U.S. patent application number 12/135648 was filed with the patent office on 2008-11-13 for treatment of asthma and chronic obstructive pulmonary disease with anti-proliferate and anti-inflammatory drugs.
Invention is credited to Lixiao Wang.
Application Number | 20080276935 12/135648 |
Document ID | / |
Family ID | 39968408 |
Filed Date | 2008-11-13 |
United States Patent
Application |
20080276935 |
Kind Code |
A1 |
Wang; Lixiao |
November 13, 2008 |
TREATMENT OF ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE WITH
ANTI-PROLIFERATE AND ANTI-INFLAMMATORY DRUGS
Abstract
Embodiments of the present invention provide a method for
treatment of respiratory disorders such as asthma, chronic
obstructive pulmonary disease, and chronic sinusitis, including
cystic fibrosis, interstitial fibrosis, chronic bronchitis,
emphysema, bronchopulmonary dysplasia and neoplasia. The method
involves administration, preferably oral, nasal or pulmonary
administration, of anti-inflammatory and anti-proliferative drugs
(rapamycin or paclitaxel and their analogues) and an additive.
Inventors: |
Wang; Lixiao; (Medina,
MN) |
Correspondence
Address: |
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER;LLP
901 NEW YORK AVENUE, NW
WASHINGTON
DC
20001-4413
US
|
Family ID: |
39968408 |
Appl. No.: |
12/135648 |
Filed: |
June 9, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11942459 |
Nov 19, 2007 |
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12135648 |
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60860084 |
Nov 20, 2006 |
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60880742 |
Jan 17, 2007 |
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60897427 |
Jan 25, 2007 |
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60903529 |
Feb 26, 2007 |
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60904473 |
Mar 2, 2007 |
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60926850 |
Apr 30, 2007 |
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60981380 |
Oct 19, 2007 |
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60981384 |
Oct 19, 2007 |
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Current U.S.
Class: |
128/203.15 ;
424/423; 424/45; 514/291; 514/449; 604/103.02 |
Current CPC
Class: |
A61F 2/82 20130101; A61M
2025/105 20130101; A61K 9/0073 20130101; A61L 31/16 20130101; A61L
2420/06 20130101; A61L 2300/41 20130101; A61L 2300/416 20130101;
A61L 29/08 20130101; A61L 2420/02 20130101; A61M 2210/0618
20130101; A61K 31/337 20130101; A61F 2250/0067 20130101; A61L
29/085 20130101; A61L 29/16 20130101; A61M 25/10 20130101; A61K
9/0019 20130101; A61K 31/436 20130101; A61M 16/0434 20130101; A61K
31/337 20130101; A61K 2300/00 20130101; A61K 31/436 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
128/203.15 ;
514/291; 514/449; 424/423; 424/45; 604/103.02 |
International
Class: |
A61M 15/00 20060101
A61M015/00; A61K 31/436 20060101 A61K031/436; A61K 31/337 20060101
A61K031/337; A61M 25/10 20060101 A61M025/10; A61K 9/00 20060101
A61K009/00; A61K 9/12 20060101 A61K009/12 |
Claims
1. A method for treating a respiratory disorder in a mammal
comprising: administering a pharmaceutical formulation comprising
an effective amount of a drug and an additive to said mammal
orally, parenterally, intravascularly, intranasally,
intrabronchially, transdermally, rectally, or via an impregnated
vascular stent or balloon catheter into a body passage, wherein
said drug is chosen from rapamycin and analogues thereof and
paclitaxel and analogues thereof.
2. The method according to claim 1, wherein said administering
comprises delivery via a mist route chosen from aerosol inhalation,
dry powder inhalation, liquid inhalation, and liquid
instillation.
3. The method according to claim 2, wherein the mist is produced by
either a nebulizer, a hand-held meter dose inhaler (MDI), or dry
powder (DPI) inhaler.
4. The method according to claim 1, wherein the respiratory
disorder is chosen from chronic bronchitis, cystic fibrosis,
interstitial fibrosis, nasal and sinus dysplasia, bronchopulmonary
dysplasia and neoplasia, and emphysema.
5. The method according to claim 1, wherein the additive enhances
absorption of the drug into tissue of the body passage of the
respiratory and sinus system.
6. The method according to claim 1, wherein the additive comprises
a hydrophilic part and a drug affinity part, wherein the drug
affinity part is at least one of a hydrophobic part, a part that
has an affinity to the therapeutic agent by hydrogen bonding, and a
part that has an affinity to the therapeutic agent by van der Waals
interactions.
7. The method according to claim 1, wherein the additive is at
least one of a surfactant and a chemical compound.
8. The method according to claim 7, wherein the chemical compound
is chosen from amino alcohols, hydroxyl carboxylic acid, ester,
anhydrides, hydroxyl ketone, hydroxyl lactone, hydroxyl ester,
sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols, amino
acids, peptides, proteins, sorbitan, glycerol, polyalcohol,
phosphates, sulfates, organic acids, esters, salts, vitamins,
combinations of amino alcohol and organic acid, and their
substituted molecules.
