen Sodium Ophthalmic Solution)
Ofloxacin Ophthalmic Solution (Ofloxacin Ophthalmic Solution)
Ofloxacin Otic Solution (Floxin Otic)
Olopatadine Hydrochloride Ophthalmic Solution (Pataday)
Opticrom (Cromolyn Sodium Ophthalmic Solution)
Optipranolol (Metipranolol Ophthalmic Solution)
Patanol
Pediapred
PerioGard
Phenytoin Oral Suspension (Dilantin 125)
Phisohex
Posaconazole Oral Suspension (Noxafil)
Potassium Chloride Extended Release Formulation for Liquid
Suspension (Micro-K for
Liquid Suspension)
Pataday (Olopatadine Hydrochloride Ophthalmic Solution)
Patanase Nasal Spray (Olopatadine Hydrochloride Nasal Spray)
PEG Electrolytes Solution (CoLyte)
Pemirolast Potassium Ophthalmic Solution (Alamast)
Penlac (Ciclopirox Topical Solution)
PENNSAID (Diclofenac Sodium Topical Solution)
Perforomist (Formoterol Fumarate Inhalation Solution)
Peritoneal Dialysis Solution
Phenylephrine Hydrochloride Ophthalmic Solution
(Neo-Synephrine)
Phospholine Iodide (Echothiophate Iodide for Ophthalmic
Solution)
Podofilox (Podofilox Topical Solution)
Pred Forte (Prednisolone Acetate Ophthalmic Suspension)
Pralatrexate Solution for Intravenous Injection (Folotyn)
Pred Mild
Prednisone Intensol
Prednisolone Acetate Ophthalmic Suspension (Pred Forte)
Prevacid
PrismaSol Solution (Sterile Hemofiltration Hemodiafiltration
Solution)
Pro Air
Proglycem
ProHance (Gadoteridol Injection Solution)
Proparacaine Hydrochloride Ophthalmic Solution (Alcaine)
Propine
Pulmicort
Pulmozyme
Quixin (Levofloxacin Ophthalmic Solution 0.5%)
QVAR
Rapamune
Rebetol
Relacon-HC
Rotarix (Rotavirus Vaccine, Live, Oral Suspension)
Rotavirus Vaccine, Live, Oral Suspension (Rotarix)
Rowasa (Mesalamine Rectal Suspension Enema)
Sabril (Vigabatrin Oral Solution)
Sacrosidase Oral Solution (Sucraid)
Sandimmune
Sepra
Serevent Diskus
Solu Cortef (Hydrocortisone Sodium Succinate)
[0281] Solu Medrol (Methylprednisolone sodium succinate)
Spiriva
Sporanox Oral Solution (Itraconazole Oral Solution)
Staticin (Erythromycin Topical Solution 1.5%)
Stalevo
Starlix
Sterile Hemofiltration Hemodiafiltration Solution (PrismaSol
Solution)
Stimate
Sucralfate (Carafate Suspension)
Sulfacetamide Sodium Ophthalmic Solution 10% (Bleph 10
Synarel Nasal Solution (Nafarelin Acetate Nasal Solution for
Endometriosis)
Taclonex Scalp (Calcipotriene and Betamethasone Dipropionate
Topical Suspension)
Tamiflu
Tobi
TobraDex
Tobradex ST (Tobramycin/Dexamethasone Ophthalmic Suspension
0.3%/0.05%)
Tobramycin/Dexamethasone Ophthalmic Suspension 0.3%/0.05% (Tobradex
ST)
Timolol
Timoptic
Travatan Z
Treprostinil Inhalation Solution (Tyvaso)
Trusopt (Dorzolamide Hydrochloride Ophthalmic Solution)
Tyvaso (Treprostinil Inhalation Solution)
Ventolin
Vfend
Vibramycin Oral (Doxycycline Calcium Oral Suspension)
Videx (Didanosine Pediatric Powder for Oral Solution)
Vigabatrin Oral Solution (Sabril)
Viokase
Viracept
Viramune
Vitamin K1 (Fluid Colloidal Solution of Vitamin K1)
Voltaren Ophthalmic (Diclofenac Sodium Ophthalmic Solution)
Zarontin Oral Solution (Ethosuximide Oral Solution)
Ziagen
Zyvox
Zymar (Gatifloxacin Ophthalmic Solution)
Zymaxid (Gatifloxacin Ophthalmic Solution)
Drug Classes
[0282] 5-alpha-reductase inhibitors 5-aminosalicylates 5HT3
receptor antagonists adamantane antivirals adrenal cortical
steroids adrenal corticosteroid inhibitors adrenergic
bronchodilators agents for hypertensive emergencies agents for
pulmonary hypertension aldosterone receptor antagonists alkylating
agents alpha-adrenoreceptor antagonists alpha-glucosidase
inhibitors alternative medicines amebicides aminoglycosides
aminopenicillins aminosalicylates amylin analogs
Analgesic Combinations
Analgesics
[0283] androgens and anabolic steroids angiotensin converting
enzyme inhibitors angiotensin II inhibitors anorectal preparations
anorexiants antacids anthelmintics anti-angiogenic ophthalmic
agents anti-CTLA-4 monoclonal antibodies anti-infectives
antiadrenergic agents, centrally acting antiadrenergic agents,
peripherally acting antiandrogens antianginal agents antiarrhythmic
agents antiasthmatic combinations antibiotics/antineoplastics
anticholinergic antiemetics anticholinergic antiparkinson agents
anticholinergic bronchodilators anticholinergic chronotropic agents
anticholinergics/antispasmodics anticoagulants anticonvulsants
antidepressants antidiabetic agents antidiabetic combinations
antidiarrheals antidiuretic hormones antidotes
antiemetic/antivertigo agents antifungals antigonadotropic agents
antigout agents antihistamines antihyperlipidemic agents
antihyperlipidemic combinations antihypertensive combinations
antihyperuricemic agents antimalarial agents antimalarial
combinations antimalarial quinolines antimetabolites antimigraine
agents antineoplastic detoxifying agents antineoplastic interferons
antineoplastic monoclonal antibodies antineoplastics antiparkinson
agents antiplatelet agents antipseudomonal penicillins
antipsoriatics antipsychotics antirheumatics antiseptic and
germicides antithyroid agents antitoxins and antivenins
antituberculosis agents antituberculosis combinations antitussives
antiviral agents antiviral combinations antiviral interferons
anxiolytics, sedatives, and hypnotics aromatase inhibitors atypical
antipsychotics azole antifungals bacterial vaccines barbiturate
anticonvulsants barbiturates BCR-ABL tyrosine kinase inhibitors
benzodiazepine anticonvulsants benzodiazepines beta-adrenergic
blocking agents beta-lactamase inhibitors bile acid sequestrants
biologicals bisphosphonates bone resorption inhibitors
bronchodilator combinations bronchodilators calcitonin calcium
channel blocking agents carbamate anticonvulsants carbapenems
carbonic anhydrase inhibitor anticonvulsants carbonic anhydrase
inhibitors cardiac stressing agents cardioselective beta blockers
cardiovascular agents catecholamines CD20 monoclonal antibodies
CD33 monoclonal antibodies CD52 monoclonal antibodies central
nervous system agents cephalosporins cerumenolytics chelating
agents chemokine receptor antagonist chloride channel activators
cholesterol absorption inhibitors cholinergic agonists cholinergic
muscle stimulants cholinesterase inhibitors CNS stimulants
coagulation modifiers colony stimulating factors contraceptives
corticotropin coumarins and indandiones cox-2 inhibitors
decongestants dermatological agents diagnostic radiopharmaceuticals
dibenzazepine anticonvulsants digestive enzymes dipeptidyl
peptidase 4 inhibitors diuretics dopaminergic antiparkinsonism
agents drugs used in alcohol dependence echinocandins EGFR
inhibitors estrogen receptor antagonists estrogens expectorants
factor Xa inhibitors fatty acid derivative anticonvulsants fibric
acid derivatives first generation cephalosporins fourth generation
cephalosporins functional bowel disorder agents gallstone
solubilizing agents gamma-aminobutyric acid analogs
gamma-aminobutyric acid reuptake inhibitors gamma-aminobutyric acid
transaminase inhibitors gastrointestinal agents general anesthetics
genitourinary tract agents GI stimulants glucocorticoids glucose
elevating agents glycopeptide antibiotics glycoprotein platelet
inhibitors glycylcyclines gonadotropin releasing hormones
gonadotropin-releasing hormone antagonists gonadotropins group I
antiarrhythmics group II antiarrhythmics group III antiarrhythmics
group IV antiarrhythmics group V antiarrhythmics growth hormone
receptor blockers growth hormones H. pylori eradication agents H2
antagonists hematopoietic stem cell mobilizer heparin antagonists
heparins HER2 inhibitors herbal products histone deacetylase
inhibitors hormone replacement therapy hormones
hormones/antineoplastics hydantoin anticonvulsants illicit (street)
drugs immune globulins immunologic agents immunosuppressive agents
impotence agents in vivo diagnostic biologicals incretin mimetics
inhaled anti-infectives inhaled corticosteroids inotropic agents
insulin insulin-like growth factor integrase strand transfer
inhibitor interferons intravenous nutritional products iodinated
contrast media ionic iodinated contrast media iron products
ketolides laxatives leprostatics leukotriene modifiers lincomycin
derivatives lipoglycopeptides local injectable anesthetics loop
diuretics lung surfactants lymphatic staining agents lysosomal
enzymes macrolide derivatives macrolides magnetic resonance imaging
contrast media mast cell stabilizers medical gas meglitinides
metabolic agents methylxanthines mineralocorticoids minerals and
electrolytes miscellaneous agents miscellaneous analgesics
miscellaneous antibiotics miscellaneous anticonvulsants
miscellaneous antidepressants miscellaneous antidiabetic agents
miscellaneous antiemetics miscellaneous antifungals miscellaneous
antihyperlipidemic agents miscellaneous antimalarials miscellaneous
antineoplastics miscellaneous antiparkinson agents miscellaneous
antipsychotic agents miscellaneous antituberculosis agents
miscellaneous antivirals miscellaneous anxiolytics, sedatives and
hypnotics miscellaneous biologicals miscellaneous bone resorption
inhibitors miscellaneous cardiovascular agents miscellaneous
central nervous system agents miscellaneous coagulation modifiers
miscellaneous diuretics miscellaneous genitourinary tract agents
miscellaneous GI agents miscellaneous hormones miscellaneous
metabolic agents miscellaneous ophthalmic agents miscellaneous otic
agents miscellaneous respiratory agents miscellaneous sex hormones
miscellaneous topical agents miscellaneous uncategorized agents
miscellaneous vaginal agents mitotic inhibitors monoamine oxidase
inhibitors monoclonal antibodies mouth and throat products mTOR
inhibitors mTOR kinase inhibitors mucolytics multikinase inhibitors
muscle relaxants mydriatics narcotic analgesic combinations
narcotic analgesics nasal anti-infectives nasal antihistamines and
decongestants nasal lubricants and irrigations nasal preparations
nasal steroids natural penicillins neuraminidase inhibitors
neuromuscular blocking agents next generation cephalosporins
nicotinic acid derivatives nitrates
NNRTIs
[0284] non-cardioselective beta blockers non-iodinated contrast
media non-ionic iodinated contrast media non-sulfonylureas
nonsteroidal anti-inflammatory agents norepinephrine reuptake
inhibitors norepinephrine-dopamine reuptake inhibitors nucleoside
reverse transcriptase inhibitors (NRTIs) nutraceutical products
nutritional products ophthalmic anesthetics ophthalmic
anti-infectives ophthalmic anti-inflammatory agents ophthalmic
antihistamines and decongestants ophthalmic diagnostic agents
ophthalmic glaucoma agents ophthalmic lubricants and irrigations
ophthalmic preparations ophthalmic steroids ophthalmic steroids
with anti-infectives ophthalmic surgical agents oral nutritional
supplements otic anesthetics otic anti-infectives otic preparations
otic steroids otic steroids with anti-infectives oxazolidinedione
anticonvulsants parathyroid hormone and analogs penicillinase
resistant penicillins penicillins peripheral opioid receptor
antagonists peripheral vasodilators peripherally acting antiobesity
agents phenothiazine antiemetics phenothiazine antipsychotics
phenylpiperazine antidepressants plasma expanders platelet
aggregation inhibitors platelet-stimulating agents polyenes
potassium-sparing diuretics probiotics progesterone receptor
modulators progestins prolactin inhibitors prostaglandin D2
antagonists protease inhibitors proton pump inhibitors psoralens
psychotherapeutic agents psychotherapeutic combinations purine
nucleosides pyrrolidine anticonvulsants quinolones radiocontrast
agents radiologic adjuncts radiologic agents radiologic conjugating
agents radiopharmaceuticals RANK ligand inhibitors recombinant
human erythropoietins renin inhibitors respiratory agents
respiratory inhalant products rifamycin derivatives salicylates
sclerosing agents second generation cephalosporins selective
estrogen receptor modulators selective serotonin reuptake
inhibitors serotonin-norepinephrine reuptake inhibitors
serotoninergic neuroenteric modulators sex hormone combinations sex
hormones skeletal muscle relaxant combinations skeletal muscle
relaxants smoking cessation agents somatostatin and somatostatin
analogs spermicides statins sterile irrigating solutions
streptomyces derivatives succinimide anticonvulsants sulfonamides
sulfonylureas synthetic ovulation stimulants tetracyclic
antidepressants tetracyclines therapeutic radiopharmaceuticals
thiazide diuretics thiazolidinediones thioxanthenes third
generation cephalosporins thrombin inhibitors thrombolytics thyroid
drugs tocolytic agents topical acne agents topical agents topical
anesthetics topical anti-infectives topical antibiotics topical
antifungals topical antihistamines topical antipsoriatics topical
antivirals topical astringents topical debriding agents topical
depigmenting agents topical emollients topical keratolytics topical
steroids topical steroids with anti-infectives toxoids triazine
anticonvulsants tricyclic antidepressants trifunctional monoclonal
antibodies tumor necrosis factor (TNF) inhibitors tyrosine kinase
inhibitors ultrasound contrast media upper respiratory combinations
urea anticonvulsants urinary anti-infectives urinary antispasmodics
urinary pH modifiers uterotonic agents vaccine vaccine combinations
vaginal anti-infectives vaginal preparations vasodilators
vasopressin antagonists vasopressors VEGF/VEGFR inhibitors viral
vaccines viscosupplementation agents vitamin and mineral
combinations vitamins
Diagnostic Tests
17-Hydroxyprogesterone
[0285] ACE (Angiotensin I converting enzyme)
Acetaminophen
[0286] Acid phosphatase
ACTH
[0287] Activated clotting time Activated protein C resistance
Adrenocorticotropic hormone (ACTH) Alanine aminotransferase
(ALT)
Albumin
Aldolase
Aldosterone
[0288] Alkaline phosphatase Alkaline phosphatase (ALP)
Alpha1-antitrypsin
Alpha-fetoprotein
Alpha-fetoprotien
[0289] Ammonia levels
Amylase
[0290] ANA (antinuclear antbodies) ANA (antinuclear antibodies)
Angiotensin-converting enzyme (ACE)
Anion gap
[0291] Anticardiolipin antibody Anticardiolipin antivbodies (ACA)
Anti-centromere antibody Antidiuretic hormone
Anti-DNA
Anti-Dnase-B
[0292] Anti-Gliadin antibody Anti-glomerular basement membrane
antibody Anti-HBc (Hepatitis B core antibodies Anti-HBs (Hepatitis
B surface antibody Antiphospholipid antibody Anti-RNA polymerase
Anti-Smith (Sm) antibodies Anti-Smooth Muscle antibody
Antistreptolysin O (ASO)
Antithrombin III
[0293] Anti-Xa activity Anti-Xa assay
Apolipoproteins
Arsenic
[0294] Aspartate aminotransferase (AST)
B12
Basophil
Beta-2-Microglobulin
Beta-hydroxybutyrate
B-HCG
Bilirubin
[0295] Bilirubin, direct Bilirubin, indirect Bilirubin, total
Bleeding time Blood gases (arterial) Blood urea nitrogen (BUN)
BUN
[0296] BUN (blood urea nitrogen)
CA 125
CA 15-3
CA 19-9
Calcitonin
Calcium
[0297] Calcium (ionized) Carbon monoxide (CO) Carcinoembryonic
antigen (CEA)
CBC
CEA
[0298] CEA (carcinoembryonic antigen)
Ceruloplasmin
CH50Chloride
Cholesterol
Cholesterol, HDL
[0299] Clot lysis time Clot retraction time
CMP
CO.sub.2
[0300] Cold agglutinins
Complement C3
Copper
[0301] Corticotrophin releasing hormone (CRH) stimulation test
Cortisol
[0302] Cortrosyn stimulation test
C-peptide
CPK (Total)
CPK-MB
[0303] C-reactive protein
Creatinine
[0304] Creatinine kinase (CK)
Cryoglobulins
[0305] DAT (Direct antiglobulin test)
D-Dimer
[0306] Dexamethasone suppression test
DHEA-S
[0307] Dilute Russell viper venom
Elliptocytes
Eosinophil
[0308] Erythrocyte sedimentation rate (ESR)
Estradiol
Estriol
Ethanol
[0309] Ethylene glycol Euglobulin lysis
Factor V Leiden
[0310] Factor VIII inhibitor Factor VIII level
Ferritin
[0311] Fibrin split products
Fibrinogen
Folate
[0312] Folate (serum Fractional excretion of sodium (FENA) FSH
(follicle stimulating factor)
FTA-ABS
[0313] Gamma glutamyl transferase (GGT)
Gastrin
[0314] GGTP (Gamma glutamyl transferase)
Glucose
[0315] Growth hormone
Haptoglobin
[0316] HBeAg (Hepatitis Be antigen) HBs-Ag (Hepatitis B surface
antigen) Helicobacter pylori
Hematocrit
Hematocrit (HCT)
Hemoglobin
Hemoglobin A1C
[0317] Hemoglobin electrophoresis Hepatitis A antibodies Hepatitis
C antibodies IAT (Indirect antiglobulin test)
Immunofixation (IFE)
Iron
[0318] Lactate dehydrogenase (LDH) Lactic acid (lactate)
LDH
[0319] LH (Leutinizing hormone
Lipase
[0320] Lupus anticoagulant
Lymphocyte
Magnesium
[0321] MCH (mean corpuscular hemoglobin MCHC (mean corpuscular
hemoglobin concentration) MCV (mean corpuscular volume)
Methylmalonate
Monocyte
[0322] MPV (mean platelet volume)
Myoglobin
Neutrophil
[0323] Parathyroid hormone (PTH)
Phosphorus
[0324] Platelets (pit)
Potassium
Prealbumin
Prolactin
[0325] Prostate specific antigen (PSA)
Protein C
Protein S
[0326] PSA (prostate specific antigen) PT (Prothrombin time) PTT
(Partial thromboplastin time) RDW (red cell distribution width)
Renin
Rennin
[0327] Reticulocyte count reticulocytes Rheumatoid factor (RF)
Sed Rate
[0328] Serum glutamic-pyruvic transaminase (SGPT Serum protein
electrophoresis (SPEP)
Sodium
[0329] T3-resin uptake (T3RU)
T4, Free
[0330] Thrombin time Thyroid stimulating hormone (TSH)
Thyroxine (T4
[0331] Total iron binding capacity (TIBC) Total protein
Transferrin
[0332] Transferrin saturation
Triglyceride (TG)
Troponin
[0333] Uric acid
Vitamin B12
[0334] White blood cells (WBC) Widal test
[0335] As several examples, the fluid composition 218 can be an
inhalation anesthetic, a drug, or a diagnostic test material. Any
of these fluid compositions 218 can be an injectable material, a
volatile material capable of being inhaled, or otherwise capable of
being introduced into a subject.
[0336] In the embodiment of FIG. 8 in particular, the
pharmaceutical package 210 is a syringe. The syringe can comprise a
syringe barrel 250 and a plunger 258. The wall 214 can define at
least a portion of the syringe barrel 250. The plunger 258 can be a
relatively sliding part of the syringe, with respect to the syringe
barrel 250. The term "syringe," however, is broadly defined to
include cartridges, injection "pens," and other types of barrels or
reservoirs adapted to be assembled with one or more other
components to provide a functional syringe. "Syringe" is also
broadly defined to include related articles such as auto-injectors,
which provide a mechanism for dispensing the contents.
[0337] Another aspect of the invention illustrated by FIGS. 8-10 is
an article such as any of the pharmaceutical packages or other
vessels 210 including a wall 214, a fluid composition 218, a
composite barrier coating or layer 288, and a pH protective coating
286.
[0338] The wall 214 has an inner or interior surface 254.
[0339] The fluid composition 218 is contained in the lumen 212 and
has a pH between 5 and 9.
[0340] The composite barrier coating or layer 288 is made at least
in part of SiO.sub.x, wherein x is from 1.5 to 2.4, from 2 to 1000
nm thick. The composite barrier coating or layer 288 of SiO.sub.x
has an interior surface 220 facing the lumen 212 and an outer
surface 222 facing the wall inner or interior surface 254. The
composite barrier coating or layer 288 is effective to reduce the
ingress of atmospheric gas into the lumen 212, compared to an
uncoated container otherwise the same as the pharmaceutical package
or other vessel 210.
[0341] The pH protective coating 286 is made at least in part of
SiO.sub.xC.sub.y or SiN.sub.xC.sub.y where x is from about 0.5 to
about 2.4 and y is from about 0.6 to about 3. The pH protective
coating 286 has an interior surface 224 facing the lumen 212 and an
outer surface 226 facing the interior surface 254 of the composite
barrier coating or layer 288. The pH protective coating 286 is
formed by chemical vapor deposition of a precursor selected from a
monocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane, a
monocyclic silazane, a polycyclic silazane, a polysilsesquiazane, a
silatrane, a silquasilatrane, a silproatrane, an azasilatrane, an
azasilquasiatrane, an azasilproatrane, or a combination of any two
or more of these precursors. One specific example of a suitable pH
protective coating precursor of this type is
octamethylcyclotetrasiloxane or OMCTS. Other specific examples of
precursors within this broad definition are provided elsewhere in
this specification.
[0342] The rate of erosion, dissolution, or leaching (different
names for related concepts) of the pH protective coating 286, if
directly contacted by the fluid composition 218, is less than the
rate of erosion of the composite barrier coating or layer 288, if
directly contacted by the fluid composition 218.
[0343] The pH protective coating 286 is effective to isolate the
fluid composition 218 from the composite barrier coating or layer
288, at least for sufficient time to allow the barrier coating to
act as a barrier during the shelf life of the pharmaceutical
package or other vessel 210.
[0344] Still another aspect of the invention, again illustrated by
FIGS. 8-10, is a pharmaceutical package or other vessel 210
including a thermoplastic wall 214 having an inner or interior
surface 220 enclosing a lumen 212. A fluid composition 218
contained in the lumen 212 has a pH greater than 5.
[0345] A composite barrier coating or layer 286 of SiO.sub.x, in
which x is between 1.5 and 2.4, is applied by plasma enhanced
chemical vapor deposition (PECVD) directly or indirectly to the
thermoplastic wall 214 so that in the filled pharmaceutical package
or other vessel 210 the composite barrier coating or layer 286 is
located between the inner or interior surface 220 of the
thermoplastic wall 214 and the fluid composition 218. The composite
barrier coating or layer 286 of SiO.sub.x is supported by the
thermoplastic wall 214. The composite barrier coating or layer 286
has the characteristic of being subject to being measurably
diminished in barrier improvement factor in less than six months as
a result of attack by the fluid composition 218. The composite
barrier coating or layer 286 as described elsewhere in this
specification, or in U.S. Pat. No. 7,985,188, can be used in any
embodiment.