9. The method according to claim 7, wherein the surfactant is
chosen from ionic, nonionic, aliphatic, and aromatic surfactants,
PEG fatty esters, PEG omega-3 fatty esters, ether, and alcohols,
glycerol fatty esters, sorbitan fatty esters, PEG glyceryl fatty
esters, PEG sorbitan fatty esters, sugar fatty esters, PEG sugar
esters, and derivatives thereof.
10. The method according to claim 7, wherein the chemical compound
has one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or
ester groups.
11. The method according to claim 10, wherein the chemical compound
having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide
or ester groups is chosen from amino alcohols, hydroxyl carboxylic
acid, ester, anhydrides, hydroxyl ketone, hydroxyl lactone,
hydroxyl ester, sugar phosphate, sugar sulfate, ethyl oxide, ethyl
glycols, amino acids, peptides, proteins, sorbitan, glycerol,
polyalcohol, phosphates, sulfates, organic acids, esters, salts,
vitamins, combinations of amino alcohol and organic acid, and their
substituted molecules.
12. The method according to claim 1, wherein the additive is chosen
from p-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween
40, Tween 60, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG
glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate,
plyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate,
polyglyceryl-6 laurate, plyglyceryl-6 oleate, polyglyceryl-6
myristate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate,
plyglyceryl-10 oleate, polyglyceryl-10 myristate, polyglyceryl-10
palmitate PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG
sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG
laurayl ether, octoxynol, monoxynol, tyloxapol, sucrose
monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,
n-decyl-.beta.-D-glucopyranoside, n-decyl-.beta.-D-maltopyranoside,
n-dodecyl-.beta.-D-glucopyranoside, n-dodecyl-.beta.-D-maltoside,
heptanoyl-N-methylglucamide, n-heptyl-.beta.-D-glucopyranoside,
n-heptyl-.beta.-D-thioglucoside, n-hexyl-.beta.-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-.beta.-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside,
octyl-.beta.-D-thioglucopyranoside; cystine, tyrosine, tryptophan,
leucine, isoleucine, phenylalanine, asparagine, aspartic acid,
glutamic acid, and methionine; acetic anhydride, benzoic anhydride,
ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone
carboxylate, ethylenediaminetetraacetic dianhydride, maleic and
anhydride, succinic anhydride, diglycolic anhydride, glutaric
anhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;
cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal
5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin
phosphate, thiamine, folic acid, menadiol diphosphate, menadione
sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6,
vitamin K6, and vitamin U; albumin, immunoglobulins, caseins,
hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin,
fibronectins, vitronectins, firbinogens, lipases, benzalkonium
chloride, benzethonium chloride, docecyl trimethyl ammonium
bromide, sodium docecylsulfates, dialkyl methylbenzyl ammonium
chloride, and dialkylesters of sodium sulfonsuccinic acid,
L-ascorbic acid and its salt, D-glucoascorbic acid and its salt,
tromethamine, triethanolamine, diethanolamine, meglumine,
glucamine, amine alcohols, glucoheptonic acid, glucomic acid,
hydroxyl ketone, hydroxyl lactone, gluconolactone,
glucoheptonolactone, glucooctanoic lactone, gulonic acid lactone,
mannoic lactone, ribonic acid lactone, lactobionic acid,
glucosamine, glutamic acid, benzyl alcohol, benzoic acid,
hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt,
gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic
acid, vanillin, methyl paraben, propyl paraben, sorbitol, xylitol,
cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,
ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,
catechin gallate, tiletamine, ketamine, propofol, lactic acids,
acetic acid, salts of any organic acid and organic amine,
polyglycidol, glycerol, multiglycerols, galactitol, di(ethylene
glycol), tri(ethylene glycol), tetra(ethylene glycol),
penta(ethylene glycol), poly(ethylene glycol) oligomers,
di(propylene glycol), tri(propylene glycol), tetra(propylene
glycol, and penta(propylene glycol), poly(propylene glycol)
oligomers, a block copolymer of polyethylene glycol and
polypropylene glycol, and derivatives and combinations thereof.
13. The method according to claim 7, wherein the surfactant is
chosen from PEG-fatty acids and PEG-fatty acid mono and diesters,
polyethylene glycol glycerol fatty acid esters, alcohol-oil
transesterification products, polyglyceryl fatty acids, propylene
glycol fatty acid esters, sterols and derivatives thereof,
polyethylene glycol sorbitan fatty acid esters, polyethylene glycol
alkyl ethers, polyethylene glycol alkyl phenols,
polyoxyethylene-polyoxypropylene block copolymers, and sorbitan
fatty acid esters.
14. The method according to claim 7, wherein the surfactant is
chosen from esters of lauric acid, oleic acid, and stearic acid,
PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10
laurate, PEG-10 oleate, PEG-12 laurate, PEG-12 oleate, PEG-15
oleate, PEG-20 laurate, PEG-20 oleate, PEG-20 dilaurate, PEG-20
dioleate, PEG-20 distearate, PEG-32 dilaurate, PEG-32 dioleate,
PEG-25 trioleate, PEG-60 corn glycerides, PEG-60 almond oil, PEG-40
palm kernel oil, PEG-8 caprylic/capric glycerides, and PEG-6
caprylic/capric glycerides, PEG-6 corn oil, PEG-6 almond oil, PEG-6
apricot kernel oil, PEG-6 olive oil, PEG-6 peanut oil, PEG-6
hydrogenated palm kernel oil, PEG-6 palm kernel oil, PEG-6
triolein, PEG-8 corn oil, PEG-20 corn glycerides, PEG-20 almond
glycerides, polyglyceryl oleate, polyglyceryl-2 dioleate,
polyglyceryl-10 trioleate, polyglyceryl stearate, polyglyceryl
laurate, polyglyceryl myristate, polyglyceryl palmitate, and
polyglyceryl linoleate, polyglyceryl-10 laurate, polyglyceryl-10
oleate, polyglyceryl-10 mono, dioleate, polyglyceryl-10 stearate,
polyglyceryl-10 laurate, polyglyceryl-10 myristate, polyglyceryl-10
palmitate, polyglyceryl-10 linoleate, polyglyceryl-6 stearate,
polyglyceryl-6 laurate, polyglyceryl-6 myristate, polyglyceryl-6
palmitate, and polyglyceryl-6 linoleate, polyglyceryl
polyricinoleate, propylene glycol monolaurate, propylene glycol
ricinoleate, propylene glycol monooleate, propylene glycol
dicaprylate/dicaprate, propylene glycol dioctanoate, PEG-20
sorbitan monolaurate, PEG-20 sorbitan monopalmitate, PEG-20
sorbitan monostearate, PEG-20 sorbitan monooleate, PEG-10-100 nonyl
phenol, PEG-15-100 octyl phenol ether, Tyloxapol, octoxynol,
nonoxynol, sucrose monopalmitate, sucrose monolaurate,
decanoyl-N-methylglucamide, n-decyl-.beta.-D-glucopyranoside,
n-decyl-.beta.-D-maltopyranoside,
n-dodecyl-.beta.-D-glucopyranoside, n-dodecyl-.beta.-D-maltoside,
heptanoyl-N-methylglucamide, n-heptyl-.beta.-D-glucopyranoside,
n-heptyl-.beta.-D-thioglucoside, n-hexyl-.beta.-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-.beta.-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside,
octyl-.beta.-D-thioglucopyranoside, sorbitan monolaurate, sorbitan
monopalmitate, sorbitan monooleate, sorbitan monostearate,
benzalkonium chloride, benzethonium chloride, cetylpyridinium
chloride, docecyl trimethyl ammonium bromide, sodium
docecylsulfates, dialkyl methylbenzyl ammonium chloride,
edrophonium chloride, domiphen bromide, dialkylesters of sodium
sulfonsuccinic acid, sodium dioctyl sulfosuccinate, sodium cholate,
sodium taurocholate, and derivatives thereof.
15. The method according to claim 10, wherein the chemical compound
having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide
or ester groups is chosen from cystine, tyrosine, tryptophan,
leucine, isoleucine, phenylalanine, asparagine, aspartic acid,
glutamic acid, and methionine (Aminoacids); acetic anhydride,
benzoic anhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid,
sodium pyrrolidone carboxylate, ethylenediaminetetraacetic
dianhydride, maleic and anhydride, succinic anhydride, diglycolic
anhydride, glutaric anhydride, acetiamine, benfotiamine,
pantothenic acid (organic acids and anhydrides); cetotiamine;
cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal
5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin
phosphate, thiamine, folic acid, menadiol diphosphate, menadione
sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6,
vitamin K6, and vitamin U (vitamins); albumin, immunoglobulins,
caseins, hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin,
fibronectins, vitronectins, firbinogens, lipases, L-ascorbic acid
and its salt, D-glucoascorbic acid and its salt, tromethamine,
triethanolamine, diethanolamine, meglumine, glucamine, amine
alcohols, glucoheptonic acid, glucomic acid, gluconolactone,
D-glucoheptono-1,4-lactone, glucooctanoic lactone, gulonic acid
lactone, mannoic lactone, erythronic acid lactone, ribonic acid
lactone, glucosamine, glutamic acid, benzyl alcohol, benzoic acid,
hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt,
gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic
acid, vanillin, methyl paraben, propyl paraben, acetaminophen,
ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,
catechin gallate, tiletamine, ketamine, propofol, lactic acids,
acetic acid, salts of any organic acid and organic amine,
lysine/glutamic acid, lysine acetate, lactobionic acid/meglumine,
lactobionic acid/tromethanemine, lactobionic acid/diethanolamine,
lactic acid/meglumine, lactic acid/tromethanemine, lactic
acid/diethanolamine, gentisic acid/meglumine, gentisic
acid/tromethanemine, gensitic acid/diethanolamine, vanillic
acid/meglumine, vanillic acid/tromethanemine, vanillic
acid/diethanolamine, benzoic acid/meglumine, benzoic
acid/tromethanemine, benzoic acid/diethanolamine, acetic
acid/meglumine, acetic acid/tromethanemine, acetic
acid/diethanolamine, polyglycidol, glycerols, multiglycerols, and
derivatives thereof.