[0346] The barrier improvement factor (BIF) of the barrier layer
can be determined by providing two groups of identical containers,
adding a barrier layer to one group of containers, testing a
barrier property (such as the rate of outgassing in micrograms per
minute or another suitable measure) on containers having a barrier,
doing the same test on containers lacking a barrier, and taking a
ratio of the properties of the materials with versus without a
barrier. For example, if the rate of outgassing through the barrier
is one-third the rate of outgassing without a barrier, the barrier
has a BIF of 3.
[0347] A pH protective coating 286 of SiO.sub.xC.sub.y, in which x
is between 0.5 and 2.4 and y is between 0.6 and 3, is applied by
PECVD directly or indirectly to the composite barrier coating or
layer 288 so it is located between the composite barrier coating or
layer 288 and the fluid composition 218 in the finished article.
The pH protective coating 286 is supported by the thermoplastic
wall 214. The pH protective coating 286 is effective to keep the
composite barrier coating or layer 288 at least substantially
undissolved as a result of attack by the fluid composition 218 for
a period of at least six months.
[0348] Any embodiment of FIGS. 8-10 can further optionally include
a lubricity layer 287. The lubricity layer 287 can be applied
between the pH protective coating and the lumen. Lubricity layers
287 as described elsewhere in this specification, or in U.S. Pat.
No. 7,985,188, can be used in any embodiment.
[0349] Any embodiment of FIGS. 8-10 can further optionally include
a further coating applied adjacent to the inner surface of the pH
protective coating, the further coating having an outer surface
facing the interior surface of the thermoplastic wall and an inner
surface facing the lumen.
[0350] Optionally, any embodiment of FIGS. 8-10 can further include
a fluid composition 218 in contact with the pH protective
coating
[0351] The pH protective and lubricity layers 286 and 287 of any
embodiment of FIGS. 8-10 can be either separate layers with a sharp
transition or a single, graduated layer that transitions between
the pH protective coating 286 and the lubricity layer 287, without
a sharp interface between them.
[0352] Optionally an FTIR absorbance spectrum of the pH protective
coating 286 of any embodiment of FIGS. 8-10 has a ratio greater
than 0.75 between the maximum amplitude of the Si--O--Si
symmetrical stretch peak normally located between about 1000 and
1040 cm.sup.-1, and the maximum amplitude of the Si--O--Si
asymmetric stretch peak normally located between about 1060 and
about 1100 cm.sup.-1. Alternatively in any embodiment, this ratio
can be at least 0.8, or at least 0.9, or at least 1.0, or at least
1.1, or at least 1.2. Alternatively in any embodiment, this ratio
can be at most 1.7, or at most 1.6, or at most 1.5, or at most 1.4,
or at most 1.3. Any minimum ratio stated here can be combined with
any maximum ratio stated here, as an alternative embodiment of the
invention of FIGS. 8-10.
[0353] Optionally, in any embodiment of FIGS. 8-10 the pH
protective coating, in the absence of the medicament, has a
non-oily appearance. This appearance has been observed in some
instances to distinguish an effective pH protective coating from a
lubricity layer, which in some instances has been observed to have
an oily (i.e. shiny) appearance.
[0354] Optionally, in any embodiment of FIGS. 8-10 the silicon
dissolution rate by a 50 mM potassium phosphate buffer diluted in
water for injection, adjusted to pH 8 with concentrated nitric
acid, and containing 0.2 wt. % polysorbate-80 surfactant, (measured
in the absence of the medicament, to avoid changing the dissolution
reagent), at 40.degree. C., is less than 170 ppb/day.
(Polysorbate-80 is a common ingredient of pharmaceutical
preparations, available for example as Tween.RTM.-80 from Uniqema
Americas LLC, Wilmington Del.) As will be seen from the working
examples, the silicon dissolution rate is measured by determining
the total silicon leached from the vessel into its contents, and
does not distinguish between the silicon derived from the pH
protective coating 286, the lubricity layer 287, the composite
barrier coating or layer 288, or other materials present.
[0355] Optionally, in any embodiment of FIGS. 8-10 the silicon
dissolution rate is less than 160 ppb/day, or less than 140
ppb/day, or less than 120 ppb/day, or less than 100 ppb/day, or
less than 90 ppb/day, or less than 80 ppb/day. Optionally, in any
embodiment of FIGS. 8-10 the silicon dissolution rate is more than
10 ppb/day, or more than 20 ppb/day, or more than 30 ppb/day, or
more than 40 ppb/day, or more than 50 ppb/day, or more than 60
ppb/day. Any minimum rate stated here can be combined with any
maximum rate stated here, as an alternative embodiment of the
invention of FIGS. 8-10.
[0356] Optionally, in any embodiment of FIGS. 8-10 the total
silicon content of the pH protective coating and barrier coating,
upon dissolution into a test composition with a pH of 8 from the
vessel, is less than 66 ppm, or less than 60 ppm, or less than 50
ppm, or less than 40 ppm, or less than 30 ppm, or less than 20
ppm.
[0357] Optionally, in any embodiment of FIGS. 8-10 the calculated
shelf life of the package (total Si/Si dissolution rate) is more
than six months, or more than 1 year, or more than 18 months, or
more than 2 years, or more than 21/2 years, or more than 3 years,
or more than 4 years, or more than 5 years, or more than 10 years,
or more than 20 years. Optionally, in any embodiment of FIGS. 8-10
the calculated shelf life of the package (total Si/Si dissolution
rate) is less than 60 years.
[0358] Any minimum time stated here can be combined with any
maximum time stated here, as an alternative embodiment of the
invention of FIGS. 8-10.
[0359] Optionally, in any embodiment of FIGS. 8-10 the pH
protective coating is applied by PECVD at a power level per of more
than 22,000 kJ/kg of mass of precursor, or more than 30,000 kJ/kg
of mass of precursor, or more than 40,000 kJ/kg of mass of
precursor, or more than 50,000 kJ/kg of mass of precursor, or more
than 60,000 kJ/kg of mass of precursor, or more than 62,000 kJ/kg
of mass of precursor, or more than 70,000 kJ/kg of mass of
precursor, or more than 80,000 kJ/kg of mass of precursor, or more
than 100,000 kJ/kg of mass of precursor, or more than 200,000 kJ/kg
of mass of precursor, or more than 300,000 kJ/kg of mass of
precursor, or more than 400,000 kJ/kg of mass of precursor, or more
than 500,000 kJ/kg of mass of precursor.
[0360] Optionally, in any embodiment of FIGS. 8-10 the pH
protective coating is applied by PECVD at a power level per of less
than 2,000,000 kJ/kg of mass of precursor, or less than 1,000,000
kJ/kg of mass of precursor, or less than 700,000 kJ/kg of mass of
precursor, or less than 500,000 kJ/kg of mass of precursor, or less
than 100,000 kJ/kg of mass of precursor, or less than 90,000 kJ/kg
of mass of precursor, or less than 81,000 kJ/kg of mass of
precursor.
[0361] Optionally, in any embodiment of FIGS. 8-10, the
thermoplastic wall is a syringe barrel. A plunger is positioned for
sliding in the barrel and a lubricity coating or layer is present
on at least a portion of the plunger.
[0362] Optionally, in any embodiment of FIGS. 8-10, the lubricity
coating or layer is configured to provide a lower piston sliding
force or breakout force than the uncoated substrate.
[0363] Optionally, in any embodiment of FIGS. 8-10, the lubricity
layer has one of the atomic ratios previously defined for the
lubricity and/or pH protective coating, measured by X-ray
photoelectron spectroscopy (XPS). The lubricity layer has a
thickness by transmission electron microscopy (TEM) between 10 and
500 nm; the lubricity layer deposited by plasma enhanced chemical
vapor deposition (PECVD) under conditions effective to form a
coating from a precursor selected from a linear siloxane, a
monocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane, a
linear silazane, a monocyclic silazane, a polycyclic silazane, a
polysilsesquiazane, a silatrane, a silquasilatrane, a silproatrane,
an azasilatrane, an azasilquasiatrane, an azasilproatrane, or a
combination of any two or more of these precursors.
[0364] Even another aspect of the invention, exemplified in FIGS.
8-10, is a composite material including a substrate such as a wall
214, a composite barrier coating or layer 288 disposed on the
substrate or wall 214, and a passivation layer or pH protective
coating 286 on the barrier layer or coating 288. Several examples
of articles made from such a composite material are a syringe
barrel, a vial, and a medical device of any kind. The passivation
layer or pH protective coating 286 is deposited by PECVD using a
source material comprising a monocyclic siloxane, a polycyclic
siloxane, a polysilsesquioxane, a monocyclic silazane, a polycyclic
silazane, a polysilsesquiazane, a silatrane, a silquasilatrane, a
silproatrane, an azasilatrane, an azasilquasiatrane, an
azasilproatrane, or a combination of any two or more of these
precursors.
[0365] The passivation layer or pH protective coating, taking into
account the H atoms, may thus in one aspect have the formula
Si.sub.wO.sub.xC.sub.yH.sub.z, for example where w is 1, x is from
about 0.5 to about 2.4, y is from about 0.6 to about 3, and z is
from about 2 to about 9. Typically, expressed as the formula
Si.sub.wO.sub.xC.sub.y, the atomic ratios of Si, O, and C are, as
several options: [0366] Si 100: O 80-130: C 90-150, [0367] Si 100:
O 90-120: C 90-140, or [0368] Si 100: O 92-107: C 116-133.
[0369] The passivation layer or pH protective coating 286 shows an
O-Parameter measured with attenuated total reflection (ATR) of less
than 0.4, measured as:
O - Parameter = Intensity at 1253 cm - 1 Maximum intensity in the
range 1000 to 1100 cm - 1 ##EQU00003##
[0370] The O-Parameter is defined in U.S. Pat. No. 8,067,070, which
claims an O-parameter value of most broadly from 0.4 to 0.9. It can
be measured from physical analysis of an FTIR amplitude versus wave
number plot to find the numerator and denominator of the above
expression, as shown in FIG. 15, which is the same as FIG. 5 of
U.S. Pat. No. 8,067,070, except annotated to show interpolation of
the wave number and absorbance scales to arrive at an absorbance at
1253 cm.sup.-1 of 0.0424 and a maximum absorbance at 1000 to 1100
cm.sup.-1 of 0.08, resulting in a calculated O-parameter of 0.53.
The O-Parameter can also be measured from digital wave number
versus absorbance data.
[0371] U.S. Pat. No. 8,067,070 asserts that the claimed O-parameter
range provides a superior pH protective coating or layer, relying
on experiments only with HMDSO and HMDSN, which are both non-cyclic
siloxanes. Surprisingly, it has been found by the present inventors
that if the PECVD precursor is a cyclic siloxane, for example
OMCTS, O-parameters outside the ranges claimed in U.S. Pat. No.
8,067,070, using OMCTS, provide even better results than are
obtained in U.S. Pat. No. 8,067,070 with HMDSO.
[0372] Alternatively in the embodiment of FIGS. 8-10, the
O-parameter has a value of from 0.1 to 0.39, or from 0.15 to 0.37,
or from 0.17 to 0.35.
[0373] Even another aspect of the invention is a composite material
as just described, exemplified in FIGS. 8-10, wherein the
passivation layer shows an N-Parameter measured with attenuated
total reflection (ATR) of less than 0.7, measured as:
N - Parameter = Intensity at 840 cm - 1 Intensity at 799 cm - 1 .
##EQU00004##
[0374] The N-Parameter is also described in U.S. Pat. No.
8,067,070, and is measured analogously to the O-Parameter except
that intensities at two specific wave numbers are used--neither of
these wave numbers is a range. U.S. Pat. No. 8,067,070 claims a
passivation layer with an N-Parameter of 0.7 to 1.6. Again, the
present inventors have made better coatings employing a pH
protective coating 286 having an N-Parameter lower than 0.7, as
described above. Alternatively, the N-parameter has a value of at
least 0.3, or from 0.4 to 0.6, or at least 0.53.
Theory of Operation
[0375] The inventors offer the following theory of operation of the
pH protective coating or layer described here. The invention is not
limited by the accuracy of this theory or to the embodiments
predictable by use of this theory.
[0376] The dissolution rate of the SiO.sub.x barrier layer is
believed to be dependent on SiO bonding within the layer. Oxygen
bonding sites (silanols) are believed to increase the dissolution
rate.
[0377] It is believed that the OMCTS-based pH protective coating or
layer bonds with the silanol sites on the SiO.sub.x barrier layer
to "heal" or passivate the SiO.sub.x surface and thus dramatically
reduces the dissolution rate. In this hypothesis, the thickness of
the OMCTS layer is not the primary means of protection--the primary
means is passivation of the SiO.sub.x surface. It is contemplated
that a pH protective coating as described in this specification can
be improved by increasing the crosslink density of the pH
protective coating or layer.
ADDITIONAL EMBODIMENTS
[0378] The pH protective coating described in this specification
can be applied in many different ways. For one example, the
low-pressure PECVD process described in U.S. Pat. No. 7,985,188 can
be used. For another example, instead of using low-pressure PECVD,
atmospheric PECVD can be employed to deposit the pH protective
coating. For another example, the coating can be simply evaporated
and allowed to deposit on the SiO.sub.x layer to be protected. For
another example, the coating can be sputtered on the SiO.sub.x
layer to be protected. For still another example, the pH protective
coating or layer can be applied from a liquid medium used to rinse
or wash the SiO.sub.x layer.
[0379] Other precursors and methods can be used to apply the pH
protective coating or passivating treatment. For example,
hexamethylene disilazane (HMDZ) can be used as the precursor. HMDZ
has the advantage of containing no oxygen in its molecular
structure. This passivation treatment is contemplated to be a
surface treatment of the SiO.sub.x barrier layer with HMDZ. To slow
down and/or eliminate the decomposition of the silicon dioxide
coatings at silanol bonding sites, the coating must be passivated.
It is contemplated that passivation of the surface with HMDZ (and
optionally application of a few mono layers of the HMDZ-derived
coating) will result in a toughening of the surface against
dissolution, resulting in reduced decomposition. It is contemplated
that HMDZ will react with the --OH sites that are present in the
silicon dioxide coating, resulting in the evolution of NH.sub.3 and
bonding of S--(CH.sub.3).sub.3 to the silicon (it is contemplated
that hydrogen atoms will be evolved and bond with nitrogen from the
HMDZ to produce NH.sub.3).
[0380] It is contemplated that this HMDZ passivation can be
accomplished through several possible paths.
[0381] One contemplated path is dehydration/vaporization of the
HMDZ at ambient temperature. First, an SiO.sub.x surface is
deposited, for example using hexamethylene disiloxane (HMDSO). The
as-coated silicon dioxide surface is then reacted with HMDZ vapor.
In an embodiment, as soon as the SiO.sub.x surface is deposited
onto the article of interest, the vacuum is maintained. The HMDSO
and oxygen are pumped away and a base vacuum is achieved. Once base
vacuum is achieved, HMDZ vapor is flowed over the surface of the
silicon dioxide (as coated on the part of interest) at pressures
from the mTorr range to many Torr. The HMDZ is then pumped away
(with the resulting NH.sub.3 that is a byproduct of the reaction).
The amount of NH.sub.3 in the gas stream can be monitored (with a
residual gas analyzer--RGA--as an example) and when there is no
more NH.sub.3 detected, the reaction is complete. The part is then
vented to atmosphere (with a clean dry gas or nitrogen). The
resulting surface is then found to have been passivated. It is
contemplated that this method optionally can be accomplished
without forming a plasma.
[0382] Alternatively, after formation of the SiO.sub.x composite
barrier coating or layer, the vacuum can be broken before
dehydration/vaporization of the HMDZ. Dehydration/vaporization of
the HMDZ can then be carried out in either the same apparatus used
for formation of the SiO.sub.x composite barrier coating or layer
or different apparatus.
[0383] Dehydration/vaporization of HMDZ at an elevated temperature
is also contemplated. The above process can alternatively be
carried out at an elevated temperature exceeding room temperature
up to about 150.degree. C. The maximum temperature is determined by
the material from which the coated part is constructed. An upper
temperature should be selected that will not distort or otherwise
damage the part being coated.
[0384] Dehydration/vaporization of HMDZ with a plasma assist is
also contemplated. After carrying out any of the above embodiments
of dehydration/vaporization, once the HMDZ vapor is admitted into
the part, a plasma is generated. The plasma power can range from a
few watts to 100+ watts (similar powers as used to deposit the
SiO.sub.x). The above is not limited to HMDZ and could be
applicable to any molecule that will react with hydrogen, for
example any of the nitrogen-containing precursors described in this
specification.
[0385] Another way of applying the pH protective coating is to
apply as the pH protective coating an amorphous carbon or
fluorocarbon coating, or a combination of the two.
[0386] Amorphous carbon coatings can be formed by PECVD using a
saturated hydrocarbon, (e.g. methane or propane) or an unsaturated
hydrocarbon (e.g. ethylene, acetylene) as a precursor for plasma
polymerization. Fluorocarbon coatings can be derived from
fluorocarbons (for example, hexafluoroethylene or
tetrafluoroethylene). Either type of coating, or a combination of
both, can be deposited by vacuum PECVD or atmospheric pressure
PECVD. It is contemplated that that an amorphous carbon and/or
fluorocarbon coating will provide better passivation of an
SiO.sub.x barrier layer than a siloxane coating since an amorphous
carbon and/or fluorocarbon coating will not contain silanol
bonds.
[0387] It is further contemplated that fluorosilicon precursors can
be used to provide a pH protective coating or layer over an
SiO.sub.x barrier layer. This can be carried out by using as a
precursor a fluorinated silane precursor such as hexafluorosilane
and a PECVD process. The resulting coating would also be expected
to be a non-wetting coating.
[0388] It is further contemplated that any embodiment of the pH
protective coating processes described in this specification can
also be carried out without using the article to be coated to
contain the plasma. For example, external surfaces of medical
devices, for example catheters, surgical instruments, closures, and
others can be protected or passivated by sputtering the coating,
employing a radio frequency target.
[0389] Yet another coating modality contemplated for protecting or
passivating an SiO.sub.x barrier layer is coating the barrier layer
using a polyamidoamine epichlorohydrin resin. For example, the
barrier coated part can be dip coated in a fluid polyamidoamine
epichlorohydrin resin melt, solution or dispersion and cured by
autoclaving or other heating at a temperature between 60 and
100.degree. C. It is contemplated that a coating of polyamidoamine
epichlorohydrin resin can be preferentially used in aqueous
environments between pH 5-8, as such resins are known to provide
high wet strength in paper in that pH range. Wet strength is the
ability to maintain mechanical strength of paper subjected to
complete water soaking for extended periods of time, so it is
contemplated that a coating of polyamidoamine epichlorohydrin resin
on an SiO.sub.x barrier layer will have similar resistance to
dissolution in aqueous media. It is also contemplated that, because
polyamidoamine epichlorohydrin resin imparts a lubricity
improvement to paper, it will also provide lubricity in the form of
a coating on a thermoplastic surface made of, for example, COC or
COP.
[0390] Even another approach for protecting an SiO.sub.x layer is
to apply as a pH protective coating or layer a liquid-applied
coating of a polyfluoroalkyl ether, followed by atmospheric plasma
curing the pH protective coating. For example, it is contemplated
that the process practiced under the trademark TriboGlide.RTM.,
described in this specification, can be used to provide a pH
protective coating or layer that is also a lubricity layer, as
TriboGlide.RTM. is conventionally used to provide lubricity.
PECVD Apparatus and Methods for pH Protective Coating
[0391] Suitable methods and apparatus for applying a barrier or
lubricity coating or layer such as 90 of SiO.sub.x,
SiO.sub.xC.sub.y, or SiN.sub.xC.sub.y to a substrate such as the
vessel 80 (FIG. 1) or a vial are described, for example, in U.S.
Pat. No. 7,985,188 or the EP applications cited in paragraph [002],
under conditions effective to form a coating or layer.
[0392] For depositing a pH protective coating, a precursor feed or
process gas can be employed having a standard volume ratio of, for
example: [0393] from 0.5 to 10 standard volumes, optionally from 1
to 6 standard volumes, optionally from 2 to 4 standard volumes,
optionally equal to or less than 6 standard volumes, optionally
equal to or less than 2.5 standard volumes, optionally equal to or
less than 1.5 standard volumes, optionally equal to or less than
1.25 standard volumes of the precursor, for example OMCTS or one of
the other precursors of any embodiment; [0394] from 0 to 100
standard volumes, optionally from 1 to 80 standard volumes,
optionally from 5 to 100 standard volumes, optionally from 10 to 70
standard volumes, of a carrier gas of any embodiment; [0395] from
0.1 to 10 standard volumes, optionally from 0.1 to 2 standard
volumes, optionally from 0.2 to 1.5 standard volumes, optionally
from 0.2 to 1 standard volumes, optionally from 0.5 to 1.5 standard
volumes, optionally from 0.8 to 1.2 standard volumes of an
oxidizing agent.
[0396] Another embodiment is a pH protective coating or layer of
the type made by the above process.
[0397] Another embodiment is a vessel such as the vessel 80 (FIG.
1) including a lumen defined by a surface defining a substrate. A
pH protective coating or layer is present on at least a portion of
the substrate, typically deposited over an SiO.sub.x barrier layer
to protect the barrier layer from dissolution. The pH protective
coating or layer is made by the previously defined process.
[0398] Still another embodiment is a chemical vapor deposition
apparatus such as the apparatus 28 illustrated in FIG. 5 (or any
other illustrated coating apparatus, such as the apparatus
illustrated in FIGS. 1-4), for applying a pH protective coating or
layer to a substrate.
[0399] Referring now to FIG. 5, suitable chemical vapor deposition
apparatus is shown.
[0400] Referring to FIG. 8, yet another embodiment is a syringe
such as 252 comprising a plunger 258, a barrel 250, and a pH
protective coating or layer on the inner or interior surface 264.
The barrel 250 is a vessel and has an inner or interior surface 264
defining the vessel lumen 274 and receiving the plunger 258 for
sliding. The vessel inner or interior surface 264 is a substrate. A
pH protective coating or layer can be applied on the substrate 264,
the plunger 258, or both, by chemical vapor deposition. In addition
to this pH protective coating or layer, the syringe may contain one
or more other coatings or layers, for example an SiOxcomposite
barrier coating or layer. Said additional coating(s) or layer(s)
may be located under the lubricity and/orcomposite barrier coating
or layer, i.e. nearer to the barrel of the syringe.
[0401] For any embodiment of a syringe such as 252, in particular a
syringe that is stored or intended to be stored for an extended
time while prefilled, the plunger 258 optionally is provided with a
lubricity layer, at least on its surface in contact with the barrel
interior surface 264, and the barrel interior surface 264 is
provided with an SiO.sub.x barrier layer protected by a pH
protective coating or layer wherever it is in contact or likely to
be in contact with a fluid pharmaceutical composition contained in
the syringe. An advantage of this construction is that the pH
protective coating or layer, which is in contact with the fluid
pharmaceutical composition when the syringe is stored prefilled,
can be optimized for protection of the SiO.sub.x barrier layer,
while the lubricity layer, which is located where the plunger
typically contacts the inner surface 264 at a fixed location during
storage, can be optimized for lubricity. The lubricity coating or
layer on the plunger is in the right position to prevent
"sticktion" during storage and to continue to lower the friction
between the plunger and barrel when the plunger is advanced, and if
applied by CVD is contemplated to be less subject to displacement
by the force exerted by the plunger on the barrel than traditional
silicon oil coatings or layers and more uniformly applied as a
uniform coating rather than as isolated droplets of liquid. As a
further option, an adhesion layer or coating of SiO.sub.xC.sub.y
can be applied to the substrate and the barrier layer can be
applied to the adhesion layer to improve adhesion of the SiO.sub.x
barrier layer or coating to the substrate.