16. The method according to claim 1, wherein the pharmaceutical
formulation further comprises an additional drug.
17. The method according to claim 16, wherein the additional drug
is chosen from corticosteroids, anticholinergics, beta-agonists,
non-steroidal anti-inflammatory drugs, macrolide antibiotics,
bronchodilators, leukotriene receptor inhibitors, cromolyn sulfate,
and combinations thereof.
18. A pharmaceutical formulation comprising an effective amount of
a drug for treatment of a respiratory or sinus system, and an
additive that enhances absorption of the drug into tissue of the
respiratory system, and wherein the additive comprises a
hydrophilic part and a drug affinity part, wherein the drug
affinity part is at least one of a hydrophobic part, a part that
has an affinity to the therapeutic agent by hydrogen bonding, and a
part that has an affinity to the therapeutic agent by van der Waals
interactions.
19. The formulation according to claim 18, wherein the formulation
is an aqueous aerosol formulation, a dry powder aerosol
formulation, or a propellant-based formulation.
20. The formulation according to claim 18, wherein the drug is
chosen from paclitaxel and analogues thereof and rapamycin and
analogues thereof.
21. The formulation according to claim 18, wherein the drug is
present in a concentration of about 0.05 mg/ml to about 600
mg/ml.
22. The formulation according to claim 18, wherein the additive is
at least one of a surfactant and a chemical compound.
23. The formulation according to claim 22, wherein the chemical
compound is chosen from amino alcohols, hydroxyl carboxylic acid,
ester, anhydrides, hydroxyl ketone, hydroxyl lactone, hydroxyl
ester, sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols,
amino acids, peptides, proteins, sorbitan, glycerol, polyalcohol,
phosphates, sulfates, organic acids, esters, salts, vitamins,
combinations of amino alcohol and organic acid, and their
substituted molecules.
24. The formulation according to claim 22, wherein the surfactant
is chosen from ionic, nonionic, aliphatic, and aromatic
surfactants, PEG fatty esters, PEG omega-3 fatty esters, ether, and
alcohols, glycerol fatty esters, sorbitan fatty esters, PEG
glyceryl fatty esters, PEG sorbitan fatty esters, sugar fatty
esters, PEG sugar esters, and derivatives thereof.
25. The formulation according to claim 22, wherein the chemical
compound has one or more hydroxyl, amino, carbonyl, carboxyl, acid,
amide or ester groups.
26. The formulation according to claim 25, wherein the chemical
compound having one or more hydroxyl, amino, carbonyl, carboxyl,
acid, amide or ester groups is chosen from amino alcohols, hydroxyl
carboxylic acid, ester, anhydrides, hydroxyl ketone, hydroxyl
lactone, hydroxyl ester, sugar phosphate, sugar sulfate, ethyl
oxide, ethyl glycols, amino acids, peptides, proteins, sorbitan,
glycerol, polyalcohol, phosphates, sulfates, organic acids, esters,
salts, vitamins, combinations of amino alcohol and organic acid,
and their substituted molecules.
27. The formulation according to claim 18, wherein the additive is
chosen from p-isononylphenoxypolyglycidol, PEG laurate, Tween 20,
Tween 40, Tween 60, PEG oleate, PEG stearate, PEG glyceryl laurate,
PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate,
plyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate,
polyglyceryl-6 laurate, plyglyceryl-6 oleate, polyglyceryl-6
myristate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate,
plyglyceryl-10 oleate, polyglyceryl-10 myristate, polyglyceryl-10
palmitate PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG
sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG
laurayl ether, octoxynol, monoxynol, tyloxapol, sucrose
monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,
n-decyl-.beta.-D-glucopyranoside, n-decyl-.beta.-D-maltopyranoside,
n-dodecyl-.beta.-D-glucopyranoside, n-dodecyl-.beta.-D-maltoside,
heptanoyl-N-methylglucamide, n-heptyl-.beta.-D-glucopyranoside,
n-heptyl-.beta.-D-thioglucoside, n-hexyl-.beta.-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-.beta.-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside,
octyl-.beta.-D-thioglucopyranoside; cystine, tyrosine, tryptophan,
leucine, isoleucine, phenylalanine, asparagine, aspartic acid,
glutamic acid, and methionine; acetic anhydride, benzoic anhydride,
ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone
carboxylate, ethylenediaminetetraacetic dianhydride, maleic and
anhydride, succinic anhydride, diglycolic anhydride, glutaric
anhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;
cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal
5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin
phosphate, thiamine, folic acid, menadiol diphosphate, menadione
sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6,
vitamin K6, and vitamin U; albumin, immunoglobulins, caseins,
hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin,
fibronectins, vitronectins, firbinogens, lipases, benzalkonium
chloride, benzethonium chloride, docecyl trimethyl ammonium
bromide, sodium docecylsulfates, dialkyl methylbenzyl ammonium
chloride, and dialkylesters of sodium sulfonsuccinic acid,
L-ascorbic acid and its salt, D-glucoascorbic acid and its salt,
tromethamine, triethanolamine, diethanolamine, meglumine,
glucamine, amine alcohols, glucoheptonic acid, glucomic acid,
hydroxyl ketone, hydroxyl lactone, gluconolactone,
glucoheptonolactone, glucooctanoic lactone, gulonic acid lactone,
mannoic lactone, ribonic acid lactone, lactobionic acid,
glucosamine, glutamic acid, benzyl alcohol, benzoic acid,
hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt,
gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic
acid, vanillin, methyl paraben, propyl paraben, sorbitol, xylitol,
cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,
ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,
catechin gallate, tiletamine, ketamine, propofol, lactic acids,
acetic acid, salts of any organic acid and organic amine,
polyglycidol, glycerol, multiglycerols, galactitol, di(ethylene
glycol), tri(ethylene glycol), tetra(ethylene glycol),
penta(ethylene glycol), poly(ethylene glycol) oligomers,
di(propylene glycol), tri(propylene glycol), tetra(propylene
glycol, and penta(propylene glycol), poly(propylene glycol)
oligomers, a block copolymer of polyethylene glycol and
polypropylene glycol, and derivatives and combinations thereof.
28. The formulation according to claim 22, wherein the surfactant
is chosen from esters of lauric acid, oleic acid, and stearic acid,
PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10
laurate, PEG-10 oleate, PEG-12 laurate, PEG-12 oleate, PEG-15
oleate, PEG-20 laurate, PEG-20 oleate, PEG-20 dilaurate, PEG-20
dioleate, PEG-20 distearate, PEG-32 dilaurate, PEG-32 dioleate,
PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-40 glyceryl
laurate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-25
trioleate, PEG-60 corn glycerides, PEG-60 almond oil, PEG-40 palm
kernel oil, PEG-8 caprylic/capric glycerides, PEG-6 caprylic/capric
glycerides, PEG-6 corn oil, PEG-6 almond oil, PEG-6 apricot kernel
oil, PEG-6 olive oil, PEG-6 peanut oil, PEG-6 hydrogenated palm
kernel oil, PEG-6 palm kernel oil, PEG-6 triolein, PEG-8 corn oil,
PEG-20 corn glycerides, PEG-20 almond glycerides, polyglyceryl
oleate, polyglyceryl-2 dioleate, polyglyceryl-10 trioleate,
polyglyceryl stearate, polyglyceryl laurate, polyglyceryl
myristate, polyglyceryl palmitate, and polyglyceryl linoleate,
polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10
mono, dioleate, polyglyceryl-10 stearate, polyglyceryl-10 laurate,
polyglyceryl-10 myristate, polyglyceryl-10 palmitate,
polyglyceryl-10 linoleate, polyglyceryl-6 stearate, polyglyceryl-6
laurate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate, and
polyglyceryl-6 linoleate, and polyglyceryl polyricinoleate,
propylene glycol monolaurate, propylene glycol ricinoleate,
propylene glycol monooleate, propylene glycol
dicaprylate/dicaprate, propylene glycol dioctanoate, PEG-20
sorbitan monolaurate, PEG-20 sorbitan monopalmitate, PEG-20
sorbitan monostearate, PEG-20 sorbitan monooleate, PEG-3 oleyl
ether and PEG-4 lauryl ether, sucrose monopalmitate, sucrose
monolaurate, decanoyl-N-methylglucamide,
n-decyl-.beta.-D-glucopyranoside, n-decyl-.beta.-D-maltopyranoside,
n-dodecyl-.beta.-D-glucopyranoside, n-dodecyl-.beta.-D-maltoside,
heptanoyl-N-methylglucamide, n-heptyl-.beta.-D-glucopyranoside,
n-heptyl-.beta.-D-thioglucoside, n-hexyl-.beta.-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-.beta.-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside,
octyl-.beta.-D-thioglucopyranoside, PEG-10-100 nonyl phenol,
PEG-15-100 octyl phenol ether, Tyloxapol, octoxynol, nonoxynol,
sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate,
sorbitan monostearate, benzalkonium chloride, benzethonium
chloride, docecyl trimethyl ammonium bromide, sodium
docecylsulfates, dialkyl methylbenzyl ammonium chloride, and
dialkylesters of sodium sulfonsuccinic acid (ionic surfactants),
n-octyl-.beta.-D-glucopyranoside, octoxynol-9, Polysorbates,
Tyloxapol, octoxynol, nonoxynol, isononylphenylpolyglycidol, PEG
glyceryl monooleate, sorbitan monolaurate, sorbitan monopalmitate,
sorbitan monooleate, sorbitan monostearate, polyglyceryl-10 oleate,
polyglyceryl-10 laurate, polyglyceryl-10 palmitate, polyglyceryl-10
stearate, and their derivatives.