[0402] A concern of converting from glass to plastic syringes
centers around the potential for leachable materials from plastics.
With plasma coating technology, the coatings or layers derived from
non-metal gaseous precursors, for example HMDSO or OMCTS or other
organosilicon compounds, will itself contain no trace metals and
function as a barrier to inorganic, metals and organic solutes,
preventing leaching of these species from the coated substrate into
syringe fluids. In addition to leaching control of plastic
syringes, the same plasma pH protective coating or layer technology
offers potential to provide a solute barrier to the plunger tip,
typically made of elastomeric plastic compositions containing even
higher levels of leachable organic oligomers and catalysts.
[0403] Moreover, certain syringes prefilled with synthetic and
biological pharmaceutical formulations are very oxygen and moisture
sensitive. A critical factor in the conversion from glass to
plastic syringe barrels will be the improvement of plastic oxygen
and moisture barrier performance. The plasma pH protective coating
or layer technology is suitable to maintain the SiO.sub.x composite
barrier coating or layer for protection against oxygen and moisture
over an extended shelf life.
[0404] Even another embodiment is a plunger 258 for a syringe 252,
comprising a piston or tip, a pH protective coating or layer, and a
push rod. The piston or tip has a front face, a generally
cylindrical side face that slides within the barrel 250, comprising
a substrate, and a back portion. The side face is configured to
movably seat within a syringe barrel. The pH protective coating or
layer is on the substrate and is a lubricity and/or pH protective
coating interfacing with the side face. The lubricity and/or pH
protective coating is produced from a chemical vapor deposition
(CVD) process employing the previously defined precursor feed or
process gas. The push rod engages the back portion of the piston
and is configured for advancing the piston in a syringe barrel.
[0405] Even another embodiment is a medical or diagnostic kit
including a vessel having a coating or layer as defined in any
embodiment herein on a substrate as defined in any embodiment
above. Optionally, the kit additionally includes a medicament or
diagnostic agent which is contained in the vessel with a pH
protective coating in contact with the coating or layer; and/or a
hypodermic needle, double-ended needle, or other delivery conduit;
and/or an instruction sheet.
[0406] Other aspects of the invention include any one or more of
the following:
[0407] Use of the pH protective coating or layer according to any
embodiment described above for treating a surface and thereby
preventing or reducing mechanical and/or chemical effects of the
surface on a compound or composition in contact with the pH
protective coating or layer;
[0408] Use of the coating or layer according to any described
embodiment as a lubricity and/or pH protective coating;
[0409] Use of the coating or layer according to any described
embodiment for protecting a compound or composition contacting the
pH protective coating or layer against mechanical and/or chemical
effects of the surface of the vessel material without a pH
protective coating;
[0410] Use of the coating or layer according to any described
embodiment for preventing or reducing precipitation and/or clotting
or platelet activation of a compound or a component of the
composition in contact with the coating or layer.
[0411] As one option, the compound or a component of the
composition is insulin, and precipitation of the insulin is
prevented or reduced. As another option, the compound or a
component of the composition is blood or a blood fraction, and
blood clotting or platelet activation is prevented or reduced. As
still another option, the vessel with a pH protective coating is a
blood collection tube. Optionally, the blood collection tube can
contain an agent for preventing blood clotting or platelet
activation, for example ethylenediamineteetraacetic acid (EDTA), a
sodium salt thereof, or heparin.
[0412] Additional options for use of the invention include any one
or more of the following:
[0413] Use of a coated substrate according to any described
embodiment, for example a vessel such as a sample collection tube,
for example a blood collection tube and/or a closed-ended sample
collection tube; a vial; a conduit; a cuvette; or a vessel part,
for example a stopper; or a syringe, or a syringe part, for example
a barrel or piston for reception and/or storage and/or delivery of
a compound or composition.
[0414] The use of a coated substrate according to any described
embodiment is contemplated for storing insulin.
[0415] The use of a coated substrate according to any described
embodiment is contemplated for storing blood. Optionally, the
stored blood is viable for return to the vascular system of a
patient.
[0416] Use of a coating or layer according to any described
embodiment is contemplated as (i) a lubricity coating having a
lower frictional resistance than the uncoated surface; and/or (ii)
a pH protective coating preventing dissolution of the barrier
coating in contact with a fluid, and/or (iii) a hydrophobic layer
that is more hydrophobic than the uncoated surface.
[0417] Other aspects of the invention include any of the uses
defined above in the summary section.
Precursors for PECVD pH Protective Coating or Layer
[0418] The organosilicon precursor for the composite barrier
coating or layer and the pH protective layer can include any of the
following precursors useful for PECVD. The precursor for the PECVD
pH protective coating or layer of the present invention is broadly
defined as an organometallic precursor. An organometallic precursor
is defined in this specification as comprehending compounds of
metal elements from Group III and/or Group IV of the Periodic Table
having organic residues, for example hydrocarbon, aminocarbon or
oxycarbon residues. Organometallic compounds as presently defined
include any precursor having organic moieties bonded to silicon or
other Group III/IV metal atoms directly, or optionally bonded
through oxygen or nitrogen atoms. The relevant elements of Group
III of the Periodic Table are Boron, Aluminum, Gallium, Indium,
Thallium, Scandium, Yttrium, and Lanthanum, Aluminum and Boron
being preferred. The relevant elements of Group IV of the Periodic
Table are Silicon, Germanium, Tin, Lead, Titanium, Zirconium,
Hafnium, and Thorium, with Silicon and Tin being preferred. Other
volatile organic compounds can also be contemplated. However,
organosilicon compounds are preferred for performing present
invention.
[0419] An organosilicon precursor is contemplated, where an
"organosilicon precursor" is defined throughout this specification
most broadly as a compound having at least one of the linkages:
##STR00002##
[0420] The first structure immediately above is a tetravalent
silicon atom connected to an oxygen atom and an organic carbon atom
(an organic carbon atom being a carbon atom bonded to at least one
hydrogen atom). The second structure immediately above is a
tetravalent silicon atom connected to an --NH-- linkage and an
organic carbon atom (an organic carbon atom being a carbon atom
bonded to at least one hydrogen atom). Optionally, the
organosilicon precursor is selected from the group consisting of a
linear siloxane, a monocyclic siloxane, a polycyclic siloxane, a
polysilsesquioxane, a linear silazane, a monocyclic silazane, a
polycyclic silazane, a polysilsesquiazane, and a combination of any
two or more of these precursors. Also contemplated as a precursor,
though not within the two formulas immediately above, is an alkyl
trimethoxysilane.
[0421] If an oxygen-containing precursor (for example a Siloxane)
is used, a representative predicted empirical composition resulting
from PECVD under conditions forming a hydrophobic or lubricating pH
protective coating or layer would be Si.sub.wO.sub.xC.sub.yH.sub.z
or its equivalent SiO.sub.xC.sub.y as defined in the Definition
Section, while a representative predicted empirical composition
resulting from PECVD under conditions forming a composite barrier
coating or layer would be SiO.sub.x, where x in this formula is
from about 1.5 to about 2.4. If a nitrogen-containing precursor
(for example a silazane) is used, the predicted composition would
be Si.sub.w*N.sub.x*C.sub.y*H.sub.z*, i.e. in
Si.sub.wO.sub.xC.sub.yH.sub.z or its equivalent SiO.sub.xC.sub.y as
specified in the Definition Section, O is replaced by N and the
indices for H are adapted to the higher valency of N as compared to
O (3 instead of 2. The latter adaptation will generally follow the
ratio of w, x, y and z in a Siloxane to the corresponding indices
in its aza counterpart. In a particular aspect of the invention,
Si.sub.w*N.sub.x*C.sub.y*H.sub.z* (or its equivalent
SiN.sub.x*C.sub.y*) in which w*, x*, y*, and z* are defined the
same as w, x, y, and z for the siloxane counterparts, but for an
optional deviation in the number of hydrogen atoms.
[0422] One type of precursor starting material having the above
empirical formula is a linear siloxane, for example a material
having the following formula:
##STR00003##
in which each R is independently selected from alkyl, for example
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, vinyl,
alkyne, or others, and n is 1, 2, 3, 4, or greater, optionally two
or greater. Several examples of contemplated linear siloxanes are
hexamethyldisiloxane (HMDSO), octamethyltrisiloxane,
decamethyltetrasiloxane, dodecamethylpentasiloxane, or combinations
of two or more of these. The analogous silazanes in which --NH-- is
substituted for the oxygen atom in the above structure are also
useful for making analogous pH protective coatings or layers.
Several examples of contemplated linear silazanes are
octamethyltrisilazane, decamethyltetrasilazane, or combinations of
two or more of these.
[0423] Another type of precursor starting material, among the
preferred starting materials in the present context, is a
monocyclic siloxane, for example a material having the following
structural formula:
##STR00004##
in which R is defined as for the linear structure and "a" is from 3
to about 10, or the analogous monocyclic silazanes. Several
examples of contemplated hetero-substituted and unsubstituted
monocyclic siloxanes and silazanes include
1,3,5-trimethyl-1,3,5-tris(3,3,3-trifluoropropyl)methyl]cyclotrisiloxane
2,4,6,8-tetramethyl-2,4,6,8-tetravinylcyclotetrasiloxane,
pentamethylcyclopentasiloxane,
pentavinylpentamethylcyclopentasiloxane,
hexamethylcyclotrisiloxane, hexaphenylcyclotrisiloxane,
octamethylcyclotetrasiloxane (OMCTS), octaphenylcyclotetrasiloxane,
decamethylcyclopentasiloxane dodecamethylcyclohexasiloxane,
methyl(3,3,3-trifluoropropl)cyclosiloxane, Cyclic organosilazanes
are also contemplated, such as
Octamethylcyclotetrasilazane,
[0424] 1,3,5,7-tetravinyl-1,3,5,7-tetramethylcyclotetrasilazane
hexamethylcyclotrisilazane, octamethylcyclotetrasilazane,
decamethylcyclopentasilazane, dodecamethylcyclohexasilazane, or
combinations of any two or more of these.
[0425] Another type of precursor starting material, among the
preferred starting materials in the present context, is a
polycyclic siloxane, for example a material having one of the
following structural formulas:
##STR00005##
in which Y can be oxygen or nitrogen, E is silicon, and Z is a
hydrogen atom or an organic substituent, for example alkyl such as
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, vinyl,
alkyne, or others. When each Y is oxygen, the respective
structures, from left to right, are a Silatrane, a Silquasilatrane,
and a Silproatrane. When Y is nitrogen, the respective structures
are an azasilatrane, an azasilquasiatrane, and an
azasilproatrane.
[0426] Another type of polycyclic siloxane precursor starting
material, among the preferred starting materials in the present
context, is a polysilsesquioxane, with the empirical formula
RSiO.sub.1.5 and the structural formula:
##STR00006##
in which each R is a hydrogen atom or an organic substituent, for
example alkyl such as methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, t-butyl, vinyl, alkyne, or others. Two commercial
materials of this sort are SST-eM01 poly(methylsilsesquioxane), in
which each R is methyl, and SST-3MH1.1
poly(Methyl-Hydridosilsesquioxane), in which 90% of the R groups
are methyl, 10% are hydrogen atoms. This material is available in a
10% solution in tetrahydrofuran, for example. Combinations of two
or more of these are also contemplated. Other examples of a
contemplated precursor are methylsilatrane, CAS No. 2288-13-3, in
which each Y is oxygen and Z is methyl, methylazasilatrane,
poly(methylsilsesquioxane) (for example SST-eM01
poly(methylsilsesquioxane)), in which each R optionally can be
methyl, SST-3MH1.1 poly(Methyl-Hydridosilsesquioxane) (for example
SST-3MH1.1 poly(Methyl-Hydridosilsesquioxane)), in which 90% of the
R groups are methyl and 10% are hydrogen atoms, or a combination of
any two or more of these.
[0427] The analogous polysilsesquiazanes in which --NH-- is
substituted for the oxygen atom in the above structure are also
useful for making analogous pH protective coating or layer.
Examples of contemplated polysilsesquiazanes are a
poly(methylsilsesquiazane), in which each R is methyl, and a
poly(Methyl-Hydridosilsesquiazane, in which 90% of the R groups are
methyl, 10% are hydrogen atoms. Combinations of two or more of
these are also contemplated.
[0428] One particularly contemplated precursor for the composite
barrier coating or layer according to the present invention is a
linear siloxane, for example is HMDSO. One particularly
contemplated precursor for the lubricity coating or layer and the
pH protective coating or layer according to the present invention
is a cyclic siloxane, for example octamethylcyclotetrasiloxane
(OMCTS).
[0429] It is believed that the OMCTS or other cyclic siloxane
molecule provides several advantages over other siloxane materials.
First, its ring structure results in a less dense pH protective
coating or layer (as compared to pH protective coating or layer
prepared from HMDSO). The molecule also allows selective ionization
so that the final structure and chemical composition of the pH
protective coating or layer can be directly controlled through the
application of the plasma power. Other organosilicon molecules are
readily ionized (fractured) so that it is more difficult to retain
the original structure of the molecule.
[0430] In any of the PECVD methods according to the present
invention, the applying step optionally can be carried out by
vaporizing the precursor and providing it in the vicinity of the
substrate. For example, OMCTS is usually vaporized by heating it to
about 50.degree. C. before applying it to the PECVD apparatus.
[0431] Cyclic organosilicon precursors, in particular monocyclic
organosilicon precursors (like the monocyclic precursors listed
elsewhere in present description), and specifically OMCTS, are
particularly suitable to achieve a pH protective coating or
layer.
Other Components of PECVD Reaction Mixture and Ratios of Components
for pH Protective Coating or Layer
[0432] Generally, for a pH protective coating or layer, O.sub.2 can
be present in an amount (which can, for example be expressed by the
flow rate in seem) which is less than one order of magnitude
greater than the organosilicon amount. In contrast, in order to
achieve a composite barrier coating or layer, the amount of 02
typically is at least one order of magnitude higher than the amount
of organosilicon precursor. In particular, the volume ratio (in
seem) of organosilicon precursor to O.sub.2 for a pH protective
coating or layer can be in the range from 0.1:1 to 10:1, optionally
in the range from 0.3:1 to 8:1, optionally in the range from 0.5:1
to 5:1, optionally from 1:1 to 3:1. The presence of the precursor
and O.sub.2 in the volume ratios as given in Tables 1 to 3 is
specifically suitable to achieve a pH protective coating or
layer.
[0433] In one aspect of the invention, a carrier gas is absent in
the reaction mixture, in another aspect of the invention, it is
present. Suitable carrier gases include Argon, Helium and other
noble gases such as Neon and Xenon. When the carrier gas is present
in the reaction mixture, it is typically present in a volume (in
seem) exceeding the volume of the organosilicon precursor. For
example, the ratio of the organosilicon precursor to carrier gas
can be from 1:1 to 1:50, optionally from 1:5 to 1:40, optionally
from 1:10 to 1:30. One function of the carrier gas is to dilute the
reactants in the plasma, encouraging the formation of a coating on
the substrate instead of powdered reaction products that do not
adhere to the substrate and are largely removed with the exhaust
gases.
[0434] Since the addition of Argon gas improves the lubricity
and/or pH protective performance (see the working examples below),
it is believed that additional ionization of the molecule in the
presence of Argon contributes to providing lubricity. The Si--O--Si
bonds of the molecule have a high bond energy followed by the
Si--C, with the C--H bonds being the weakest. Lubricity and/or pH
protective appears to be achieved when a portion of the C--H bonds
are broken. This allows the connecting (cross-linking) of the
structure as it grows. Addition of oxygen (with the Argon) is
understood to enhance this process. A small amount of oxygen can
also provide C--O bonding to which other molecules can bond. The
combination of breaking C--H bonds and adding oxygen all at low
pressure and power leads to a chemical structure that is solid
while providing lubricity.
[0435] In any of embodiments, one preferred combination of process
gases includes octamethylcyclotetrasiloxane (OMCTS) or another
cyclic siloxane as the precursor, in the presence of oxygen as an
oxidizing gas and argon as a carrier gas. Without being bound to
the accuracy of this theory, the inventors believe this particular
combination is effective for the following reasons. The presence of
O.sub.2, N.sub.2O, or another oxidizing gas and/or of a carrier
gas, in particular of a carrier gas, for example a noble gas, for
example Argon (Ar), is contemplated to improve the resulting pH
protective coating or layer.
[0436] Some non-exhaustive alternative selections and suitable
proportions of the precursor gas, oxygen, and a carrier gas are
provided below.
OMCTS: 0.5-5.0 sccm Oxygen: 0.1-5.0 sccm Argon: 1.0-20 sccm
PECVD Apparatus for Forming pH Protective Coating or Layer
[0437] The low-pressure PECVD process described in U.S. Pat. No.
7,985,188 can be used to provide the barrier, lubricity, and pH
protective layers described in this specification. A brief synopsis
of that process follows.
[0438] A PECVD apparatus suitable for performing the present
invention includes a vessel holder, an inner electrode, an outer
electrode, and a power supply. A vessel seated on the vessel holder
defines a plasma reaction chamber, which optionally can be a vacuum
chamber. Optionally, a source of vacuum, a reactant gas source, a
gas feed or a combination of two or more of these can be supplied.
Optionally, a gas drain, not necessarily including a source of
vacuum, is provided to transfer gas to or from the interior of a
vessel seated on the port to define a closed chamber.
[0439] The PECVD apparatus can be used for atmospheric-pressure
PECVD, in which case the plasma reaction chamber does not need to
function as a vacuum chamber.
[0440] Referring to FIGS. 1 and 2, the vessel holder 50 comprises a
gas inlet port 104 for conveying a gas into a vessel seated on the
vessel port. The gas inlet port 104 has a sliding seal provided by
at least one O-ring 106, or two O-rings in series, or three O-rings
in series, which can seat against a cylindrical probe 108 when the
probe 108 is inserted through the gas inlet port 104. The probe 108
can be a gas inlet conduit that extends to a gas delivery port at
its distal end 110. The distal end 110 of the illustrated
embodiment can be inserted deep into the vessel 80 for providing
one or more PECVD reactants and other precursor feed or process
gases.
[0441] FIG. 5 shows additional optional details of the coating or
layer station 28 that are usable, for example, with all the
illustrated embodiments. The coating or layer station 28 can also
have a main vacuum valve 574 in its vacuum line 576 leading to the
pressure sensor 152. A manual bypass valve 578 is provided in the
bypass line 580. A vent valve 582 controls flow at the vent
404.
[0442] Flow out of the PECVD gas or precursor source 144 is
controlled by a main reactant gas valve 584 regulating flow through
the main reactant feed line 586. One component of the gas source
144 is the organosilicon liquid reservoir 588. The contents of the
reservoir 588 are drawn through the organosilicon capillary line
590, which is provided at a suitable length to provide the desired
flow rate. Flow of organosilicon vapor is controlled by the
organosilicon shut-off valve 592. Pressure is applied to the
headspace 614 of the liquid reservoir 588, for example a pressure
in the range of 0-15 psi (0 to 78 cm. Hg), from a pressure source
616 such as pressurized air connected to the headspace 614 by a
pressure line 618 to establish repeatable organosilicon liquid
delivery that is not dependent on atmospheric pressure (and the
fluctuations therein). The reservoir 588 is sealed and the
capillary connection 620 is at the bottom of the reservoir 588 to
ensure that only neat organosilicon liquid (not the pressurized gas
from the headspace 614 flows through the capillary tube 590. The
organosilicon liquid optionally can be heated above ambient
temperature, if necessary or desirable to cause the organosilicon
liquid to evaporate, forming an organosilicon vapor. To accomplish
this heating, the pH protective coating or layer apparatus can
advantageously include heated delivery lines from the exit of the
precursor reservoir to as close as possible to the gas inlet into
the syringe. Preheating is useful, for example, when feeding
OMCTS.
[0443] Oxygen is provided from the oxygen tank 594 via an oxygen
feed line 596 controlled by a mass flow controller 598 and provided
with an oxygen shut-off valve 600.
[0444] For instances in which a carrier gas is used, the carrier
gas is obtained from a source of carrier gas 602 and passes via a
conduit 604, controlled by a carrier gas shut-off valve 606, to the
main reactant feed line 586 where it is combined with the other
components of the PECVD gas feed.
[0445] Referring especially to FIG. 1, the processing station 28
can include an electrode 160 fed by a radio frequency power supply
162 for providing an electric field for generating plasma within
the vessel 80 during processing. In this embodiment, the probe 108
is also electrically conductive and is grounded, thus providing a
counter-electrode within the vessel 80. Alternatively, in any
embodiment the outer electrode 160 can be grounded and the probe
108 directly connected to the power supply 162.
[0446] In the embodiment of FIG. 1, the outer electrode 160 can
either be generally cylindrical as illustrated in FIGS. 1 and 2 or
a generally U-shaped elongated channel as illustrated in FIG. 1
(FIG. 2 being an embodiment of the section taken along section line
A-A of FIG. 1). Each illustrated embodiment has one or more
sidewalls, such as 164 and 166, and optionally a top end 168,
disposed about the vessel 80 in close proximity.
[0447] Referring to FIGS. 3 and 4, a specific adaptation of the
PECVD process is described for applying PECVD coatings to a vessel
such as a syringe barrel that is open at both ends.
[0448] FIGS. 3 and 4 show a method and apparatus generally
indicated at 290 for coating or layer an inner or interior surface
292 of a restricted opening 294 of a generally tubular vessel 250
to be processed, for example the restricted front opening 294 of a
syringe barrel 250, by PECVD. The previously described process is
modified by connecting the restricted opening 294 to a processing
vessel 296 and optionally making certain other modifications.
[0449] The generally tubular vessel 250 to be processed includes an
outer surface 298, an inner or inner or interior surface 254
defining a lumen 300, a larger opening 302 having an inner
diameter, and a restricted opening 294 that is defined by an inner
or interior surface 292 and has an inner diameter smaller than the
inner diameter of the larger opening 302.
[0450] The processing vessel 296 has a lumen 304 and a processing
vessel opening 306, which optionally is the only opening, although
in other embodiments a second opening can be provided that
optionally is closed off during processing. The processing vessel
opening 306 is connected with the restricted opening 294 of the
vessel 250 to be processed to establish communication between the
lumen 300 of the vessel 250 to be processed and the processing
vessel lumen via the restricted opening 294.
[0451] At least a partial vacuum is drawn within the lumen 300 of
the vessel 250 to be processed and lumen 304 of the processing
vessel 296. A PECVD reactant is flowed from the gas source 144
through the first opening 302, then through the lumen 300 of the
vessel 250 to be processed, then through the restricted opening
294, then into the lumen 304 of the processing vessel 296.