29. The formulation according to claim 25, wherein the chemical
compound having one or more hydroxyl, amino, carbonyl, carboxyl,
acid, amide or ester groups is chosen from cystine, tyrosine,
tryptophan, leucine, isoleucine, phenylalanine, asparagine,
aspartic acid, glutamic acid, and methionine; acetic anhydride,
benzoic anhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid,
sodium pyrrolidone carboxylate, ethylenediaminetetraacetic
dianhydride, maleic and anhydride, succinic anhydride, diglycolic
anhydride, glutaric anhydride, acetiamine, benfotiamine,
pantothenic acid cetotiamine; cyclothiamine, dexpanthenol,
niacinamide, nicotinic acid, pyridoxal 5-phosphate, nicotinamide
ascorbate, riboflavin, riboflavin phosphate, thiamine, folic acid,
menadiol diphosphate, menadione sodium bisulfite, menadoxime,
vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitamin U;
albumin, immunoglobulins, caseins, hemoglobins, lysozymes,
immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,
firbinogens, lipases, L-ascorbic acid and its salt, D-glucoascorbic
acid and its salt, tromethamine, triethanolamine, diethanolamine,
meglumine, glucamine, amine alcohols, glucoheptonic acid, glucomic
acid, gluconolactone, D-glucoheptono-1,4-lactone, glucooctanoic
lactone, gulonic acid lactone, mannoic lactone, erythronic acid
lactone, ribonic acid lactone, glucosamine, glutamic acid, benzyl
alcohol, benzoic acid, hydroxybenzoic acid, propyl
4-hydroxybenzoate, lysine acetate salt, gentisic acid, lactobionic
acid, lactitol, sinapic acid, vanillic acid, vanillin, methyl
paraben, propyl paraben, acetaminophen, ibuprofen, retinoic acid,
lysine acetate, gentisic acid, catechin, catechin gallate,
tiletamine, ketamine, propofol, lactic acids, acetic acid, salts of
any organic acid and amine above described, lysine/glutamic acid,
lysine acetate,_lactobionic acid/meglumine, lactobionic
acid/tromethanemine, lactobionic acid/diethanolamine, lactic
acid/meglumine, lactic acid/tromethanemine, lactic
acid/diethanolamine, gentisic acid/meglumine, gentisic
acid/tromethanemine, gensitic acid/diethanolamine, vanillic
acid/meglumine, vanillic acid/tromethanemine, vanillic
acid/diethanolamine, benzoic acid/meglumine, benzoic
acid/tromethanemine, benzoic acid/diethanolamine, acetic
acid/meglumine, acetic acid/tromethanemine, and acetic
acid/diethanolamine, polyglycidol, glycerols, multiglycerols and a
mixture of the additives, and their derivatives.
30. The formulation according to claim 18, wherein the drug is
present in a concentration of about 0.05 mg/g to about 990
mg/g.
31. The formulation according to claim 18, wherein the formulation
further comprises an additional drug.
32. The formulation according to claim 31, wherein the additional
drug is chosen from corticosteroids, anticholinergics,
beta-agonists, non-steroidal anti-inflammatory drugs, macrolide
antibiotics, bronchodilators, leukotriene receptor inhibitors,
cromolyn sulfate, and combinations thereof.
33. A method for treating a respiratory system in a mammal
comprising: (1) forming an aerosol of a dispersion of particles,
wherein the particles comprise a water insoluble drug and an
additive that enhances absorption of the drug into tissue of the
respiratory system; and (2) administering the aerosol to the
respiratory system of the mammal.
34. The method according to claim 33, wherein the additive
comprises a hydrophilic part and a drug affinity part, wherein the
drug affinity part is at least one of a hydrophobic part, a part
that has an affinity to the therapeutic agent by hydrogen bonding,
and a part that has an affinity to the therapeutic agent by van der
Waals interactions.
35. The method according to claim 34, wherein the additive is at
least one of a surfactant and a chemical compound.
36. The method according to claim 35, wherein the chemical compound
is chosen from amino alcohols, hydroxyl carboxylic acid, ester,
anhydrides, hydroxyl ketone, hydroxyl lactone, hydroxyl ester,
sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols, amino
acids, peptides, proteins, sorbitan, glycerol, polyalcohol,
phosphates, sulfates, organic acids, esters, salts, vitamins,
combinations of amino alcohol and organic acid, and their
substituted molecules.
37. The method according to claim 35, wherein the surfactant is
chosen from ionic, nonionic, aliphatic, and aromatic surfactants,
PEG fatty esters, PEG omega-3 fatty esters, ether, and alcohols,
glycerol fatty esters, sorbitan fatty esters, PEG glyceryl fatty
esters, PEG sorbitan fatty esters, sugar fatty esters, PEG sugar
esters, and derivatives thereof.
38. The method according to claim 35, wherein the chemical compound
has one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or
ester groups.
39. The method according to claim 38, wherein the chemical compound
having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide
or ester groups is chosen from amino alcohols, hydroxyl carboxylic
acid, ester, anhydrides, hydroxyl ketone, hydroxyl lactone,
hydroxyl ester, sugar phosphate, sugar sulfate, ethyl oxide, ethyl
glycols, amino acids, peptides, proteins, sorbitan, glycerol,
polyalcohol, phosphates, sulfates, organic acids, esters, salts,
vitamins, combinations of amino alcohol and organic acid, and their
substituted molecules.
40. The method according to claim 33, wherein the additive is
chosen from p-isononylphenoxypolyglycidol, PEG laurate, Tween 20,
Tween 40, Tween 60, PEG oleate, PEG stearate, PEG glyceryl laurate,
PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate,
plyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate,
polyglyceryl-6 laurate, plyglyceryl-6 oleate, polyglyceryl-6
myristate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate,
plyglyceryl-10 oleate, polyglyceryl-10 myristate, polyglyceryl-10
palmitate PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG
sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG
laurayl ether, octoxynol, monoxynol, tyloxapol, sucrose
monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,
n-decyl-.beta.-D-glucopyranoside, n-decyl-.beta.-D-maltopyranoside,
n-dodecyl-.beta.-D-glucopyranoside, n-dodecyl-.beta.-D-maltoside,
heptanoyl-N-methylglucamide, n-heptyl-.beta.-D-glucopyranoside,
n-heptyl-.beta.-D-thioglucoside, n-hexyl-.beta.-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-.beta.-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside,
octyl-.beta.-D-thioglucopyranoside; cystine, tyrosine, tryptophan,
leucine, isoleucine, phenylalanine, asparagine, aspartic acid,
glutamic acid, and methionine; acetic anhydride, benzoic anhydride,
ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone
carboxylate, ethylenediaminetetraacetic dianhydride, maleic and
anhydride, succinic anhydride, diglycolic anhydride, glutaric
anhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;
cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal
5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin
phosphate, thiamine, folic acid, menadiol diphosphate, menadione
sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6,
vitamin K6, and vitamin U; albumin, immunoglobulins, caseins,
hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin,
fibronectins, vitronectins, firbinogens, lipases, benzalkonium
chloride, benzethonium chloride, docecyl trimethyl ammonium
bromide, sodium docecylsulfates, dialkyl methylbenzyl ammonium
chloride, and dialkylesters of sodium sulfonsuccinic acid,
L-ascorbic acid and its salt, D-glucoascorbic acid and its salt,
tromethamine, triethanolamine, diethanolamine, meglumine,
glucamine, amine alcohols, glucoheptonic acid, glucomic acid,
hydroxyl ketone, hydroxyl lactone, gluconolactone,
glucoheptonolactone, glucooctanoic lactone, gulonic acid lactone,
mannoic lactone, ribonic acid lactone, lactobionic acid,
glucosamine, glutamic acid, benzyl alcohol, benzoic acid,
hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt,
gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic
acid, vanillin, methyl paraben, propyl paraben, sorbitol, xylitol,
cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,
ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,
catechin gallate, tiletamine, ketamine, propofol, lactic acids,
acetic acid, salts of any organic acid and organic amine,
polyglycidol, glycerol, multiglycerols, galactitol, di(ethylene
glycol), tri(ethylene glycol), tetra(ethylene glycol),
penta(ethylene glycol), poly(ethylene glycol) oligomers,
di(propylene glycol), tri(propylene glycol), tetra(propylene
glycol, and penta(propylene glycol), poly(propylene glycol)
oligomers, a block copolymer of polyethylene glycol and
polypropylene glycol, and derivatives and combinations thereof.