[0452] The PECVD reactant can be introduced through the larger
opening 302 of the vessel 250 by providing a generally tubular
inner electrode 308 having an interior passage 310, a proximal end
312, a distal end 314, and a distal opening 316, in an alternative
embodiment multiple distal openings can be provided adjacent to the
distal end 314 and communicating with the interior passage 310. The
distal end of the electrode 308 can be placed adjacent to or into
the larger opening 302 of the vessel 250 to be processed. A
reactant gas can be fed through the distal opening 316 of the
electrode 308 into the lumen 300 of the vessel 250 to be processed.
The reactant will flow through the restricted opening 294, then
into the lumen 304, to the extent the PECVD reactant is provided at
a higher pressure than the vacuum initially drawn before
introducing the PECVD reactant.
[0453] Plasma 318 is generated adjacent to the restricted opening
294 under conditions effective to deposit a coating or layer of a
PECVD reaction product on the inner or interior surface 292 of the
restricted opening 294.
[0454] More details concerning adapting the PECVD process to
syringe processing are provided, for example, in U.S. Pat. No.
7,985,188.
[0455] Specific PECVD conditions for application of a pH protective
coating or layer are provided below.
Plasma Conditions for pH Protective Coating or Layer
[0456] Typically, the plasma in the PECVD process is generated at
RF frequency. For providing a pH protective layer on the interior
of a vessel by a plasma reaction carried out within the vessel, the
plasma of any embodiment can be generated with an electric power of
from 0.1 to 500 W, optionally from 0.1 to 400 W, optionally from
0.1 to 300 W, optionally from 1 to 250 W, optionally from 1 to 200
W, even optionally from 10 to 150 W, optionally from 20 to 150 W,
for example of 40 W, optionally from 40 to 150 W, even optionally
from 60 to 150 W. The ratio of the electrode power to the plasma
volume can be less than 100 W/ml, optionally is from 5 W/ml to 75
W/ml, optionally is from 6 W/ml to 60 W/ml, optionally is from 10
W/ml to 50 W/ml, optionally from 20 W/ml to 40 W/ml. These power
levels are suitable for applying pH protective coatings or layers
to syringes and sample tubes and pharmaceutical packages or other
vessels of similar geometry having a void volume of 5 mL in which
PECVD plasma is generated. It is contemplated that for larger or
smaller objects the power applied, in Watts, should be increased or
reduced accordingly to scale the process to the size of the
substrate.
[0457] Exemplary reaction conditions for preparing a pH protective
coating or layer according to the present invention in a 3 ml
sample size syringe with a 1/8'' diameter tube (open at the end)
are as follows:
Flow Rate Ranges:
[0458] OMCTS: 0.5-10 sccm Oxygen: 0.1-10 sccm Argon: 1.0-200 sccm
Power: 0.1-500 watts
Specific Flow Rates:
[0459] OMCTS: 2.0 sccm Oxygen: 0.7 sccm Argon: 7.0 sccm Power: 3.5
watts
[0460] The pH protective coating or layer and its application are
described in more detail below. A method for applying the coating
includes several steps. A vessel wall is provided, as is a reaction
mixture comprising plasma forming gas, i.e. an organosilicon
compound gas, optionally an oxidizing gas, and optionally a
hydrocarbon gas.
[0461] Plasma is formed in the reaction mixture that is
substantially free of hollow cathode plasma. The vessel wall is
contacted with the reaction mixture, and the pH protective coating
or layer of SiO.sub.x is deposited on at least a portion of the
vessel wall.
[0462] In certain embodiments, the generation of a uniform plasma
throughout the portion of the vessel to be coated is contemplated,
as it has been found in certain instances to generate a better pH
protective coating or layer. Uniform plasma means regular plasma
that does not include a substantial amount of hollow cathode plasma
(which has a higher emission intensity than regular plasma and is
manifested as a localized area of higher intensity interrupting the
more uniform intensity of the regular plasma).
Method of Applying a Lubricity Coating or Layer
[0463] A method of applying an optional lubricity coating or layer
derived from an organosilicon precursor, and the resulting pH
protective coating or layer and coated item are described for
example in U.S. Pat. No. 7,985,188. A "lubricity coating" or any
similar term is generally defined as a coating or layer that
reduces the frictional resistance of the coated surface, relative
to the uncoated surface. If the coated object is a syringe (or
syringe part, for example syringe barrel) or any other item
generally containing a plunger or movable part in sliding contact
with the coated surface, the frictional resistance has two main
aspects--breakout force and plunger sliding force.
[0464] It should be understood that a coating optionally can be
both a lubricity coating or layer and a pH protective coating or
layer, respectively as explained in this description.
Hydrophobic Layer
[0465] The pH protective or lubricity coating or layer of
Si.sub.wO.sub.xC.sub.y or its equivalent SiO.sub.xC.sub.y also can
have utility as a hydrophobic layer. A coating or layer of this
kind is contemplated to be hydrophobic, independent of whether it
also functions as a lubricity and/or pH protective coating. A
coating or layer or treatment is defined as "hydrophobic" if it
lowers the wetting tension of a surface, compared to the
corresponding uncoated or untreated surface. Hydrophobicity is thus
a function of both the untreated substrate and the treatment.
[0466] Suitable hydrophobic coatings or layers and their
application, properties, and use are described in U.S. Pat. No.
7,985,188. Dual functional pH protective/hydrophobic coatings or
layers having the properties of both types of coatings or layers
can be provided for any embodiment of the present invention.
Measurement of Coating Thickness
[0467] The thickness of a PECVD coating or layer such as the pH
protective coating or layer, the composite barrier coating or
layer, the lubricity coating or layer, and/or a composite of any
two or more of these layers can be measured, for example, by
transmission electron microscopy (TEM). An exemplary TEM image for
a lubricity and/or pH protective coating or layer is shown in FIG.
6. An exemplary TEM image for an SiO.sub.2 composite barrier
coating or layer is shown in FIG. 7.
[0468] The TEM can be carried out, for example, as follows. Samples
can be prepared for Focused Ion Beam (FIB) cross-sectioning in two
ways. Either the samples can be first coated with a thin layer of
carbon (50-100 nm thick) and then coated with a sputtered coating
or layer of platinum (50-100 nm thick) using a K575X Emitech pH
protective coating or layer system, or the samples can be coated
directly with the pH protective sputtered Pt layer. The coated
samples can be placed in an FEI FIB200 FIB system. An additional
coating or layer of platinum can be FIB-deposited by injection of
an organometallic gas while rastering the 30 kV gallium ion beam
over the area of interest. The area of interest for each sample can
be chosen to be a location half way down the length of the syringe
barrel. Thin cross sections measuring approximately 15 .mu.m
("micrometers") long, 2 .mu.m wide and 15 .mu.m deep can be
extracted from the die surface using an in-situ FIB lift-out
technique. The cross sections can be attached to a 200 mesh copper
TEM grid using FIB-deposited platinum. One or two windows in each
section, measuring about 8 .mu.m wide, can be thinned to electron
transparency using the gallium ion beam of the FEI FIB.
[0469] Cross-sectional image analysis of the prepared samples can
be performed utilizing either a Transmission Electron Microscope
(TEM), or a Scanning Transmission Electron Microscope (STEM), or
both. All imaging data can be recorded digitally. For STEM imaging,
the grid with the thinned foils can be transferred to a Hitachi
HD2300 dedicated STEM. Scanning transmitted electron images can be
acquired at appropriate magnifications in atomic number contrast
mode (ZC) and transmitted electron mode (TE). The following
instrument settings can be used.
TABLE-US-00002 Instrument Scanning Transmission Electron Microscope
Manufacturer/Model Hitachi HD2300 Accelerating Voltage 200 kV
Objective Aperture #2 Condenser Lens 1 Setting 1.672 Condenser Lens
2 Setting 1.747 Approximate Objective Lens Setting 5.86 ZC Mode
Projector Lens 1.149 TE Mode Projector Lens 0.7 Image Acquisition
Pixel Resolution 1280 .times. 960 Acquisition Time 20
sec.(.times.4
[0470] For TEM analysis the sample grids can be transferred to a
Hitachi HF2000 transmission electron microscope. Transmitted
electron images can be acquired at appropriate magnifications. The
relevant instrument settings used during image acquisition can be
those given below.
TABLE-US-00003 Instrument Transmission Electron Microscope
Manufacturer/Model Hitachi HF2000 Accelerating Voltage 200 kV
Condenser Lens 1 0.78 Condenser Lens 2 0 Objective Lens 6.34
Condenser Lens Aperture #1 Objective Lens Aperture for #3 imaging
Selective Area Aperture for N/A SAD
Measurement of Adhesion
[0471] The following methods can be used to measure the degree of
adhesion of the composite barrier coating or layer to a substrate.
Key references are: [0472] (1) ASTM D3359-09 "Standard Test Methods
for Measuring Adhesion by Tape Test" [0473] (2) B905-00 "Standard
Test Methods for Assessing the Adhesion of Metallic and Inorganic
Coatings by the Mechanized Tape Test."
(A1) Coated Article Deformation/Tape Test Method
[0474] (Sections of References 1 and 2 followed whenever
relevant)
General
[0475] In this method as used in this specification, a deformation
force is applied to an SiO.sub.x coated article to stress the
coating, after which the extent of removal of the coating with
adhesive tape is assessed.
Sample Preparation:
[0476] A coated vial, syringe barrel, cartridge or other article
having a cylindrical section is cut at each end of the article
resulting in a uniform constant inner diameter (ID) open-ended
cylinder. The non-cylindrical or differing ID sections are
discarded. Cutting is performed with a hot wire cutter. If
appropriate, careful removal of any particles that may be present
is achieved with clean, dry compressed air (no physical contact
should be made with the coated interior of the cylinder).
Sample Deformation:
[0477] The uniform coated cylinder derived from the vial, syringe
barrel, cartridge, or other article is placed in an Instron.RTM.
stress-strain material testing machine, either (a) in an axial
deformation orientation, with open ends vertical; the stainless
Instron.RTM. plates contacting the circular open edges (also known
as "top down deformation") or (b) in a diametric deformation
orientation with its open ends horizontal; the stainless
Instron.RTM. plates contacting two parallel opposed lengths of the
cylinder (also known as "side deformation"). Unless otherwise
stated, axial deformation is employed in the test methods specified
in the claims.
[0478] Depending on the plastic composition, mold conditions, and
cylinder thickness, compression deformation forces are applied;
forces should not exceed levels which would result in any
irreversible physical deformation or failure of the cylinder. For
axial testing of thermoplastic containers as recited in the claims,
a compression force of 350 lb. (158 Kg) is employed. For diametric
deformation in alternative testing, the same compression force is
applied. If side compression or diametric deformation is selected,
reproducible contact location of the cylinder on the stainless
plates relative to mold lines should be established.
Tape Application: Half Cylinder Approach
[0479] The cylinder is cut longitudinally in half using the same
cutting methods applied in the Sample Preparation Section.
[0480] The curved nature of the cylinders requires a narrow tape
strip to facilitate uniform, bubble-free tape adhesion to the
coated inner wall surface. A one-sided Scotch Brand adhesive tape
is cut to a width of three millimeters and length about six
millimeters longer than the overall cylinder length. The adhesive
tape section is clamped from about three millimeters from each end
of the tape with long handled needle-nose tweezers or
micro-hemostats, without touching the walls. Once the tape extends
axially and its ends are equally positioned beyond each open end of
the cylinder, the tape is contacted with the curved coated inner
wall. A small pencil eraser head or hemispherical-rounded end three
millimeter stainless rod is then moved up and down the tape surface
between the clamps, removing any bubbles under the tape. It is
important to apply a uniform force on the tape.
[0481] Once the tape is uniformly adhered to the inner wall, the
clamps can be removed, but making sure the previously clamped ends
do not adhere to the wall.
[0482] Tape Removal:
[0483] (See Reference 2-p3 (Section 7.4) for details of Tape Pull
Time, Rate, and Angle). For the tests carried out in this
specification, a 90 o tape pull was used as described below.
90.degree. Tape Pull
[0484] A single needle-nose tweezer or micro-hemostat used
previously in the Tape Application Section is clamped on the
opposite free end of the wall surface affixed tape, followed by
uniform pulling at a 90.degree. angle (perpendicular to the adhered
tape) on the clamped tape end with removal of the tape. Clamps
attached to an Instron.RTM. vertical motion bar can be utilized to
provide a uniform rate of tape pull removal.
Adhesion Assessment:
Coating Thickness Determination (Line Scanning)
[0485] Using a Layer Explorer UT Instrument (www.rap-id.com) or
equivalent interferometric thickness measurement device, the
coating thickness before and after tape application is measured
along an axial line bisecting the location of the adherent tape.
The reduction of area (coating thickness x length of scan) of the
difference after tape pull versus before tape adhesion is a measure
of the degree of coating adhesion. This is represented as a percent
of original coating retained after tape pull.
(A2) Coated Article Cross-Scratch/Tape Test Method
[0486] (Sections of References 1 and 2 followed whenever
relevant)
General
[0487] In this method as used in this specification, the coating of
an SiOx coated article is scratched to stress the coating, after
which the extent of removal of the coating with adhesive tape is
assessed.
Sample Preparation:
[0488] A coated vial, syringe barrel, or cartridge is cut at each
end of the article and cut in half along an axial plane as
described above, resulting in a uniform constant inner diameter
(ID) half cylinder.
X scratch pattern:
[0489] If an X scratch pattern is selected, as specified in certain
claims, an "X" is scribed onto the inner coated wall surface of the
half cylinder, using a stainless pointed dental pick. The shape of
the X is a uniformly shaped and positioned pair of scratches
forming an axially elongated pattern. The smaller angle between the
two scratches is a uniform value between 30.degree. and
40.degree..
Half Cylinder Cross-Cut
[0490] If a rectangular scratch pattern is selected, as specified
in certain claims or described in Reference 2, Section 10 (p3), an
"square cross-cut" is scribed onto the inner coated wall surface of
the cylinder, using a sharp razor blade, scalpel, knife or other
cutting device.
Tape Application:
Half Cylinder Approach
[0491] The tape is applied as described above, but is positioned to
overlie the scratches. If an X scratch pattern is employed, the
tape is positioned to extend axially with the center of the X
centered circumferentially on the tape. If a rectangular scratch
pattern is employed, the tape is positioned to extend axially with
the tape centered circumferentially on the scratch pattern.
Tape Removal:
[0492] (See Reference 2-p3 (Section 7.4) for details of Tape Pull
Time, Rate, and Angle)
90.degree. Tape Pull
[0493] A single clamp is clamped on the opposite free end of the
wall surface affixed tape, followed by uniform pulling at a
90.degree. angle (perpendicular to the adhered tape) on the clamped
tape end with removal of the tape. The clamp is attached to an
Instron.RTM. vertical motion bar to provide a uniform rate of tape
pull removal.
Adhesion Assessment:
Coating Thickness Determination (Line Scanning)
[0494] Using a Layer Explorer UT Instrument (www.rap-id.com) or
equivalent interferometric thickness measurement device, the
coating thickness before and after tape application (but both after
X-cut or Cross-cut) along a line bisecting the location of the
adherent tape is measured. The reduction of area (coating thickness
x length of scan) of the difference after tape pull versus before
tape adhesion is a measure of the degree of coating adhesion. This
can be represented as a percent of original coating retained after
tape pull.
[0495] (B1) Inventive Adhesion performance of SiO.sub.x barrier
coating on a COP 5 millilter vial versus comparative borosilicate
glass vial using A1 and A2 Adhesion Assessment Methods.
[0496] Using established SiO.sub.x coating procedures discussed in
the Protocol for Coating Syringe Barrel Interior with SiO.sub.x in
this specification, 5 millilter injection blow-molded vials
(SiO.sub.2 Medical Products) and borosilicate glass 5 milliliter
vials (Schott) are coated with a composite barrier coating or
layer.
[0497] Utilizing A1 and A2 Adhesion assessment methods, adhesion
results (Table 4) are obtained.
[0498] (B2) Inventive Adhesion performance of Bilayer Coated (SiOx
barrier and p-OMCTS pH protective) coating on a COP 5 millilter
vial versus comparative borosilicate glass vial using A1 and A2
Adhesion Assessment Methods.
[0499] Using established SiO.sub.x coating procedures discussed
previously in Protocol for Coating Syringe Barrel Interior with
SiO.sub.x in this specification, 5 millilter injection blow-molded
vials (SiO.sub.2 Medical Products) and borosilicate glass 5
milliliter vials (Schott) were coated with a standard SiOx
composite barrier coating or layer and a standard pH protective
coating or layer.
[0500] Utilizing A1 and A2 Adhesion assessment methods, adhesion
results (Table 4) are obtained.
[0501] (B3) Inventive Adhesion performance of SiO.sub.x barrier
coating on a COP 1 millilter long staked needle syringe barrel
versus comparative borosilicate glass syringe barrel using A1 and
A2 Adhesion Assessment Methods.
[0502] Using the Protocol for Coating Syringe Barrel Interior with
SiO.sub.x in this specification, one millilter injection
blow-molded staked needle syringe barrel (SiO.sub.2 Medical
Products) and borosilicate glass syringe barrel (Becton-Dickenson,
silicone oil previously removed with hexane) were coated under
standard SiO.sub.x coating procedures.
[0503] Utilizing A1 and A2 Adhesion assessment methods, adhesion
results (Table 4) are obtained.
[0504] (B4) Inventive Adhesion performance of Bilayer Coated (SiOx
composite barrier coating or layer and p-OMCTS pH protective
coating or layer) coating on a thermoplastic vial versus
comparative borosilicate glass vial using A1 and A2 Adhesion
Assessment Methods.
[0505] Using the Protocol for Coating Syringe Barrel Interior with
SiO.sub.x in this specification, one mL (milliliter) injection
blow-molded staked needle syringe barrel (SiO.sub.2 Medical
Products) and borosilicate glass syringe barrel (Becton-Dickenson,
silicone oil previously removed with hexane) are coated under SiOx
composite barrier coating or layer and pH protective coating or
layer protocols as shown in this specification.
[0506] Utilizing A1 and A2 Adhesion assessment methods, adhesion
results (Table 5) are predicted.
PECVD Treated Pharmaceutical Packages or Other Vessels
Coated Pharmaceutical Packages or Other Vessels
[0507] Pharmaceutical packages or other vessels, such as a
prefilled syringe (schematically shown in FIG. 8) or a vial or
blister pack (schematically shown in FIGS. 9 and 10) are
contemplated having a composite barrier coating or layer such as
288 at least partially covered by a pH protective coating or layer
such as 286.
[0508] The pharmaceutical package 210 as shown in any embodiment,
for example FIGS. 8-10, comprises a vessel or vessel part such as
250; optionally a composite barrier coating or layer such as 288 on
the vessel or vessel part; a pH protective coating or layer such as
286 on the vessel, vessel part, or composite barrier coating or
layer; and a pharmaceutical composition or preparation such as 218
contained within the vessel.
[0509] The composite barrier coating or layer such as 288 can be an
SiO.sub.x composite barrier coating or layer applied as described
in any embodiment of this specification. For example, the composite
barrier coating or layer such as 288 of any embodiment can be
applied at a thickness of at least 2 nm, or at least 4 nm, or at
least 7 nm, or at least 10 nm, or at least 20 nm, or at least 30
nm, or at least 40 nm, or at least 50 nm, or at least 100 nm, or at
least 150 nm, or at least 200 nm, or at least 300 nm, or at least
400 nm, or at least 500 nm, or at least 600 nm, or at least 700 nm,
or at least 800 nm, or at least 900 nm. The composite barrier
coating or layer can be up to 1000 nm, or at most 900 nm, or at
most 800 nm, or at most 700 nm, or at most 600 nm, or at most 500
nm, or at most 400 nm, or at most 300 nm, or at most 200 nm, or at
most 100 nm, or at most 90 nm, or at most 80 nm, or at most 70 nm,
or at most 60 nm, or at most 50 nm, or at most 40 nm, or at most 30
nm, or at most 20 nm, or at most 10 nm, or at most 5 nm thick.
Specific thickness ranges composed of any one of the minimum
thicknesses expressed above, plus any equal or greater one of the
maximum thicknesses expressed above, are expressly contemplated.
The thickness of the SiO.sub.x or other composite barrier coating
or layer can be measured, for example, by transmission electron
microscopy (TEM), and its composition can be measured by X-ray
photoelectron spectroscopy (XPS). The pH protective coating or
layer described herein can be applied to a variety of
pharmaceutical packages or other vessels made from plastic or
glass, for example to plastic tubes, vials, and syringes.
[0510] The pH protective coating or layer such as 286 can be an
SiO.sub.xC.sub.y pH protective coating or layer applied as
described in any embodiment of this specification. For example, the
pH protective coating or layer such as 286 of any embodiment
comprises or consists essentially of a coating or layer of
SiO.sub.xC.sub.y applied over the composite barrier coating or
layer 288 to protect at least a portion of the composite barrier
coating or layer from the pharmaceutical preparation such as 218 in
FIGS. 8-10. The pH protective coating or layer such as 286 is
provided, for example, by applying one of the described precursors
on or in the vicinity of a substrate in a PECVD process, providing
a pH protective coating. The coating can be applied, for example,
at a thickness of 1 to 5000 nm, or 10 to 1000 nm, or 10 to 500 nm,
or 10 to 200 nm, or 20 to 100 nm, or 30 to 1000 nm, or 30 to 500 nm
thick, or 30 to 1000 nm, or 20 to 100 nm, or 80 to 150 nm, and
crosslinking or polymerizing (or both) the pH protective layer,
optionally in a PECVD process, to provide a protected surface.
[0511] Although not intending to be bound according to the accuracy
of the following theory, the inventors contemplate that the pH
protective coating or layer, applied over an SiO.sub.x barrier
layer on a vessel wall, functions at least in part by passivating
the SiO.sub.x barrier layer surface against attack by the contents
of the vessel, as well as providing a more resistant or sacrificial
independent layer to isolate the SiO.sub.x barrier layer from the
contents of the vessel. It is thus contemplated that the pH
protective coating or layer can be very thin, and even so improve
the shelf life of the pharmaceutical package.
[0512] A lubricity coating or layer can be applied after applying
an SiO.sub.x barrier layer and/or a pH protective coating or layer
to the inner or interior surface or to other parts of the
pharmaceutical package, as described in U.S. Pat. No.
7,985,188.
[0513] Thus, the coating or layer 90 can comprise a composite
barrier coating or layer of SiO.sub.x and a pH protective layer of
Si.sub.wO.sub.xC.sub.y (which for all embodiments in this
specification is equivalent to SiO.sub.xC.sub.y, since w=1) and
optionally in any embodiment further including a lubricity coating
or layer, each characterized as defined in this specification. As
another option, the composite barrier coating or layer of SiO.sub.x
can be deposited at a location more remote from the pH protective
coating or layer, with at least one intervening coating or layer of
another material.
[0514] Another expedient contemplated here, for adjacent layers of
SiO.sub.x and a lubricity and/or pH protective coating or layer, is
a graded composite of SiO.sub.x and Si.sub.wO.sub.xC.sub.y, or its
equivalent SiO.sub.xC.sub.y, as defined in the Definition Section.
A graded composite can be separate layers of a lubricity and/or pH
protective and/or barrier layer or coating with a transition or
interface of intermediate composition between them, or separate
layers of a lubricity and/or pH protective and/or hydrophobic layer
and SiO.sub.x with an intermediate distinct pH protective coating
or layer of intermediate composition between them, or a single
coating or layer that changes continuously or in steps from a
composition of a lubricity and/or pH protective and/or hydrophobic
layer to a composition more like SiO.sub.x, going through the pH
protective coating or layer in a normal direction.
[0515] The grade in the graded composite can go in either
direction. For example, the composition of SiO.sub.x can be applied
directly to the substrate and graduate to a composition further
from the surface of a pH protective coating or layer, and
optionally can further graduate to another type of coating or
layer, such as a hydrophobic coating or layer or a lubricity
coating or layer. Additionally, in any embodiment an adhesion
coating or layer, for example Si.sub.wO.sub.xC.sub.y, or its
equivalent SiO.sub.xC.sub.y, optionally can be applied directly to
the substrate before applying the barrier layer. A graduated pH
protective coating or layer is particularly contemplated if a layer
of one composition is better for adhering to the substrate than
another, in which case the better-adhering composition can, for
example, be applied directly to the substrate. It is contemplated
that the more distant portions of the graded pH protective coating
or layer can be less compatible with the substrate than the
adjacent portions of the graded pH protective coating or layer,
since at any point the pH protective coating or layer is changing
gradually in properties, so adjacent portions at nearly the same
depth of the pH protective coating or layer have nearly identical
composition, and more widely physically separated portions at
substantially different depths can have more diverse properties. It
is also contemplated that a pH protective coating or layer portion
that forms a better barrier against transfer of material to or from
the substrate can be directly against the substrate, to prevent the
more remote pH protective coating or layer portion that forms a
poorer barrier from being contaminated with the material intended
to be barred or impeded by the barrier.
[0516] The applied coatings or layers, instead of being graded,
optionally can have sharp transitions between one layer and the
next, without a substantial gradient of composition. Such pH
protective coating or layer can be made, for example, by providing
the gases to produce a layer as a steady state flow in a non-plasma
state, then energizing the system with a brief plasma discharge to
form a coating or layer on the substrate. If a subsequent pH
protective coating or layer is to be applied, the gases for the
previous pH protective coating or layer are cleared out and the
gases for the next pH protective coating or layer are applied in a
steady-state fashion before energizing the plasma and again forming
a distinct layer on the surface of the substrate or its outermost
previous pH protective coating or layer, with little if any gradual
transition at the interface.
Vessel Made of Glass
[0517] Another embodiment is a pharmaceutical package 210 as shown
in any embodiment, for example FIGS. 8-10, comprising a vessel or
vessel part such as 214 or 250 made of glass; optionally a
composite barrier coating or layer such as 288 on the vessel or
vessel part; a pH protective coating or layer such as 286 on the
vessel, vessel part, or composite barrier coating or layer; and a
pharmaceutical composition or preparation such as 218 contained
within the vessel. In this embodiment the composite barrier coating
or layer is optional because a glass vessel wall in itself is an
extremely good barrier layer. It is contemplated to optionally
provide a barrier layer primarily to provide isolation: in other
words, to prevent contact and interchange of material of any kind,
such as ions of the glass or constituents of the pharmaceutical
composition or preparation between the vessel wall and the contents
of the vessel. The pH protective layer as defined in this
specification is contemplated to perform the isolation function
independently, at least to a degree. This protection layer is
contemplated to provide a useful function on glass in contact with
the pharmaceutical composition or preparation, as the present
working examples show that borosilicate glass, commonly used today
for pharmaceutical packaging, is dissolved by a fluid composition
having a pH exceeding 5. Particularly in applications where such
dissolution is disadvantageous or perceived to be disadvantageous,
the present pH protective coatings or layers will find utility.
[0518] The vessel can be made, for example of glass of any type
used in medical or laboratory applications, such as soda-lime
glass, borosilicate glass, or other glass formulations. One
function of a pH protective coating or layer on a glass vessel can
be to reduce the ingress of ions in the glass, either intentionally
or as impurities, for example sodium, calcium, or others, from the
glass to the contents of the pharmaceutical package or other
vessel, such as a reagent or blood in an evacuated blood collection
tube. Alternatively, a dual functional pH protective/lubricity
coating or layer can be used on a glass vessel in whole or in part,
such as selectively at surfaces contacted in sliding relation to
other parts, to provide lubricity, for example to ease the
insertion or removal of a stopper or passage of a sliding element
such as a piston in a syringe, as well as to provide the isolation
of a pH protective coating or layer. Still another reason to coat a
glass vessel, for example with a dual functional hydrophobic and pH
protective coating or layer, is to prevent a reagent or intended
sample for the pharmaceutical package or other vessel, such as
blood, from sticking to the wall of the vessel or an increase in
the rate of coagulation of the blood in contact with the wall of
the vessel, as well as to provide the isolation of a pH protective
coating or layer.
[0519] A related embodiment is a vessel as described in the
previous paragraphs, in which the composite barrier coating or
layer is made of soda lime glass, borosilicate glass, or another
type of glass coating or layer on a substrate.
Vessels Generally
[0520] A vessel with a pH protective coating as described herein
and/or prepared according to a method described herein can be used
for reception and/or storage and/or delivery of a compound or
composition. The compound or composition can be sensitive, for
example air-sensitive, oxygen-sensitive, sensitive to humidity
and/or sensitive to mechanical influences. It can be a biologically
active compound or composition, for example a pharmaceutical
preparation or medicament like insulin or a composition comprising
insulin. In another aspect, it can be a biological fluid,
optionally a bodily fluid, for example blood or a blood fraction.
In certain aspects of the present invention, the compound or
composition can be a product to be administrated to a subject in
need thereof, for example a product to be injected, like blood (as
in transfusion of blood from a donor to a recipient or
reintroduction of blood from a patient back to the patient) or
insulin.
[0521] A vessel with a pH protective coating as described herein
and/or prepared according to a method described herein can further
be used for protecting a compound or composition contained in its
interior space against mechanical and/or chemical effects of the
surface of the vessel material. For example, it can be used for
preventing or reducing precipitation and/or clotting or platelet
activation of the compound or a component of the composition, for
example insulin precipitation or blood clotting or platelet
activation.
[0522] It can further be used for protecting a compound or
composition contained in its interior against the environment
outside of the pharmaceutical package or other vessel, for example
by preventing or reducing the entry of one or more compounds from
the environment surrounding the vessel into the interior space of
the vessel. Such environmental compound can be a gas or liquid, for
example an atmospheric gas or liquid containing oxygen, air, and/or
water vapor.
[0523] A vessel with a pH protective coating as described herein
can also be evacuated and stored in an evacuated state. For
example, the pH protective coating or layer allows better
maintenance of the vacuum in comparison to a corresponding vessel
without a pH protective coating. In one aspect of this embodiment,
the vessel with a pH protective coating is a blood collection tube.
The tube can also contain an agent for preventing blood clotting or
platelet activation, for example EDTA or heparin.
[0524] Any of the above-described embodiments can be made, for
example, by providing as the vessel a length of tubing from about 1
cm to about 200 cm, optionally from about 1 cm to about 150 cm,
optionally from about 1 cm to about 120 cm, optionally from about 1
cm to about 100 cm, optionally from about 1 cm to about 80 cm,
optionally from about 1 cm to about 60 cm, optionally from about 1
cm to about 40 cm, optionally from about 1 cm to about 30 cm long,
and processing it with a probe electrode as described below.
Particularly for the longer lengths in the above ranges, it is
contemplated that relative motion between the probe and the vessel
can be useful during pH protective coating or layer formation. This
can be done, for example, by moving the vessel with respect to the
probe or moving the probe with respect to the vessel.
[0525] In these embodiments, it is contemplated that the composite
barrier coating or layer can be thinner or less complete than would
be preferred to provide the high gas barrier integrity needed in an
evacuated blood collection tube. In these embodiments, it is
contemplated that the pH protective coating or layer can be thinner
or less complete than would be preferred to provide the long shelf
life needed to store a liquid material in contact with the barrier
layer for an extended period.
[0526] As an optional feature of any of the foregoing embodiments
the vessel has a central axis.
[0527] As an optional feature of any of the foregoing embodiments
the vessel wall is sufficiently flexible to be flexed at least once
at 20.degree. C., without breaking the wall, over a range from at
least substantially straight to a bending radius at the central
axis of not more than 100 times as great as the outer diameter of
the vessel.
[0528] As an optional feature of any of the foregoing embodiments
the bending radius at the central axis is not more than 90 times as
great as, or not more than 80 times as great as, or not more than
70 times as great as, or not more than 60 times as great as, or not
more than 50 times as great as, or not more than 40 times as great
as, or not more than 30 times as great as, or not more than 20
times as great as, or not more than 10 times as great as, or not
more than 9 times as great as, or not more than 8 times as great
as, or not more than 7 times as great as, or not more than 6 times
as great as, or not more than 5 times as great as, or not more than
4 times as great as, or not more than 3 times as great as, or not
more than 2 times as great as, or not more than, the outer diameter
of the vessel.
[0529] As an optional feature of any of the foregoing embodiments
the vessel wall can be a fluid-contacting surface made of flexible
material.
[0530] As an optional feature of any of the foregoing embodiments
the vessel lumen can be the fluid flow passage of a pump.
[0531] As an optional feature of any of the foregoing embodiments
the vessel can be a blood bag adapted to maintain blood in good
condition for medical use.
[0532] As an optional feature of any of the foregoing embodiments
the polymeric material can be a silicone elastomer or a
thermoplastic polyurethane, as two examples, or any material
suitable for contact with blood, or with insulin.
[0533] In an optional embodiment, the vessel has an inner diameter
of at least 2 mm, or at least 4 mm.
[0534] As an optional feature of any of the foregoing embodiments
the vessel is a tube.
[0535] As an optional feature of any of the foregoing embodiments
the lumen has at least two open ends.
Vessel Containing Viable Blood, Having a pH Protective Coating or
Layer Deposited from an Organosilicon Precursor
[0536] Even another embodiment is a blood containing vessel.
Several non-limiting examples of such a vessel are a blood
transfusion bag, a blood sample collection vessel in which a sample
has been collected, the tubing of a heart-lung machine, a
flexible-walled blood collection bag, or tubing used to collect a
patient's blood during surgery and reintroduce the blood into the
patient's vasculature. If the vessel includes a pump for pumping
blood, a particularly suitable pump is a centrifugal pump or a
peristaltic pump. The vessel has a wall; the wall has an inner or
interior surface defining a lumen. The inner or interior surface of
the wall has an at least partial pH protective coating or layer of
a pH protective layer, which optionally also presents a hydrophobic
surface. The pH protective coating or layer can be as thin as
monomolecular thickness or as thick as about 1000 nm. The vessel
contains blood viable for return to the vascular system of a
patient disposed within the lumen in contact with the hydrophobic
layer.
[0537] An embodiment is a blood containing vessel including a wall
and having an inner or interior surface defining a lumen. The inner
or interior surface has an at least partial pH protective coating
or layer that optionally also presents a hydrophobic surface. The
pH protective coating or layer can also comprise or consist
essentially of SiO.sub.xC.sub.y where x and y are as defined in
this specification. The thickness of the hydrophobic coating or
layer is within the range from monomolecular thickness to about
1000 nm thick on the inner or interior surface. The vessel contains
blood viable for return to the vascular system of a patient
disposed within the lumen in contact with the hydrophobic coating
or layer.
pH Protective Coating or Layer Deposited from an Organosilicon
Precursor Reduces Clotting or Platelet Activation of Blood in the
Vessel
[0538] Another embodiment is a vessel having a wall. The wall has
an inner or interior surface defining a lumen and has an at least
partial pH protective coating or layer that presents a hydrophobic
surface, where optionally x and y are as previously defined. The
thickness of the pH protective coating or layer is from
monomolecular thickness to about 1000 nm thick on the inner or
interior surface. The pH protective coating or layer is effective
to reduce the clotting or platelet activation of blood exposed to
the inner or interior surface, compared to the same type of wall
uncoated with a hydrophobic layer.
[0539] It is contemplated that the incorporation of a hydrophobic
layer will reduce the adhesion or clot forming tendency of the
blood, as compared to its properties in contact with an unmodified
polymeric or SiO.sub.x surface. This property is contemplated to
reduce or potentially eliminate the need for treating the blood
with heparin, as by reducing the necessary blood concentration of
heparin in a patient undergoing surgery of a type requiring blood
to be removed from the patient and then returned to the patient, as
when using a heart-lung machine during cardiac surgery. It is
contemplated that this will reduce the complications of surgery
involving the passage of blood through such a pharmaceutical
package or other vessel, by reducing the bleeding complications
resulting from the use of heparin.
[0540] Another embodiment is a vessel including a wall and having
an inner or interior surface defining a lumen. The inner or
interior surface has an at least partial pH protective coating or
layer that presents a hydrophobic surface, the thickness of the pH
protective coating or layer being from monomolecular thickness to
about 1000 nm thick on the inner or interior surface, the pH
protective coating or layer being effective to reduce the clotting
or platelet activation of blood exposed to the inner or interior
surface.
Vessel Containing Viable Blood, Having a pH Protective Coating or
Layer of Group III or IV Element
[0541] Another embodiment is a blood containing vessel having a
wall having an inner or interior surface defining a lumen. The
inner or interior surface has an at least partial pH protective
coating or layer of a composition comprising one or more elements
of Group III, one or more elements of Group IV, or a combination of
two or more of these. The thickness of the pH protective coating or
layer is between monomolecular thickness and about 1000 nm thick,
inclusive, on the inner or interior surface. The vessel contains
blood viable for return to the vascular system of a patient
disposed within the lumen in contact with the pH protective coating
or layer.
pH Protective Coating or Layer of Group III or IV Element Reduces
Clotting or Platelet Activation of Blood in the Vessel
[0542] Optionally, in the vessel of the preceding paragraph, the pH
protective coating or layer of the Group III or IV Element is
effective to reduce the clotting or platelet activation of blood
exposed to the inner or interior surface of the vessel wall.
Pharmaceutical Delivery Vessels
[0543] A vessel with a pH protective coating or vessel as described
herein can be used for preventing or reducing the escape of a
compound or composition contained in the vessel into the
environment surrounding the vessel.
[0544] Further uses of the pH protective coating or layer and
vessel as described herein, which are apparent from any part of the
description and claims, are also contemplated.
Common Conditions for all Embodiments
[0545] In any embodiment contemplated here, many common conditions
can be used, for example any of the following, in any combination.
Alternatively, any different conditions described elsewhere in this
specification or claims can be employed.
I. Coating Receiver of any Embodiment
Vessel of any Embodiment
[0546] The vessel can be a sample collection tube, for example a
blood collection tube, or a syringe, or a syringe part, for example
a barrel or piston or plunger; a vial; a conduit; or a cuvette. The
substrate can be a closed-ended tube, for example a medical sample
collection tube. The substrate can be the inside wall of a vessel
having a lumen, the lumen having a void volume of from 0.5 to 50
mL, optionally from 1 to 10 mL, optionally from 0.5 to 5 mL,
optionally from 1 to 3 mL. The substrate surface can be part or all
of the inner or interior surface of a vessel having at least one
opening and an inner or interior surface, and wherein the gaseous
reactant, also known in any embodiment as a precursor feed, fills
the interior lumen of the vessel and the plasma can be generated in
part or all of the interior lumen of the vessel.
Syringe and Parts
[0547] The substrate can be a syringe barrel. The syringe barrel
can have a plunger sliding surface and the pH protective coating or
layer can be disposed on at least a portion of the plunger sliding
surface. The pH protective coating or layer can be a lubricity
and/or pH protective coating. The lubricity and/or pH protective
coating or layer can be on the barrel inner or interior surface.
The lubricity and/or pH protective coating or layer can be on the
plunger. In a particular aspect, the substrate is a staked needle
syringe or part of a staked needle syringe.
Vessel to Receive Stopper
[0548] The substrate can be a stopper receiving surface in the
mouth of a vessel. The substrate can be a generally conical or
cylindrical inner or interior surface of an opening of a vessel
adapted to receive a stopper.
Stopper
[0549] The substrate can be a sliding surface of a stopper. The
substrates can be coated by providing a multiplicity of the
stoppers located in a single substantially evacuated vessel. The
chemical vapor deposition can be plasma-enhanced chemical vapor
deposition and the stopper can be contacted with the plasma. The
chemical vapor deposition can be plasma-enhanced chemical vapor
deposition. The plasma can be formed upstream of the stopper,
producing plasma product, and the plasma product can be contacted
with the stopper.
[0550] A closure can define a substrate coated with a pH protective
coating or layer, optionally a stopper coated with a lubricity
and/or pH protective coating. The substrate can be a closure seated
in a vessel defining a lumen and a surface of the closure facing
the lumen can be coated with the pH protective coating or
layer.
[0551] The pH protective coating or layer can be effective to
reduce the transmission of a metal ion constituent of the stopper
into the lumen of the vessel.
Substrate of any Embodiment
[0552] The substrate can be a vessel wall. A portion of the vessel
wall in contact with a wall-contacting surface of a closure can be
coated with the pH protective coating or layer. The pH protective
coating or layer can be a composite of material having first and
second layers. The first coating or layer can interface with the
elastomeric stopper. The first layer of the pH protective coating
or layer can be effective to reduce the transmission of one or more
constituents of the stopper into the vessel lumen. The second pH
protective coating or layer can interface with the inner wall of
the vessel. The second layer can be effective to reduce friction
between the stopper and the inner wall of the vessel when the
stopper is seated on the vessel.
[0553] Alternatively, the first and second layers of any embodiment
can be defined by a pH protective coating or layer of graduated
properties containing carbon and hydrogen, in which the proportions
of carbon and hydrogen are less in the first coating or layer
(applied to the substrate) than in the second coating or layer
(exposed to the contents of the vessel).
[0554] The pH protective coating or layer of any embodiment can be
applied by plasma enhanced chemical vapor deposition.
[0555] The substrate of any embodiment can comprise glass,
alternatively a polymer, alternatively a polycarbonate polymer,
alternatively an olefin polymer, alternatively a cyclic olefin
copolymer, alternatively a polypropylene polymer, alternatively a
polyester polymer, alternatively a polyethylene terephthalate
polymer, alternatively a polyethylene naphthalate polymer,
alternatively a combination, composite or blend of any two or more
of the above materials.
II. Gaseous Reactant or Process Gas Limitations of any
Embodiment
Deposition Conditions of any Embodiment
[0556] The plasma for PECVD, if used, can be generated at reduced
pressure and the reduced pressure can be less than 300 mTorr,
optionally less than 200 mTorr, even optionally less than 100
mTorr. The physical and chemical properties of the pH protective
coating or layer can be set by setting the ratio of 02 to the
organosilicon precursor in the gaseous reactant, and/or by setting
the electric power used for generating the plasma.
Relative Proportions of Gases of any Embodiment
[0557] The process gas can contain this ratio of gases for
preparing a lubricity and/or pH protective coating or layer: [0558]
from 0.5 to 10 standard volumes of the precursor; [0559] from 1 to
100 standard volumes of a carrier gas, [0560] from 0.1 to 10
standard volumes of an oxidizing agent. alternatively this ratio:
[0561] from 1 to 6 standard volumes of the precursor; [0562] from 1
to 80 standard volumes of a carrier gas, [0563] from 0.1 to 2
standard volumes of an oxidizing agent. alternatively this ratio:
[0564] from 2 to 4 standard volumes, of the precursor; [0565] from
1 to 100 standard volumes of a carrier gas, [0566] from 0.1 to 2
standard volumes of an oxidizing agent. alternatively this ratio:
[0567] from 1 to 6 standard volumes of the precursor; [0568] from 3
to 70 standard volumes, of a carrier gas, [0569] from 0.1 to 2
standard volumes of an oxidizing agent. alternatively this ratio:
[0570] from 2 to 4 standard volumes, of the precursor; [0571] from
3 to 70 standard volumes of a carrier gas, [0572] from 0.1 to 2
standard volumes of an oxidizing agent. alternatively this ratio:
[0573] from 1 to 6 standard volumes of the precursor; [0574] from 1
to 100 standard volumes of a carrier gas, [0575] from 0.2 to 1.5
standard volumes of an oxidizing agent. alternatively this ratio:
[0576] z from 2 to 4 standard volumes, of the precursor; [0577]
from 1 to 100 standard volumes of a carrier gas, [0578] from 0.2 to
1.5 standard volumes of an oxidizing agent. alternatively this
ratio: [0579] from 1 to 6 standard volumes of the precursor; [0580]
from 3 to 70 standard volumes of a carrier gas, [0581] from 0.2 to
1.5 standard volumes of an oxidizing agent. alternatively this
ratio: [0582] from 2 to 4 standard volumes of the precursor; [0583]
from 3 to 70 standard volumes of a carrier gas, [0584] from 0.2 to
1.5 standard volumes of an oxidizing agent. alternatively this
ratio: [0585] from 1 to 6 standard volumes of the precursor; [0586]
from 1 to 100 standard volumes of a carrier gas, [0587] from 0.2 to
1 standard volumes of an oxidizing agent. alternatively this ratio:
[0588] from 2 to 4 standard volumes of the precursor; [0589] from 1
to 100 standard volumes of a carrier gas, [0590] from 0.2 to 1
standard volumes of an oxidizing agent. alternatively this ratio:
[0591] from 1 to 6 standard volumes of the precursor; [0592] from 3
to 70 standard volumes of a carrier gas, [0593] from 0.2 to 1
standard volumes of an oxidizing agent. alternatively this ratio:
[0594] 2 to 4 standard volumes, of the precursor; [0595] from 3 to
70 standard volumes of a carrier gas, [0596] from 0.2 to 1 standard
volumes of an oxidizing agent. alternatively this ratio: [0597]
from 1 to 6 standard volumes of the precursor; [0598] from 5 to 100
standard volumes of a carrier gas, [0599] from 0.1 to 2 standard
volumes of an oxidizing agent. alternatively this ratio: [0600]
from 2 to 4 standard volumes, of the precursor; [0601] from 5 to
100 standard volumes of a carrier gas, [0602] from 0.1 to 2
standard volumes [0603] of an oxidizing agent. alternatively this
ratio: [0604] from 1 to 6 standard volumes of the precursor; [0605]
from 10 to 70 standard volumes, of a carrier gas, [0606] from 0.1
to 2 standard volumes of an oxidizing agent. alternatively this
ratio: [0607] from 2 to 4 standard volumes, of the precursor;
[0608] from 10 to 70 standard volumes of a carrier gas, [0609] from
0.1 to 2 standard volumes of an oxidizing agent. alternatively this
ratio: [0610] from 1 to 6 standard volumes of the precursor; [0611]
from 5 to 100 standard volumes of a carrier gas, [0612] from 0.5 to
1.5 standard volumes of an oxidizing agent. alternatively this
ratio: [0613] from 2 to 4 standard volumes, of the precursor;
[0614] from 5 to 100 standard volumes of a carrier gas, [0615] from
0.5 to 1.5 standard volumes of an oxidizing agent. alternatively
this ratio: [0616] from 1 to 6 standard volumes of the precursor;
[0617] from 10 to 70 standard volumes, of a carrier gas, [0618]
from 0.5 to 1.5 standard volumes of an oxidizing agent.
alternatively this ratio: [0619] from 2 to 4 standard volumes of
the precursor; [0620] from 10 to 70 standard volumes of a carrier
gas, [0621] from 0.5 to 1.5 standard volumes of an oxidizing agent.
alternatively this ratio: [0622] from 1 to 6 standard volumes of
the precursor; [0623] from 5 to 100 standard volumes of a carrier
gas, [0624] from 0.8 to 1.2 standard volumes of an oxidizing agent.
alternatively this ratio: [0625] from 2 to 4 standard volumes of
the precursor; [0626] from 5 to 100 standard volumes of a carrier
gas, [0627] from 0.8 to 1.2 standard volumes of an oxidizing agent.
alternatively this ratio: [0628] from 1 to 6 standard volumes of
the precursor; [0629] from 10 to 70 standard volumes of a carrier
gas, [0630] from 0.8 to 1.2 standard volumes of an oxidizing agent.
alternatively this ratio: [0631] 2 to 4 standard volumes, of the
precursor; [0632] from 10 to 70 standard volumes of a carrier gas,
[0633] from 0.8 to 1.2 standard volumes of an oxidizing agent.
Precursor of any Embodiment
[0634] The organosilicon precursor has been described elsewhere in
this description.
[0635] The organosilicon compound can in certain aspects,
particularly when a lubricity and/or pH protective coating or layer
is formed, comprise octamethylcyclotetrasiloxane (OMCTS). The
organosilicon compound for any embodiment of said certain aspects
can consist essentially of octamethylcyclotetrasiloxane (OMCTS).
The organosilicon compound can in certain aspects, particularly
when a barrier coating or layer is formed, be or comprise
hexamethyldisiloxane.
[0636] The reaction gas can also include a hydrocarbon. The
hydrocarbon can comprise methane, ethane, ethylene, propane,
acetylene, or a combination of two or more of these.
[0637] The organosilicon precursor can be delivered at a rate of
equal to or less than 10 sccm, optionally equal to or less than 6
sccm, optionally equal to or less than 2.5 seem, optionally equal
to or less than 1.5 sccm, optionally equal to or less than 1.25
seem. Larger pharmaceutical packages or other vessels or other
changes in conditions or scale may require more or less of the
precursor. The precursor can be provided at less than 1 Torr
absolute pressure.
Carrier Gas of any Embodiment
[0638] The carrier gas can comprise or consist of an inert gas, for
example argon, helium, xenon, neon, another gas that is inert to
the other constituents of the process gas under the deposition
conditions, or any combination of two or more of these.
Oxidizing Gas of any Embodiment
[0639] The oxidizing gas can comprise or consist of oxygen (O.sub.2
and/or O.sub.3 (commonly known as ozone)), nitrous oxide, or any
other gas that oxidizes the precursor during PECVD at the
conditions employed. The oxidizing gas comprises about 1 standard
volume of oxygen. The gaseous reactant or process gas can be at
least substantially free of nitrogen.
III. Plasma of any Embodiment
[0640] The plasma of any PECVD embodiment can be formed in the
vicinity of the substrate. The plasma can in certain cases,
especially when preparing a composite barrier coating or layer, be
a non-hollow-cathode plasma. In other certain cases, especially
when preparing a lubricity coating or layer, a non-hollow-cathode
plasma is not desired. The plasma can be formed from the gaseous
reactant at reduced pressure. Sufficient plasma generation power
input can be provided to induce pH protective coating or layer
formation on the substrate.
IV. RF Power of any Embodiment
[0641] The precursor can be contacted with a plasma made by
energizing the vicinity of the precursor with electrodes powered at
a frequency of 10 kHz to 2.45 GHz, alternatively from about 13 to
about 14 MHz.
[0642] The precursor can be contacted with a plasma made by
energizing the vicinity of the precursor with electrodes powered at
radio frequency, optionally at a frequency of from 10 kHz to less
than 300 MHz, optionally from 1 to 50 MHz, even optionally from 10
to 15 MHz, optionally at 13.56 MHz.
[0643] The precursor can be contacted with a plasma made by
energizing the vicinity of the precursor with electrodes supplied
with electric power at from 0.1 to 25 W, optionally from 1 to 22 W,
optionally from 1 to 10 W, even optionally from 1 to 5 W,
optionally from 2 to 4 W, for example of 3 W, optionally from 3 to
17 W, even optionally from 5 to 14 W, for example 6 or 7.5 W,
optionally from 7 to 11 W, for example of 8 W, from 0.1 to 500 W,
optionally from 0.1 to 400 W, optionally from 0.1 to 300 W,
optionally from 1 to 250 W, optionally from 1 to 200 W, even
optionally from 10 to 150 W, optionally from 20 to 150 W, for
example of 40 W, optionally from 40 to 150 W, even optionally from
60 to 150 W.
[0644] The precursor can be contacted with a plasma made by
energizing the vicinity of the precursor with electrodes supplied
with electric power density at less than 10 W/ml of plasma volume,
alternatively from 6 W/ml to 0.1 W/ml of plasma volume,
alternatively from 5 W/ml to 0.1 W/ml of plasma volume,
alternatively from 4 W/ml to 0.1 W/ml of plasma volume,
alternatively from 2 W/ml to 0.2 W/ml of plasma volume,
alternatively from 10 W/ml to 50 W/ml, optionally from 20 W/ml to
40 W/ml.
[0645] The plasma can be formed by exciting the reaction mixture
with electromagnetic energy, alternatively microwave energy.
V. Other Process Options of any Embodiment
[0646] The applying step for applying a pH protective coating or
layer to the substrate can be carried out by vaporizing the
precursor and providing it in the vicinity of the substrate.
[0647] The chemical vapor deposition employed can be PECVD and the
deposition time can be from 1 to 30 sec, alternatively from 2 to 10
sec, alternatively from 3 to 9 sec. The purposes for optionally
limiting deposition time can be to avoid overheating the substrate,
to increase the rate of production, and to reduce the use of
process gas and its constituents. The purposes for optionally
extending deposition time can be to provide a thicker pH protective
coating or layer for particular deposition conditions.
VI. pH Protective Coating or Layer Properties of any Embodiment
Hydrophobicity Properties of any Embodiment
[0648] An embodiment can be carried out under conditions effective
to form a hydrophobic pH protective coating or layer on the
substrate. Optionally, the hydrophobic characteristics of the pH
protective coating or layer can be set by setting the ratio of the
02 to the organosilicon precursor in the gaseous reactant, and/or
by setting the electric power used for generating the plasma.
Optionally, the pH protective coating or layer can have a lower
wetting tension than the uncoated surface, optionally a wetting
tension of from 20 to 72 dyne/cm, optionally from 30 to 60
dynes/cm, optionally from 30 to 40 dynes/cm, optionally 34 dyne/cm.
Optionally, the pH protective coating or layer can be more
hydrophobic than the uncoated surface.
Thickness of any Embodiment
[0649] Optionally, the pH protective coating or layer can have a
thickness determined by transmission electron microscopy (TEM), of
any amount stated in this disclosure.
Composition of any Embodiment
[0650] Optionally, the lubricity and/or pH protective coating or
layer can be composed of Si.sub.wO.sub.xC.sub.yH.sub.z (or its
equivalent SiO.sub.xC.sub.y) or Si.sub.wN.sub.xC.sub.yH.sub.z or
its equivalent SiN.sub.xC.sub.y), each as defined previously. The
atomic ratio of Si:O:C can be determined by XPS (X-ray
photoelectron spectroscopy). Taking into account the H atoms, the
pH protective coating or layer may thus in one aspect have the
formula Si.sub.wO.sub.xC.sub.yH.sub.z, or its equivalent
SiO.sub.xC.sub.y, for example where w is 1, x is from about 0.5 to
about 2.4, y is from about 0.6 to about 3, and z is from about 2 to
about 9.
[0651] Typically, expressed as the formula Si.sub.wO.sub.xC.sub.y,
the atomic ratios of Si, O, and C are, as several options: [0652]
Si 100: O 50-150: C 90-200 (i.e. w=1, x=0.5 to 1.5, y=0.9 to 2);
[0653] Si 100: O 70-130: C 90-200 (i.e. w=1, x=0.7 to 1.3, y=0.9 to
2) [0654] Si 100: O 80-120: C 90-150 (i.e. w=1, x=0.8 to 1.2, y=0.9
to 1.5) [0655] Si 100: O 90-120: C 90-140 (i.e. w=1, x=0.9 to 1.2,
y=0.9 to 1.4), or [0656] Si 100: O 92-107: C 116-133 (i.e. w=1,
x=0.92 to 1.07, y=1.16 to 1.33).
[0657] Alternatively, the pH protective coating or layer can have
atomic concentrations normalized to 100% carbon, oxygen, and
silicon, as determined by X-ray photoelectron spectroscopy (XPS) of
less than 50% carbon and more than 25% silicon. Alternatively, the
atomic concentrations are from 25 to 45% carbon, 25 to 65% silicon,
and 10 to 35% oxygen. Alternatively, the atomic concentrations are
from 30 to 40% carbon, 32 to 52% silicon, and 20 to 27% oxygen.
Alternatively, the atomic concentrations are from 33 to 37% carbon,
37 to 47% silicon, and 22 to 26% oxygen.
[0658] Optionally, the atomic concentration of carbon in the pH
protective layer, normalized to 100% of carbon, oxygen, and
silicon, as determined by X-ray photoelectron spectroscopy (XPS),
can be greater than the atomic concentration of carbon in the
atomic formula for the organosilicon precursor. For example,
embodiments are contemplated in which the atomic concentration of
carbon increases by from 1 to 80 atomic percent, alternatively from
10 to 70 atomic percent, alternatively from 20 to 60 atomic
percent, alternatively from 30 to 50 atomic percent, alternatively
from 35 to 45 atomic percent, alternatively from 37 to 41 atomic
percent.
[0659] Optionally, the atomic ratio of carbon to oxygen in the pH
protective coating or layer can be increased in comparison to the
organosilicon precursor, and/or the atomic ratio of oxygen to
silicon can be decreased in comparison to the organosilicon
precursor.
[0660] Optionally, the pH protective coating or layer can have an
atomic concentration of silicon, normalized to 100% of carbon,
oxygen, and silicon, as determined by X-ray photoelectron
spectroscopy (XPS), less than the atomic concentration of silicon
in the atomic formula for the feed gas. For example, embodiments
are contemplated in which the atomic concentration of silicon
decreases by from 1 to 80 atomic percent, alternatively by from 10
to 70 atomic percent, alternatively by from 20 to 60 atomic
percent, alternatively by from 30 to 55 atomic percent,
alternatively by from 40 to 50 atomic percent, alternatively by
from 42 to 46 atomic percent.
[0661] As another option, a pH protective coating or layer is
contemplated that can be characterized by a sum formula wherein the
atomic ratio C:O can be increased and/or the atomic ratio Si:O can
be decreased in comparison to the sum formula of the organosilicon
precursor.
Other pH Protective Coating or Layer Properties of any
Embodiment
[0662] The pH protective coating or layer can have a density
between 1.25 and 1.65 g/cm.sup.3, alternatively between 1.35 and
1.55 g/cm.sup.3, alternatively between 1.4 and 1.5 g/cm.sup.3,
alternatively between 1.4 and 1.5 g/cm.sup.3, alternatively between
1.44 and 1.48 g/cm.sup.3, as determined by X-ray reflectivity
(XRR). Optionally, the organosilicon compound can be
octamethylcyclotetrasiloxane and the pH protective coating or layer
can have a density which can be higher than the density of a pH
protective coating or layer made from HMDSO as the organosilicon
compound under the same PECVD reaction conditions.
[0663] The pH protective coating or layer optionally can prevent or
reduce the precipitation of a compound or component of a
composition in contact with the pH protective coating or layer, in
particular can prevent or reduce insulin precipitation or blood
clotting, in comparison to the uncoated surface and/or to a barrier
coated surface using HMDSO as precursor.
[0664] The substrate can be a pharmaceutical package or other
vessel, for protecting a compound or composition contained or
received in the vessel with a pH protective coating against
mechanical and/or chemical effects of the surface of the uncoated
substrate.
[0665] The substrate can be a pharmaceutical package or other
vessel, for preventing or reducing precipitation and/or clotting of
a compound or a component of the composition in contact with the
inner or interior surface of the vessel. The compound or
composition can be a biologically active compound or composition,
for example a medicament, for example the compound or composition
can comprise insulin, wherein insulin precipitation can be reduced
or prevented. Alternatively, the compound or composition can be a
biological fluid, for example a bodily fluid, for example blood or
a blood fraction wherein blood clotting can be reduced or
prevented.
[0666] The pH protective coating or layer optionally can have an
RMS surface roughness value (measured by AFM) of from about 5 to
about 9, optionally from about 6 to about 8, optionally from about
6.4 to about 7.8. The Ra surface roughness value of the pH
protective coating or layer, measured by AFM, can be from about 4
to about 6, optionally from about 4.6 to about 5.8. The Rmax
surface roughness value of the pH protective coating or layer,
measured by AFM, can be from about 70 to about 160, optionally from
about 84 to about 142, optionally from about 90 to about 130.
VII. Product Made of Vessel Plus Contents, Optional for any
Embodiment
[0667] In any embodiment, the substrate can be a vessel having an
inner or interior surface defining a lumen and an exterior surface,
the pH protective coating or layer can be on the inner or interior
surface of the pharmaceutical package or other vessel, and the
vessel can contain a compound or composition in its lumen, for
example citrate or a citrate containing composition, or for example
insulin or an insulin containing composition. A prefilled syringe
is especially considered which contains injectable or other liquid
drugs like insulin.
EXAMPLES
[0668] The following Examples are in part already disclosed in EP 2
251 455. In order to avoid unnecessary repetition, not all of the
Examples in EP 2 251 455 A2 are repeated here, but explicit
reference is herewith made to them.
Basic Protocols for Forming and Coating Syringe Barrels
[0669] The pharmaceutical packages or other vessels tested in the
subsequent working examples were formed and coated according to the
following exemplary protocols, except as otherwise indicated in
individual examples. Particular parameter values given in the
following basic protocols, for example the electric power and
gaseous reactant or process gas flow, are typical values. When
parameter values were changed in comparison to these typical
values, this will be indicated in the subsequent working examples.
The same applies to the type and composition of the gaseous
reactant or process gas.
[0670] In some instances, the reference characters and Figures
mentioned in the following protocols and additional details can be
found in U.S. Pat. No. 7,985,188.
Protocol for Coating Syringe Barrel Interior with SiO.sub.x
[0671] The apparatus and protocol generally as found in U.S. Pat.
No. 7,985,188 can be used for coating syringe barrel interiors with
an SiO.sub.x composite barrier coating or layer, varied as follows.
5 ml vials are provided for barrier coating. The feed gas is a
mixture of 1.56 sccm of HMDSO (hexamethylenedisiloxane) and 20 sccm
of O.sub.2, with no carrier gas. The RF power profile is as
follows. The initial power level is 20 W, and the final power level
is 140 W. The power level is increased linearly from 20 W to 140 W
over a period of two seconds. The power level is then maintained at
140 W for 13 seconds, the remainder of the coating sequence. The
resulting SiO.sub.x composite barrier coating or layer is a minimum
of 40 nm and a maximum of 65 nm thick. High Resolution X-ray
Photoelectron Spectroscopy (XPS) typically shows the presence of an
interface, typically not more than 3 nm thick, between the
composite barrier coating or layer and the substrate having at
least 2 mol.% O.sub.3--Si--C covalent bonding, as a proportion of
the O.sub.3--Si--C covalent bonding plus SiO.sub.4 bonding. High
Resolution X-ray Photoelectron Spectroscopy (XPS) also shows the
interface between the composite barrier coating or layer and the
substrate has Si 2p peak broadening of at least 0.2 eV, compared to
the binding energy of SiO.sub.4 bonding.
Protocol for Coating Syringe Barrel Interior with OMCTS pH
Protective Coating
[0672] Syringe barrels already interior coated with a composite
barrier coating or layer of SiO.sub.x, as previously identified,
are further interior coated with a pH protective coating as
previously identified, generally following the protocols of U.S.
Pat. No. 7,985,188 for applying the lubricity coating or layer,
except with modified conditions in certain instances as noted in
the working examples. The conditions given here are for a COC
syringe barrel, and can be modified as appropriate for syringe
barrels made of other materials. The apparatus as generally shown
in FIGS. 3 and 4 is used to hold a syringe barrel with butt sealing
at the base of the syringe barrel. Additionally a cap is provided
that seals the end of the syringe barrel (illustrated in FIG.
3).
[0673] The syringe barrel is carefully moved into the sealing
position over the extended probe or counter electrode 108 and
pushed against a plasma screen. The plasma screen is fit snugly
around the probe or counter electrode 108 insuring good electrical
contact. The probe or counter electrode 108 is grounded to the
casing of the RF matching network.
[0674] The gas delivery port 110 is connected to a manual ball
valve or similar apparatus for venting, a thermocouple pressure
gauge and a bypass valve connected to the vacuum pumping line. In
addition, the gas system is connected to the gas delivery port 110
allowing the gaseous reactant or process gas,
octamethylcyclotetrasiloxane (OMCTS) (or the specific gaseous
reactant or process gas reported for a particular example) to be
flowed through the gas delivery port 110 (under process pressures)
into the interior of the syringe barrel.
[0675] The gas system is comprised of a commercially available
heated mass flow vaporization system that heats the OMCTS to about
100.degree. C. The heated mass flow vaporization system is
connected to liquid octamethylcyclotetrasiloxane (Alfa Aesar.RTM.
Part Number A12540, 98%). The OMCTS flow rate is set to the
specific organosilicon precursor flow reported for a particular
example. To ensure no condensation of the vaporized OMCTS flow past
this point, the gas stream is diverted to the pumping line when it
is not flowing into the interior of the COC syringe barrel for
processing.
[0676] Once the syringe barrel is installed, the vacuum pump valve
is opened to the vessel holder 50 and the interior of the COC
syringe barrel. A vacuum pump and blower comprise the vacuum pump
system. The pumping system allows the interior of the COC syringe
barrel to be reduced to pressure(s) of less than 100 mTorr while
the gaseous reactant or process gases is flowing at the indicated
rates.
[0677] Once the base vacuum level is achieved, the vessel holder 50
assembly is moved into the electrode 160 assembly. The gas stream
(OMCTS vapor) is flowed into the gas delivery port 110 (by
adjusting the 3-way valve from the pumping line to the gas delivery
port 110. Pressure inside the COC syringe barrel is approximately
140 mTorr as measured by a capacitance manometer (MKS) installed on
the pumping line near the valve that controls the vacuum. In
addition to the COC syringe barrel pressure, the pressure inside
the gas delivery port 110 and gas system is also measured with the
thermocouple vacuum gauge that is connected to the gas system. This
pressure is typically less than 6 Torr.
[0678] Once the gas is flowing to the interior of the COC syringe
barrel, the RF power supply is turned on to its fixed power level.
A 600 Watt RF power supply is used (at 13.56 MHz) at a fixed power
level indicated in a specific example. The RF power supply is
connected to an auto match which matches the complex impedance of
the plasma (to be created in the vessel) to the output impedance of
the RF power supply. The forward power is as stated and the
reflected power is 0 Watts so that the stated power is delivered to
the interior of the vessel. The RF power supply is controlled by a
laboratory timer and the power on time set to 10 seconds (or a
different time stated in a given example).
[0679] Upon initiation of the RF power, a uniform plasma is
established inside the interior of the vessel. The plasma is
maintained for the entire pH protective coating or layer time,
until the RF power is terminated by the timer. The plasma produces
a pH protective coating or layer on the interior of the vessel.
[0680] After pH protective coating, the gas flow is diverted back
to the vacuum line and the vacuum valve is closed. The vent valve
is then opened, returning the interior of the COC syringe barrel to
atmospheric pressure (approximately 760 Torr). The treated vessel
is then carefully removed from the vessel holder 50 assembly (after
moving the vessel holder 50 assembly out of the electrode 160
assembly).
[0681] A similar protocol is used, except using apparatus generally
like that of FIG. 1, for applying a pH protective coating or layer
to vials.
Protocol for Total Silicon Measurement
[0682] This protocol is used to determine the total amount of
silicon coatings present on the entire vessel wall. A supply of 0.1
N potassium hydroxide (KOH) aqueous solution is prepared, taking
care to avoid contact between the solution or ingredients and
glass. The water used is purified water, 18 M.OMEGA. quality. A
Perkin Elmer Optima Model 7300DV ICP-OES instrument is used for the
measurement except as otherwise indicated.
[0683] Each device (vial, syringe, tube, or the like) to be tested
and its cap and crimp (in the case of a vial) or other closure are
weighed empty to 0.001 g, then filled completely with the KOH
solution (with no headspace), capped, crimped, and reweighed to
0.001 g. In a digestion step, each vial is placed in a sonicating
water bath at 40.degree. C. for a minimum of 8-10 hours. The
digestion step is carried out to quantitatively remove the silicon
coatings from the vessel wall into the KOH solution. After this
digestion step, the vials are removed from the sonicating water
bath and allowed to cool to room temperature. The contents of the
vials are transferred into 15 ml ICP tubes. The total Si
concentration is run on each solution by ICP/OES following the
operating procedure for the ICP/OES.
[0684] The total Si concentration is reported as parts per billion
of Si in the KOH solution. This concentration represents the total
amount of silicon coatings that were on the vessel wall before the
digestion step was used to remove it.
[0685] The total Si concentration can also be determined for fewer
than all the silicon layers on the vessel, as when an SiO.sub.x
barrier layer is applied, an SiO.sub.xC.sub.y second layer (for
example, a lubricity layer or a pH protective coating or layer) is
then applied, and it is desired to know the total silicon
concentration of just the SiO.sub.xC.sub.y layer. This
determination is made by preparing two sets of vessels, one set to
which only the SiO.sub.x layer is applied and the other set to
which the same SiO.sub.x layer is applied, followed by the
SiO.sub.xC.sub.y layer or other layers of interest. The total Si
concentration for each set of vessels is determined in the same
manner as described above. The difference between the two Si
concentrations is the total Si concentration of the
SiO.sub.xC.sub.y second layer.
Protocol for Measuring Dissolved Silicon in a Vessel
[0686] In some of the working examples, the amount of silicon
dissolved from the wall of the vessel by a test solution is
determined, in parts per billion (ppb), for example to evaluate the
dissolution rate of the test solution. This determination of
dissolved silicon is made by storing the test solution in a vessel
provided with an SiO.sub.x and/or SiO.sub.xC.sub.y coating or layer
under test conditions, then removing a sample of the solution from
the vessel and testing the Si concentration of the sample. The test
is done in the same manner as the Protocol for Total Silicon
Measurement, except that the digestion step of that protocol is
replaced by storage of the test solution in the vessel as described
in this protocol. The total Si concentration is reported as parts
per billion of Si in the test solution
Protocol for Determining Average Dissolution Rate
[0687] The average dissolution rates reported in the working
examples are determined as follows. A series of test vessels having
a known total total silicon measurement are filled with the desired
test solution analogous to the manner of filling the vials with the
KOH solution in the Protocol for Total Silicon Measurement. (The
test solution can be a physiologically inactive test solution as
employed in the present working examples or a physiologically
active pharmaceutical preparation intended to be stored in the
vessels to form a pharmaceutical package). The test solution is
stored in respective vessels for several different amounts of time,
then analyzed for the Si concentration in parts per billion in the
test solution for each storage time. The respective storage times
and Si concentrations are then plotted. The plots are studied to
find a series of substantially linear points having the steepest
slope.
[0688] The plot of dissolution amount (ppb Si) versus days
decreases in slope with time. It is believed that the dissolution
rate is not flattening out because the Si layer has been fully
digested by the test solution.
[0689] For the PC194 test data in Table 2, linear plots of
dissolution versus time data are prepared by using a least squares
linear regression program to find a linear plot corresponding to
the first five data points of each of the experimental plots. The
slope of each linear plot is then determined and reported as
representing the average dissolution rate applicable to the test,
measured in parts per billion of Si dissolved in the test solution
per unit of time.
Protocol for Determining Calculated Shelf Life
[0690] The calculated shelf life values reported in the working
examples below are determined by extrapolation of the total silicon
measurements and average dissolution rates, respectively determined
as described in the Protocol for Total Silicon Measurement and the
Protocol for Determining Average Dissolution Rate. The assumption
is made that under the indicated storage conditions the
SiO.sub.xC.sub.y pH protective coating will be removed at the
average dissolution rate until the coating is entirely removed.
Thus, the total silicon measurement for the vessel, divided by the
dissolution rate, gives the period of time required for the test
solution to totally dissolve the SiO.sub.xC.sub.y coating. This
period of time is reported as the calculated shelf life. Unlike
commercial shelf life calculations, no safety factor is calculated.
Instead, the calculated shelf life is the calculated time to
failure.
[0691] It should be understood that because the plot of ppb Si
versus hours decreases in slope with time, an extrapolation from
relatively short measurement times to relatively long calculated
shelf lives is believed to be a "worst case" test that tends to
underestimate the calculated shelf life actually obtainable.
Examples 1-4
[0692] Syringe samples were produced as follows. A COC 8007
extended barrel syringe was produced according to the Protocol for
Forming COC Syringe Barrel. An SiO.sub.x barrier coating or layer
is applied to some of the syringes according to the Protocol for
coating COC Syringe Barrel Interior with SiO.sub.x. A lubricity
and/or pH protective coating or layer is applied to the SiO.sub.x
coated syringes according to the Protocol for Coating COC Syringe
Barrel Interior with OMCTS Lubricity Coating, modified as follows.
The OMCTS was supplied from a vaporizer, due to its low volatility.
Argon carrier gas was used. The process conditions were set to the
following: [0693] OMCTS--3 sccm [0694] Argon gas--65 sccm [0695]
Power--6 watts [0696] Time--10 seconds
[0697] Several syringes are then tested for lubricity using a
Genesis Packaging Plunger Force Tester (Model SFT-01 Syringe Force
Tester, manufactured by Genesis Machinery, Lionville, Pa.)
according to the Protocol for Lubricity Testing. Both the
initiation force and maintenance forces (in Newtons) were noted
relative to an uncoated sample, and expected data based on similar
experiments are reported in Table 4.
[0698] Syringes coated with silicon oil are included as a reference
since this is the current industry standard.
[0699] The lubricity coatings produced according to these working
examples also function as pH protective coatings or layers to
increase the shelf life of the vessels, compared to similar vessels
provided with a composite barrier coating or layer but no lubricity
coating or layer.
Examples 5-8
[0700] Syringe samples are produced as follows. A COC 8007 extended
barrel syringe was produced according to the Protocol for Forming
COC Syringe Barrel. An SiO.sub.x pH protective coating or layer is
applied to the syringe barrels according to the Protocol for
Coating COC Syringe Barrel Interior with SiO.sub.x. A lubricity
and/or pH protective coating or layer is applied to the SiO.sub.x
coated syringes according to the Protocol for Coating COC Syringe
Barrel Interior with OMCTS, modified as follows. Argon carrier gas
and oxygen are used where noted in Table 6. The process conditions
are set to the following, or as indicated in Table 6: [0701]
OMCTS--3 sccm (when used) [0702] Argon gas--7.8 sccm (when used)
[0703] Oxygen 0.38 sccm (when used) [0704] Power--3 watts [0705]
Power on time--10 seconds
[0706] The syringes of Examples 5 and 6 prepared under these
conditions. The syringes of Example are 7 prepared under these
conditions except without a lubricity and/or pH protective coating
or layer, and the syringes of Example 8 (a commercial syringe
coated with silicon oil) are then tested for lubricity and/or pH
protective coatings using a Genesis Packaging Plunger Force Tester
according to the Protocol for Lubricity Testing. Both the
initiation force and maintenance forces (in Newtons) are noted
relative to an uncoated sample, and expected data based on similar
experiments are reported in Table 6. Syringes coated with silicon
oil were included as a reference since this is the current industry
standard.
[0707] The lubricity results predicted in Table 6 (Initiation Force
and Maintenance Force), illustrate under these test conditions as
well that the lubricity and/or pH protective coating or layer on
Syringes E and F are expected to markedly improve their lubricity
compared to Syringes G which lack any lubricity and/or pH
protective coating or layer. The lubricity and/or pH protective
coating or layer on the syringes of Examples 5 and 6 also are
expected to markedly improve their lubricity compared to the
syringes of Example 8, which contain the standard lubricity coating
or layer in the industry.
[0708] The syringes of Examples 5-7 are also tested to determine
total extractable silicon levels (representing extraction of the
organosilicon-based PECVD pH protective coating or layer) using the
Protocol for Measuring Dissolved Silicon in a Vessel, modified and
supplemented as shown in this example.
[0709] The silicon is extracted using saline water digestion. The
tip of each syringe plunger is covered with PTFE tape to prevent
extracting material from the elastomeric tip material, then
inserted into the syringe barrel base. The syringe barrel is filled
with two milliliters of 0.9% aqueous saline solution via a
hypodermic needle inserted through the Luer tip of the syringe.
This is an appropriate test for extractables because many prefilled
syringes are used to contain and deliver saline solution. The Luer
tip is plugged with a piece of PTFE beading of appropriate
diameter. The syringe is set into a PTFE test stand with the Luer
tip facing up and placed in an oven at 50.degree. C. for 72
hours.
[0710] Then, either a static or a dynamic mode is used to remove
the saline solution from the syringe barrel. According to the
static mode indicated in Table 6, the syringe plunger is removed
from the test stand, and the fluid in the syringe is decanted into
a vessel. According to the dynamic mode indicated in Table 6, the
Luer tip seal is removed and the plunger is depressed to push fluid
through the syringe barrel and expel the contents into a vessel. In
either case, the fluid obtained from each syringe barrel is brought
to a volume of 50 ml using 18.2M.OMEGA.-cm deionized water and
further diluted by a factor of 2 to minimize sodium background
during analysis. The CVH barrels contain two milliliters and the
commercial barrels contain 2.32 milliliters.
[0711] Next, the fluid recovered from each syringe is tested for
extractable silicon using the Protocol for Measuring Dissolved
Silicon in a Vessel. The instrument used is a Perkin Elmer Elan DRC
II equipped with a Cetac ASX-520 autosampler. The following ICP-MS
conditions are employed: [0712] Nebulizer: Quartz Meinhardt [0713]
Spray Chamber: Cyclonic [0714] RF (radio frequency) power: 1550
Watts [0715] Argon (Ar) Flow: 15.0 L/min [0716] Auxiliary Ar Flow:
1.2 L/min [0717] Nebulizer Gas Flow: 0.88 L/min [0718] Integration
time: 80 sec [0719] Scanning mode: Peak hopping [0720] RPq (The RPq
is a rejection parameter) for Cerium as CeO (m/z 156: <2%
[0721] Aliquots from aqueous dilutions obtained from the syringes
of Examples 5-7 are injected and analyzed for Si in concentration
units of micrograms per liter. The expected results of this test,
based on similar testing, are shown in Table 6. While the results
are not quantitative, they do indicate that extractables from the
lubricity and/or pH protective coating or layer are not clearly
higher than the extractables for the SiOx barrier layer only. Also,
the static mode produced far less extractables than the dynamic
mode, which was expected.
Comparative Example 9
Dissolution of SiO.sub.x Coating Versus pH
[0722] The Protocol for Measuring Dissolved Silicon in a Vessel is
followed, except as modified here. Test solutions--50 mM buffer
solutions at pH 3, 6, 7, 8, 9, and 12 are prepared. Buffers are
selected having appropriate pKa values to provide the pH values
being studied. A potassium phosphate buffer is selected for pH 3,
7, 8 and 12, a sodium citrate buffer is utilized for pH 6 and tris
buffer is selected for pH 9. 3 ml of each test solution is placed
in borosilicate glass 5 ml pharmaceutical vials and SiO.sub.x
coated 5 ml thermoplastic pharmaceutical vials. The vials are all
closed with standard coated stoppers and crimped. The vials are
placed in storage at 20-25.degree. C. and pulled at various time
points for inductively coupled plasma spectrometer (ICP) analysis
of Si content in the solutions contained in the vials, in parts per
billion (ppb) by weight, for different storage times.
[0723] The Protocol for Determining Average Dissolution Rate Si
content is used to monitor the rate of glass dissolution, except as
modified here. The data is plotted to determine an average rate of
dissolution of borosilicate glass or SiO.sub.x coating at each pH
condition.
[0724] The rate of Si dissolution in ppb is converted to a
predicted thickness (nm) rate of Si dissolution by determining the
total weight of Si removed, then using a surface area calculation
of the amount of vial surface (11.65 cm.sup.2) exposed to the
solution and a density of SiO.sub.x of 2.2 g/cm.sup.3 The predicted
initial thickness of the coating is about 36 nm at pH 5, about 80
nm at pH 6, about 230 nm at pH 7, about 400 nm at pH 7.5, about 750
nm at pH 8, and about 2600 nm at pH 9.
[0725] The coating thicknesses represent atypically harsh case
scenarios for pharma and biotech products. Most biotech products
and many pharma products are stored at refrigerated conditions and
none are typically recommended for storage above room temperature.
As a general rule of thumb, storage at a lower temperature reduces
the thickness required, all other conditions being equivalent.
[0726] The following conclusions are reached, based on this test.
First, the amount of dissolved Si in the SiO.sub.x coating or glass
increases exponentially with increasing pH. Second, the SiO.sub.x
coating dissolves more slowly than borosilicate glass at a pH lower
than 8. The SiO.sub.x coating shows a linear, monophasic
dissolution over time, whereas borosilicate glass tends to show a
more rapid dissolution in the early hours of exposure to solutions,
followed by a slower linear dissolution. This may be due to surface
accumulation of some salts and elements on borosilicate during the
forming process relative to the uniform composition of the
SiO.sub.x coating. This result incidentally suggests the utility of
an SiO.sub.x coating on the wall of a borosilicate glass vial to
reduce dissolution of the glass at a pH lower than 8. Third, PECVD
applied barrier coatings for vials in which pharmaceutical
preparations are stored will need to be adapted to the specific
pharmaceutical preparation and proposed storage conditions (or vice
versa), at least in some instances in which the pharmaceutical
preparation interacts with the barrier coating significantly.
Example 10
[0727] An experiment is conducted with vessels coated with
SiO.sub.x coating+OMCTS lubricity layer, to test the lubricity
layer for its functionality as a pH protective coating. The vessels
are 5 mL vials (the vials are normally filled with product to 5 mL;
their capacity without headspace, when capped, is about 7.5 mL)
composed of cyclic olefin co-polymer (COC, Topas.RTM.
6013M-07).
[0728] Sixty vessels are coated on their interior surfaces with an
SiO.sub.x coating produced in a plasma enhanced chemical vapor
deposition (PECVD) process using a HMDSO precursor gas according to
the Protocol for Coating Tube Interior with SiO.sub.x set forth
above, except that equipment suitable for coating a vial is used.
The following conditions are used. [0729] HMDSO flow rate: 0.47
sccm [0730] Oxygen flow rate: 7.5 sccm [0731] RF power: 70 Watts
[0732] Coating time: 12 seconds (includes a 2-sec RF power ramp-up
time)
[0733] Next the SiO.sub.x coated vials are coated over the
SiO.sub.x with an SiO.sub.xC.sub.y coating produced in a PECVD
process using an OMCTS precursor gas according to the Protocol for
Coating COC Syringe Barrel Interior with OMCTS Lubricity Coating
set forth above, except that the same coating equipment is used as
for the SiO.sub.x coating. Thus, the special adaptations in the
protocol for coating a syringe are not used. The following
conditions are used. [0734] OMCTS flow rate: 2.5 sccm [0735] Argon
flow rate: 10 sccm [0736] Oxygen flow rate: 0.7 sccm [0737] RF
power: 3.4 Watts [0738] Coating time: 5 seconds
[0739] Eight vials are selected and the total deposited quantity of
PECVD coating (SiO.sub.x+SiO.sub.xC.sub.y) is determined with a
Perkin Elmer Optima Model 7300DV ICP-OES instrument, using the
Protocol for Total Silicon Measurement set forth above. This
measurement determines the total amount of silicon in both
coatings, and does not distinguish between the respective SiO.sub.x
and SiO.sub.xC.sub.y coatings. The results are shown in Table
7.
[0740] In the following work, except as indicated otherwise in this
example, the Protocol for Determining Average Dissolution Rate is
followed. Two buffered pH test solutions are used in the remainder
of the experiment, respectively at pH 4 and pH 8 to test the effect
of pH on dissolution rate. Both test solutions are 50 mM buffers
using potassium phosphate as the buffer, diluted in water for
injection (WFI) (0.1 urn sterilized, filtered). The pH is adjusted
to pH 4 or 8, respectively, with concentrated nitric acid.
[0741] 25 vials are filled with 7.5 ml per vial of pH 4 buffered
test solution and 25 other vials are filled with 7.5 ml per vial of
pH 4 buffered test solution (note the fill level is to the top of
the vial--no head space). The vials are closed using prewashed
butyl stoppers and aluminum crimps. The vials at each pH are split
into two groups. One group at each pH containing 12 vials is stored
at 4.degree. C. and the second group of 13 vials is stored at
23.degree. C.
[0742] The vials are sampled at Days 1,3,6, and 8. The Protocol for
Measuring Dissolved Silicon in a Vessel is used, except as
otherwise indicated in this example. The analytical result is
reported on the basis of parts per billion of silicon in the
buffered test solutions of each vial. A dissolution rate is
calculated in terms of parts per billion per day as described above
in the Protocol for Determining Average Dissolution Rate. The
results at the respective storage temperatures are shown in Table
8:
[0743] The observations of Si dissolution versus time for the
OMCTS-based coating at pH 8 and pH 4 indicate the pH 4 rates are
higher at ambient conditions. Thus, the pH 4 rates are used to
determine how much material would need to be initially applied to
leave a coating of adequate thickness at the end of the shelf life,
taking account of the amount of the initial coating that would be
dissolved. The results of this calculation are shown in Table
9:
[0744] Based on this calculation, the OMCTS lubricity layer needs
to be about 2.5 times thicker--resulting in dissolution of 33945
ppb versus the 14,371 ppb representing the entire mass of coating
tested--to achieve a 3-year calculated shelf life.
Example 11
[0745] The results of Comparative Example 9 and Example 10 above
can be compared as shown in Table 10, where the "lubricity layer"
is the coating of SiO.sub.xC.sub.y referred to in Example 10.
[0746] This data shows that the silicon dissolution rate of
SiO.sub.x alone is reduced by more than 2 orders of magnitude at pH
8 in vials also coated with SiO.sub.xC.sub.y coatings.
[0747] Another comparison is shown by the data at Table 11 from
several different experiments carried out under similar accelerated
dissolution conditions.
[0748] Row A (SiO.sub.x with OMCTS coating) versus C (SiO.sub.x
without OMCTS coating) show that the OMCTS lubricity layer is also
an effective pH protective coating or layer to the SiO.sub.x
coating at pH 8. The OMCTS coating reduced the one-day dissolution
rate from 2504 ug/L ("u" or u or the Greek letter "mu" as used
herein are identical, and are abbreviations for "micro") to 165
ug/L. This data also shows that an HMDSO-based
Si.sub.wO.sub.xC.sub.y (or its equivalent SiO.sub.xC.sub.y)
overcoat (Row D) provided a far higher dissolution rate than an
OMCTS-based Si.sub.wO.sub.xC.sub.y (or its equivalent
SiO.sub.xC.sub.y) overcoat (Row A). This data shows that a
substantial benefit can be obtained by using a cyclic precursor
versus a linear one.
Example 12
[0749] Samples 1-6 as listed in Table 1 are prepared as described
in Example 9, with further details as follows.
[0750] A cyclic olefin copolymer (COC) resin is injection molded to
form a batch of 5 ml vials. Silicon chips are adhered with
double-sided adhesive tape to the internal walls of the vials. The
vials and chips are coated with a two layer coating by plasma
enhanced chemical vapor deposition (PECVD). The first layer is
composed of SiO.sub.x with barrier properties as defined in the
present disclosure, and the second layer is an SiO.sub.xC.sub.y pH
protective coating or layer.
[0751] A precursor gas mixture comprising OMCTS, argon, and oxygen
is introduced inside each vial. The gas inside the vial is excited
between capacitively coupled electrodes by a radio-frequency (13.56
MHz) power source i. The monomer flow rate (F.sub.m) in units of
seem, oxygen flow rate (F.sub.o) in units of seem, argon flowrate
in seem, and power (W) in units of watts are shown in Table 1.
[0752] A composite parameter, W/FM in units of kJ/kg, is calculated
from process parameters W, F.sub.m, F.sub.o and the molecular
weight, M in g/mol, of the individual gas species. W/FM is defined
as the energy input per unit mass of polymerizing gases.
Polymerizing gases are defined as those species that are
incorporated into the growing coating such as, but not limited to,
the monomer and oxygen. Non-polymerizing gases, by contrast, are
those species that are not incorporated into the growing coating,
such as but not limited to argon, helium and neon.
[0753] In this test, PECVD processing at high W/FM is believed to
cause higher monomer fragmentation, producing organosiloxane
coatings with higher cross-link density. PECVD processing at low
W/FM, by comparison, is believed to result in lower monomer
fragmentation producing organosiloxane coatings with a relatively
lower cross-link density.
[0754] The relative cross-link density of samples 2, 3, 5, and 6 is
compared between different coatings by measuring FTIR absorbance
spectra. The spectra of samples 2, 3, 5, and 6 are provided in
FIGS. 11-14. In each spectrum, the ratio of the peak absorbance at
the symmetric stretching mode (1000-1040 cm.sup.-1) versus the peak
absorbance at the asymmetric stretching mode (1060-1100 cm.sup.-1)
of the Si--O--Si bond is measured, and the ratio of these two
measurements is calculated, all as shown in Table 1. The respective
ratios are found to have a linear correlation to the composite
parameter W/FM.
[0755] A qualitative relation--whether the coating appeared oily
(shiny, often with irridescence) or non-oily (non-shiny) when
applied on the silicon chips--is also found to correlate with the
W/FM values in Table 1. Oily appearing coatings deposited at lower
W/FM values, as confirmed by Table 1, are believed to have a lower
crosslink density, as determined by their lower sym/asym ratio,
relative to the non-oily coatings that were deposited at higher
W/FM and a higher cross-link density. The only exception to this
general rule of thumb is sample 2 in Table 1. It is believed that
the coating of sample 2 exhibits a non-oily appearance because it
is was too thin to see. Thus, an oilyness observation is not
reported in Table 1 for sample 2. The chips were analyzed by FTIR
in transmission mode, with the infrared spectrum transmitted
through the chip and sample coating, and the transmission through
an uncoated null chip subtracted.
[0756] Non-oily organosiloxane layers produced at higher W/FM
values, which protect the underlying SiO.sub.x coating from aqueous
solutions at elevated pH and temperature, are preferred because
they provide lower Si dissolution and a longer shelf life, as
predicted by Table 1 based on similar experiments. For example, the
calculated silicon dissolution by contents of the vial at a pH of 8
and 40.degree. C. is reduced for the non-oily coatings, and the
resulting shelf life was 1381 days in one case and 1147 days in
another, as opposed to the much shorter shelf lives and higher
rates of dissolution for oily coatings. Calculated shelf life is
determined as shown for Example 9. The calculated shelf life also
correlates linearly to the ratio of symmetric to asymmetric
stretching modes of the Si--O--Si bond in organosiloxane pH
protective coatings.
[0757] Sample 6 can be particularly compared to Sample 5. An
organosiloxane, pH protective coating is deposited according to the
process conditions of sample 6 in Table 1. The coating is deposited
at a high W/FM. This results in a non-oily coating with a high
expected Si--O--Si sym/asym ratio of 0.958, which results in a low
rate of dissolution of 84.1 ppb/day (measured by the Protocol for
Determining Average Dissolution Rate) and long shelf life of 1147
days (measured by the Protocol for Determining Calculated Shelf
Life). The FTIR spectra of this coating is shown in FIG. 14, which
exhibits a relatively similar asymmetric Si--O--Si peak absorbance
compared to the symmetric Si--O--Si peak absorbance. This is an
indication of a higher cross-link density coating, which is a
preferred characteristic for pH protection and long shelf life.
[0758] An organosiloxane pH protective coating was deposited
according to the process conditions of sample 5 in Table 1. The
coating was deposited at a moderate W/FM. This resulted in an oily
coating with a low Si--O--Si sym/asym ratio of 0.673, which is
expected to result in a high rate of dissolution of 236.7 ppb/day
(following the Protocol for Determining Average Dissolution Rate)
and shorter shelf life of 271 days (following the Protocol for
Determining Calculated Shelf Life). The FTIR spectrum of this
coating exhibits a relatively high asymmetric Si--O--Si peak
absorbance compared to the symmetric Si--O--Si peak absorbance.
This is an indication of a lower cross-link density coating, which
is contemplated to be an unfavorable characteristic for pH
protection and long shelf life.
[0759] Sample 2 can be particularly compared to Sample 3. A pH
protective coating is deposited according to the process conditions
of sample 2 in Table 1. The coating is deposited at a low W/FM.
This is expected to result in a coating that exhibits a low
Si--O--Si sym/asym ratio of 0.582, which results in a high rate of
dissolution of 174 ppb/day and short shelf life of 107 days. The
FTIR spectrum of this coating exhibits a relatively high asymmetric
Si--O--Si peak absorbance compared to the symmetric Si--O--Si peak
absorbance. This is an indication of a lower cross-link density
coating, which is an unfavorable characteristic for pH protection
and long shelf life.
[0760] An organosiloxane, pH protective coating is deposited
according to the process conditions of sample 3 in Table 1. The
coating is deposited at a high W/FM. This results in a non-oily
coating with a high Si--O--Si sym/asym ratio of 0.947, which
results in a predicted low rate of Si dissolution of 79.5 ppb/day
(following the Protocol for Determining Average Dissolution Rate)
and long shelf life of 1381 days (following the Protocol for
Determining Calculated Shelf Life). The FTIR spectrum of this
coating exhibits a relatively similar asymmetric Si--O--Si peak
absorbance compared to the symmetric Si--O--Si peak absorbance.
This is an indication of a higher cross-link density coating, which
is a preferred characteristic for pH protection and long shelf
life.
Example 13
[0761] An experiment similar to Example 10 is carried out, modified
as indicated in this example and in Table 2 (where the expected
results, based on similar work with a different barrier coating or
layer, are tabulated). 100 5 mL COP vials are made and coated with
an SiO.sub.x barrier layer and an OMCTS-based pH protective coating
or layer as described previously, except that for Sample PC194 only
the pH protective coating or layer is applied. The coating quantity
is again measured in parts per billion extracted from the surfaces
of the vials to remove the entire pH protective coating, as
reported in Table 2.
[0762] In this example, several different coating dissolution
conditions are employed. The test solutions used for dissolution
contain either 0.02 or 0.2 wt. % polysorbate-80 surfactant, as well
as a buffer to maintain a pH of 8. Dissolution tests are carried
out at either 23.degree. C. or 40.degree. C.
[0763] Multiple syringes are filled with each test solution, stored
at the indicated temperature, and analyzed at several intervals to
determine the extraction profile and the amount of silicon
extracted. An average dissolution rate for protracted storage times
is then calculated by extrapolating the data obtained according to
the Protocol for Determining Average Dissolution Rate. The
predicted results, based on similar experiments, are calculated as
described previously and are shown in Table 2. Of particular note,
as shown on Table 2, were the very long calculated shelf lives of
the filled packages provided with a PC 194 pH protective coating or
layer:
[0764] 21045 days (over 57 years) based on storage at a pH of 8,
0.02 wt. % polysorbate-80 surfactant, at 23.degree. C.;
[0765] 38768 days (over 100 years) based on storage at a pH of 8,
0.2 wt. % polysorbate-80 surfactant, at 23.degree. C.;
[0766] 8184 days (over 22 years) based on storage at a pH of 8,
0.02 wt. % polysorbate-80 surfactant, at 40.degree. C.; and
[0767] 14732 days (over 40 years) based on storage at a pH of 8,
0.2 wt. % polysorbate-80 surfactant, at 40.degree. C.
[0768] Referring to Table 2, the longest calculated shelf lives
corresponded with the use of an RF power level of 150 Watts and a
corresponding high W/FM value. It is believed that the use of a
higher power level causes higher cross-link density of the pH
protective coating or layer.
Example 14
[0769] Another series of experiments similar to those of Example 13
are run, showing the effect of progressively increasing the RF
power level on the FTIR absorbance spectrum of the pH protective
coating or layer. The results are tabulated in Table 3, which in
each instance shows a symmetric/asymmetric ratio greater than 0.75
between the maximum amplitude of the Si--O--Si symmetrical stretch
peak normally located between about 1000 and 1040 cm.sup.-1, and
the maximum amplitude of the Si--O--Si asymmetric stretch peak
normally located between about 1060 and about 1100 cm.sup.-1. Thus,
the symmetric/asymmetric ratio is 0.79 at a power level of 20 W,
1.21 or 1.22 at power levels of 40, 60, or 80 W, and 1.26 at 100
Watts under otherwise comparable conditions.
[0770] The 150 Watt data in Table 3 is taken under somewhat
different conditions than the other data, so it is not directly
comparable with the 20-100 Watt data discussed above. The FTIR data
of samples 6 and 8 of Table 3 is taken from the upper portion of
the vial and the FTIR data of samples 7 and 9 of Table 3 is taken
from the lower portion of the vial. Also, the amount of OMCTS is
cut in half for samples 8 and 9 of Table 3, compared to samples 6
and 7. Reducing the oxygen level while maintaining a power level of
150 W is expected to raise the symmetric/asymmetric ratio still
further, as shown by comparing samples 6 and 7 to samples 8 and 9
in Table 3.
[0771] It is believed that, other conditions being equal,
increasing the symmetric/asymmetric ratio increases the shelf life
of a vessel filled with a material having a pH exceeding 5.
[0772] Table 12 shows the calculated O-Parameters and N-Parameters
(as defined in U.S. Pat. No. 8,067,070) for the experiments
summarized in Table 3. As Table 12 shows, the O-Parameters ranged
from 0.134 to 0.343, and the N-Parameters ranged from 0.408 to
0.623--all outside the ranges claimed in U.S. Pat. No.
8,067,070.
Examples 15-17
[0773] Syringe samples for examples 15-17, employing three
different pH protective coatings or layers, were produced in the
same manner as for Examples 5-8 except as indicated in Table
13:
[0774] Example 15 had a three-component pH protective coating or
layer employing OMCTS, oxygen, and carrier gas. Example 16 had a
two component pH protective coating or layer employing OMCTS and
oxygen, but no carrier gas. Example 17 had a one-component pH
protective coating or layer (OMCTS only). Syringes 15-17 were then
tested for lubricity as described for Examples 5-8.
[0775] The pH protective coatings or layers produced according to
these working examples are also contemplated to function as pH
protective coatings or layers to increase the shelf life of the
vessels, compared to similar vessels provided with a composite
barrier coating or layer but no pH protective coating or layer.
Examples 18-20
[0776] Examples 15-17 using an OMCTS precursor gas were repeated in
Examples 18-20, except that HMDSO was used as the precursor in
Examples 18-20. The results are shown in Table 14. The coatings
produced according to these working examples are contemplated to
function as pH protective coatings or layers, and also as pH
protective coatings or layers to increase the shelf life of the
vessels, compared to similar vessels provided with a composite
barrier coating or layer but no pH protective coating or layer.
Examples 21-32
[0777] In these examples the surface roughness of the pH protective
coating or layer was determined.
[0778] OMCTS pH protective coatings or layers were applied with
previously described equipment with the indicated specific process
conditions (Table 15) onto one milliliter COC 6013 molded syringe
barrels. Atomic force microscopy (AFM) Root Mean Square (RMS) and
other roughness determinations (Tables 15 and 16) were made using
the procedures indicated. Average RMS values are taken from three
different RMS readings on the surface. The plunger force tests, AFM
and SEM tests reported in Table 15 were performed on different
samples due to the nature of the individual tests which prohibited
a performance of all tests on one sample.
[0779] Further testing was carried out on sister samples Examples
29, 30, and 31, respectively made under conditions similar to
Example 23, 26, and 28 to show the AFM roughness data.
[0780] The pH protective coatings or layers produced according to
these working examples are also contemplated to function as pH
protective coatings or layers to increase the shelf life of the
vessels, compared to similar vessels provided with a composite
barrier coating or layer but no pH protective coating or layer.
Example 32
pH Protective Coating or Layer Extractables
[0781] Silicon extractables from syringes were measured using
ICP-MS analysis as described in the Protocol for Measuring
Dissolved Silicon in a Vessel. The syringes were evaluated in both
static and dynamic situations. The Protocol for Measuring Dissolved
Silicon in a Vessel, modified as follows, describes the test
procedure: [0782] Syringe filled with 2 ml of 0.9% saline solution
[0783] Syringe placed in a stand--stored at 50.degree. C. for 72
hours. [0784] After 72 hours saline solution test for dissolved
silicon [0785] Dissolved silicon measured before and after saline
solution expelled through syringe.
[0786] The extractable Silicon Levels from a silicon oil coated
glass syringe and a pH protective coated and SiO.sub.x coated COC
syringe are shown in Table 17. Precision of the ICP-MS total
silicon measurement is +/-3%.
Summary of Lubricity and/or pH Protective Measurements
[0787] Table 18 shows a summary of the above OMCTS coatings or
layers
Example 33
[0788] The purpose of this example was to evaluate the
recoverability or drainage of a slightly viscous aqueous solution
from glass, COP and coated vials,
[0789] This study evaluated the recovery of a 30 cps (centipoise)
carbohydrate solution in water-for-injection from (A) an uncoated
COP vial, (B) an SiO.sub.x+pH protective layer coated COP vial
prepared according to the above Protocol for Coating Syringe Barrel
Interior with SiOx, followed by the Protocol for Coating Syringe
Barrel Interior with OMCTS pH protective Coating or Layer, and (C)
a glass vial.
[0790] 2.0 ml of the carbohydrate solution was pipetted into 30
vials each of glass, COP and pH protective coated vials. The
solution was aspirated from the vials with a 10 ml syringe, through
a 23 gauge, 1.5'' needle. The vials were tipped to one side as the
solution was aspirated to maximize the amount recovered. The same
technique and similar withdrawal time was used for all vials. The
vials were weighed empty, after placing 2.0 ml of the solution to
the vial and at the conclusion of aspirating the solution from the
vial. The amount delivered to the vial (A) was determined by
subtracting the weight of the empty vial from the weight of the
vial with the 2.0 ml of solution. The weight of solution not
recovered (B) was determined by subtracting the weight of the empty
vial from the weight of the vials after aspirating the solution
from the vial. The percent unrecovered was determined by dividing B
by A and multiplying by 100.
[0791] It was observed during the aspiration of drug product that
the glass vials remained wetted with the solution. The COP vial
repelled the liquid and as the solution was aspirated from the
vials. This helped with recovery but droplets were observed to bead
on the sidewalls of the vials during the aspiration. The pH
protective coated vials also repelled the liquid during aspiration
but no beading of solution on the sidewalls was observed.
[0792] The conclusion was that pH protective coated vials do not
wet with aqueous solutions as do glass vials, leading to superior
recovery of drug product relative to glass. pH protective coated
vials were not observed to cause beading of solution on sidewall
during aspiration of aqueous products therefore coated vials
performed better than uncoated COP vials in product recovery
experiments.
[0793] While the invention has been illustrated and described in
detail in the drawings and foregoing description, such illustration
and description are to be considered illustrative or exemplary and
not restrictive; the invention is not limited to the disclosed
embodiments. Other variations to the disclosed embodiments can be
understood and effected by those skilled in the art and practicing
the claimed invention, from a study of the drawings, the
disclosure, and the appended claims. In the claims, the word
"comprising" does not exclude other elements or steps, and the
indefinite article "a" or "an" does not exclude a plurality. The
mere fact that certain measures are recited in mutually different
dependent claims does not indicate that a combination of these
measures cannot be used to advantage. Any reference signs in the
claims should not be construed as limiting the scope.
TABLE-US-00004 TABLE 1 FTIR Absorbance Si-O-Si Si-O-Si Process
Parameters Si Dissolution @ pH 8/40.degree. C. sym asym Flow
O.sub.2 Shelf Rate of stretch stretch Ratio Rate Flow Power W/FM
Total Si life Dissolution (1000- (1060- Si-O-Si Samples OMCTS Ar
Rate (W) (kJ/kg) (ppb) (days) (ppb/day) 1040 cm.sup.-1) 1100
cm.sup.-1) (sym/asym) Oilyness 1 3 10 0.5 14 21613 43464 385 293.18
0.153 0.219 0.700 YES 2 3 20 0.5 2 3088 7180 107 174.08 0.011 0.020
0.582 NA 3 1 20 0.5 14 62533 42252.17 1381 79.53 0.093 0.098 0.947
NO 4 2 15 0.5 8 18356 27398 380 187.63 0.106 0.141 0.748 YES 5 3 20
0.5 14 21613 24699 271 236.73 0.135 0.201 0.673 YES 6 1 10 0.5 14
62533 37094 1147 84.1 0.134 0.140 0.958 NO
TABLE-US-00005 TABLE 2 OMCTS Argon O.sub.2 Total Si Average Flow
Flow Flow Plasma (ppb) Calculated Rate of Rate Rate Rate Power
Duration W/FM (OMCTS) Shelf-life Dissolution Sample (sccm) (sccm)
(sccm) (W) (sec) (kJ/kg) layer) (days) (ppb/day) Process Parameters
Si Dissolution @ pH 8/23.degree. C./0.02% Tween .RTM.-80 PC194 0.5
20 0.5 150 20 1223335 73660 21045 3.5 018 1.0 20 0.5 18 15 77157
42982 1330 32.3 Process Parameters Si Dissolution @ pH 8/23.degree.
C./0.2% Tween .RTM.-80 PC194 0.5 20 0.5 150 20 1223335 73660 38768
1.9 018 1.0 20 0.5 18 15 77157 42982 665 64.6 048 4 80 2 35 20
37507 56520 1074 52.62 Process Parameters Si Dissolution @ pH
8/40.degree. C./0.02% Tween .RTM.-80 PC194 0.5 20 0.5 150 20
1223335 73660 8184 9 018 1.0 20 0.5 18 15 77157 42982 511 84
Process Parameters Si Dissolution @ pH 8/40.degree. C./0.2% Tween
.RTM.-80 PC194 0.5 20 0.5 150 20 1223335 73660 14732 5 018 1.0 20
0.5 18 15 77157 42982 255 168
TABLE-US-00006 TABLE 3 Symmetric Assymetric OMCTS Argon O.sub.2
Stretch Stretch Flow Flow Flow Plasma Peak at Peak at Symmetric/
Samples Rate Rate Rate Power Duration W/FM 1000-1040 1060-1100
Assymetric ID (sccm) (sccm) (sccm) (W) (sec) (kJ/kg) cm.sup.-1
cm.sup.-1 Ratio Process Parameters FTIR Results 1 1 20 0.5 20 20
85,730 0.0793 0.1007 0.79 2 1 20 0.5 40 20 171,460 0.0619 0.0507
1.22 3 1 20 0.5 60 20 257,190 0 .1092 0.0904 1.21 4 1 20 0.5 80 20
342,919 0.1358 0.1116 1.22 5 1 20 0.5 100 20 428,649 0.209 0.1658
1.26 6 1 20 0.5 150 20 642,973 0.2312 0.1905 1.21 7 1 20 0.5 150 20
642,973 0.2324 0.1897 1.23 8 0.5 20 0.5 150 20 1,223,335 0.1713
0.1353 1.27 9 0.5 20 0.5 150 20 1,223,335 0.1475 0.1151 1.28
TABLE-US-00007 TABLE 4 PLUNGER SLIDING FORCE MEASUREMENTS OF
OMCTS-BASED PLASMA pH protective COATING OR LAYER MADE WITH CARRIER
GAS Lubricity and/or pH Lubricity Lubricity Carrier pH pH
protective and/or pH and/or pH Gas protective protective coating
protective protective (Ar) coating or Mainte- coating or layer
OMCTS O.sub.2 Flow Flow layer Initiation nance or layer lubricity
Time Flow Rate Rate Rate Power Force, F.sub.i Force, F.sub.m
Example Type Monomer (sec) (sccm) (sccm) (sccm) (Watts) (N, Kg.)
(N, Kg.) 1 Uncoated n/a n/a n/a n/a n/a n/a >11 N >11 N
(Control) COC >1.1 Kg. >1.1 Kg. 2 Silicon oil n/a n/a n/a n/a
n/a n/a 8.2 N 6.3 N (Industry on COC 0.84 Kg. 0.64 Kg. Standard) 3
L3 lubricity OMCTS 10 sec 3 0 65 6 4.6 N 4.6 N (without coating or
0.47 Kg. 0.47 Kg. Oxygen) layer over SiO.sub.x on COC 4 L2
lubricity OMCTS 10 sec 3 1 65 6 4.8 N 3.5 N (with and/or pH 0.49
Kg. 0.36 Kg. Oxygen) protective coating or layer over SiO.sub.x on
COC
TABLE-US-00008 TABLE 5 COATED VIAL AND STAKED NEEDLE SYRINGE BARREL
ADHESION Example Relative (Inventive, Retention Exper- I, or (by
Exper- iment Compar- iment Number ative, C) Sample Method number) 1
B1 (I) SiOx Coated COP Vial A1 1 > 2 Cylinder 2 B1 (C) SiOx
Coated glass Vial A1 2 < 1 Cylinder 3 B1 (I) SiOx Coated COP
Vial A2 3 > 4 Cylinder 4 B1 (C) SiOx Coated glass Vial A2 4 <
3 Cylinder 5 B2 (I) Bilayer Coated COP Vial A1 5 > 6 Cylinder 6
B2 (C) Bilayer Coated glass Vial A1 6 < 5 Cylinder 7 B2 (I)
Bilayer Coated COP Vial A2 7 > 8 Cylinder 8 B2 (C) Bilayer
Coated glass Vial A2 8 < 7 Cylinder 9 B3 (I) SiOx Coated COP
Syringe A1 9 > 10 Barrel Cylinder 10 B3 (C) SiOx Coated
glassSyringe A1 10 < 9 Barrel Cylinder 11 B3 (I) SiOx Coated COP
Syringe A2 11 > 12 Barrel Cylinder 12 B3 (C) SiOx Coated
glassSyringe A2 12 < 11 Barrel Cylinder 13 B4 (I) Bilayer Coated
COP Syringe A1 13 > 14 Barrel Cylinder 14 B4 (C) Bilayer Coated
glassSyringe A1 14 < 13 Barrel Cylinder 15 B4 (I) Bilayer Coated
COP Syringe A2 15 > 16 Barrel Cylinder 16 B4 (C) Bilayer Coated
glassSyringe A2 16 < 15 Barrel Cylinder * {[(Pretape length
.times. coating height) - (Post tape length .times. coating
height)]/(Pretape length .times. coating height)} * 100%
TABLE-US-00009 TABLE 6 OMCTS LUBRICITY AND/OR pH protective COATING
OR LAYER (Examples 5 and 6) Initi- Mainte- ation nance ICPMS Ex-
OMCTS O.sub.2 Ar Force, Force, (.mu.g./ ICPMS ample (sccm) (sccm)
(sccm) Fi (N) Fm (N) liter) Mode 5 3.0 0.38 7.8 4.8 3.5 <5
static 6 3.0 0.38 7.8 5.4 4.3 38 dynamic 7 n/a n/a n/a 13 11 <5
static (SiO.sub.x only) 8 n/a n/a n/a 8.2 6.3 (silicon oil)
TABLE-US-00010 TABLE 7 Vial Total Silicon ug/L 1 13844 2 14878 3
14387 4 13731 5 15260 6 15017 7 15118 8 12736 Mean 14371 StdDev 877
Quantity of SiO.sub.x + Lubricity layer on Vials
TABLE-US-00011 TABLE 8 Vial SiOx + Vial SiOx + Lubricity Lubricity
Coating at pH 4 Coating at pH 8 Shelf Life Conditions 23.degree. C.
Si Dissolution Rate (PPB/day) 31 7 Shelf Life Conditions 4.degree.
C. Si Dissolution Rate (PPB/day) 7 11
TABLE-US-00012 TABLE 9 Shelf Life Calculation Vial with SiOx +
Lubricity Coating at pH 4 Si Dissolution Rate (PPB/day) 31 Mass of
Coating Tested (Total Si) 14,371 Shelf Life (days) at 23.degree. C.
464 Shelf Life (years) at 23.degree. C. 1.3 Required Mass of
Coating (Total Si) -- 2-years 22,630 Required Mass of Coating
(Total Si) -- 3-years 33,945
TABLE-US-00013 TABLE 10 Shelf Life Conditions -- pH 8 and
23.degree. C. Vial with SiOx + Vial with SiOx Lubricity Coating Si
Dissolution Rate (PPB/day) 1,250 7
TABLE-US-00014 TABLE 11 SILICON DISSOLUTION WITH PH 8 AT 40.degree.
C. (ug/L) Vial Coating 1 2 3 4 7 10 15 Description day days days
days days days days A. SiO.sub.x made 165 211 226 252 435 850 1,364
with HMDSO Plasma + Si.sub.wO.sub.xC.sub.y or its equivalent
SiO.sub.xC.sub.y made with OMCTS Plasma B. Si.sub.wO.sub.xC.sub.y
or 109 107 76 69 74 158 198 its equivalent SiO.sub.xC.sub.y made
with OMCTS Plasma C. SiO.sub.x made 2,504 4,228 5,226 5,650 9,292
10,177 9,551 with HMDSO Plasma D. SiO.sub.x made 1,607 1,341 3,927
10,182 18,148 20,446 21,889 with HMDSO Plasma +
Si.sub.wO.sub.xC.sub.y or its equivalent SiO.sub.xCy made with
HMDSO Plasma E. Si.sub.wO.sub.xCy or 1,515 1,731 1,813 1,743 2,890
3,241 3,812 its equivalent SiO.sub.xC.sub.y made with HMDSO
Plasma
TABLE-US-00015 TABLE 12 OMCTS Argon O.sub.2 Flow Flow Flow Plasma
Samples Rate Rate Rate Power Duration W/FM O- N- ID (sccm) (sccm)
(sccm) (W) (sec) (kJ/kg) Parameter Parameter Process Parameters 1 1
20 0.5 20 20 85,730 0.343 0.436 2 1 20 0.5 40 20 171,460 0.267
0.408 3 1 20 0.5 60 20 257,190 0.311 0.457 4 1 20 0.5 80 20 342,919
0.270 0.421 5 1 20 0.5 100 20 428,649 0.177 0.406 6 1 20 0.5 150 20
642,973 0.151 0.453 7 1 20 0.5 150 20 642,973 0.151 0.448 8 0.5 20
0.5 150 20 1,223,335 0.134 0.623 9 0.5 20 0.5 150 20 1,223,335
0.167 0.609
TABLE-US-00016 TABLE 13 OMCTS pH protective coating or layer OMCTS
-2.5 sccm Argon gas -7.6 sccm (when used) Oxygen 0.38 sccm (when
used) Power - 3 watts Power on time - 10 seconds
TABLE-US-00017 TABLE 14 HMDSO pH protective coating or layer HMDSO
O.sub.2 Ar Example (sccm) (sccm) (sccm) 18 2.5 0.38 7.6 19 2.5 0.38
-- 20 2.5 -- --
TABLE-US-00018 TABLE 15 SEM Micrograph Dep. (5 Ex- OMCTS Ar/O.sub.2
Power Time micronAF AFM RMS ample (sccm) (sccm) (Watts) (sec)
Vertical) (nanometers) 21 2.0 10/0.38 3.5 10 22 FIG. 6 23 19.6,
9.9, 9.4 (Average = 13.0) FIGS. 8, 9, 10 24 2.0 10/0.38 4.5 10 25
FIG. 7 26 12.5, 8.4, 6.1 (Average = 6.3) FIG. 11, 15, 16 27 2.0
10/0 3.4 10 28 1.9, 2.6, 3.0 (Average = 2.3) Fig 14, 15, 16
TABLE-US-00019 TABLE 16 Dep. Siloxane Power Time SiO.sub.x/Lub
Coater Mode Feed Ar/O.sub.2 (W) (Sec.) Example 29 SiO.sub.x:
Auto-Tube Auto HMDSO 0 sccm Ar, 37 7 SiO.sub.x/Baseline 52.5 in, 90
sccm O.sub.2 OMCTS Lub 133.4 cm. Lubricity: Auto-S same OMCTS, 10
sccm Ar 3.4 10 2.0 sccm 0.38 sccm O.sub.2 Example 30 SiO.sub.x.:
same same same same 37 7 SiO.sub.x/High Lubricity: same same same
same 4.5 10 Pwr OMCTS Lub Example 31 SiO.sub.x: Auto-Tube same same
0 sccm Ar, 37 7 SiO.sub.x/No O.sub.2 90 sccm O.sub.2 OMCTS Lub
Lubricity: Auto-S same same 10 sccm Ar 3.4 10 0 sccm O.sub.2
TABLE-US-00020 TABLE 17 Silicon Extractables Comparison of
Luburicity Coatings Package Type Statis (ug/L) Dynamic (ug/L)
Cyclic Olefin Syringe with CV 70 81 Holdings SiOCH Lubricity
Coating Borocilicate Glass Syringe with 825 835 Silicon Oil
TABLE-US-00021 TABLE 18 Summary Table of OMCTS pH protective
COATING OR LAYER from Tables 4, 6, 13 and 15 OMCTS O.sub.2 Ar Power
Dep Time Example (sccm) (sccm) (sccm) (Watt) (sec) 3 3.0 0.00 65 6
10 4 3.0 1.00 65 6 10 5 3.0 0.38 7.8 6 10 6 3.0 0.38 7.8 6 10 15
2.5 0.38 7.6 6 10 16 2.5 0.38 0.0 6 10 17 2.5 0.00 0.0 6 10 21 2.0
0.38 10 3.5 10 24 2.0 0.38 10 4.5 10 27 2.0 0.00 10 3.4 10 29 2.0
0.38 10 3.4 10 30 2.0 0.38 10 4.5 10 31 2.0 0.00 10 3.4 10
* * * * *