41. The method according to claim 35, wherein the surfactant is
chosen from esters of lauric acid, oleic acid, and stearic acid,
PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10
laurate, PEG-10 oleate, PEG-12 laurate, PEG-12 oleate, PEG-15
oleate, PEG-20 laurate, PEG-20 oleate, PEG-20 dilaurate, PEG-20
dioleate, PEG-20 distearate, PEG-32 dilaurate, PEG-32 dioleate,
PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-40 glyceryl
laurate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-25
trioleate, PEG-60 corn glycerides, PEG-60 almond oil, PEG-40 palm
kernel oil, PEG-8 caprylic/capric glycerides, PEG-6 caprylic/capric
glycerides, PEG-6 corn oil, PEG-6 almond oil, PEG-6 apricot kernel
oil, PEG-6 olive oil, PEG-6 peanut oil, PEG-6 hydrogenated palm
kernel oil, PEG-6 palm kernel oil, PEG-6 triolein, PEG-8 corn oil,
PEG-20 corn glycerides, PEG-20 almond glycerides, polyglyceryl
oleate, polyglyceryl-2 dioleate, polyglyceryl-10 trioleate,
polyglyceryl stearate, polyglyceryl laurate, polyglyceryl
myristate, polyglyceryl palmitate, and polyglyceryl linoleate,
polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10
mono, dioleate, polyglyceryl-10 stearate, polyglyceryl-10 laurate,
polyglyceryl-10 myristate, polyglyceryl-10 palmitate,
polyglyceryl-10 linoleate, polyglyceryl-6 stearate, polyglyceryl-6
laurate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate, and
polyglyceryl-6 linoleate, and polyglyceryl polyricinoleate,
propylene glycol monolaurate, propylene glycol ricinoleate,
propylene glycol monooleate, propylene glycol
dicaprylate/dicaprate, propylene glycol dioctanoate, PEG-20
sorbitan monolaurate, PEG-20 sorbitan monopalmitate, PEG-20
sorbitan monostearate, PEG-20 sorbitan monooleate, PEG-3 oleyl
ether and PEG-4 lauryl ether, sucrose monopalmitate, sucrose
monolaurate, decanoyl-N-methylglucamide,
n-decyl-.beta.-D-glucopyranoside, n-decyl-.beta.-D-maltopyranoside,
n-dodecyl-.beta.-D-glucopyranoside, n-dodecyl-.beta.-D-maltoside,
heptanoyl-N-methylglucamide, n-heptyl-.beta.-D-glucopyranoside,
n-heptyl-.beta.-D-thioglucoside, n-hexyl-.beta.-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-.beta.-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside,
octyl-.beta.-D-thioglucopyranoside, PEG-10-100 nonyl phenol,
PEG-15-100 octyl phenol ether, Tyloxapol, octoxynol, nonoxynol,
sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate,
sorbitan monostearate, benzalkonium chloride, benzethonium
chloride, docecyl trimethyl ammonium bromide, sodium
docecylsulfates, dialkyl methylbenzyl ammonium chloride, and
dialkylesters of sodium sulfonsuccinic acid (ionic surfactants),
n-octyl-.beta.-D-glucopyranoside, octoxynol-9, Polysorbates,
Tyloxapol, octoxynol, nonoxynol, isononylphenylpolyglycidol, PEG
glyceryl monooleate, sorbitan monolaurate, sorbitan monopalmitate,
sorbitan monooleate, sorbitan monostearate, polyglyceryl-10 oleate,
polyglyceryl-10 laurate, polyglyceryl-10 palmitate, polyglyceryl-10
stearate, and their derivatives.
42. The method according to claim 38, wherein the chemical compound
having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide
or ester groups is chosen from cystine, tyrosine, tryptophan,
leucine, isoleucine, phenylalanine, asparagine, aspartic acid,
glutamic acid, and methionine; acetic anhydride, benzoic anhydride,
ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone
carboxylate, ethylenediaminetetraacetic dianhydride, maleic and
anhydride, succinic anhydride, diglycolic anhydride, glutaric
anhydride, acetiamine, benfotiamine, pantothenic acid cetotiamine;
cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal
5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin
phosphate, thiamine, folic acid, menadiol diphosphate, menadione
sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6,
vitamin K6, and vitamin U; albumin, immunoglobulins, caseins,
hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin,
fibronectins, vitronectins, firbinogens, lipases, benzalkonium
chloride, L-ascorbic acid and its salt, D-glucoascorbic acid and
its salt, tromethamine, triethanolamine, diethanolamine, meglumine,
glucamine, amine alcohols, glucoheptonic acid, glucomic acid,
gluconolactone, D-glucoheptono-1,4-lactone, glucooctanoic lactone,
gulonic acid lactone, mannoic lactone, erythronic acid lactone,
ribonic acid lactone, glucosamine, glutamic acid, benzyl alcohol,
benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine
acetate salt, gentisic acid, lactobionic acid, lactitol, sinapic
acid, vanillic acid, vanillin, methyl paraben, propyl paraben,
acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic
acid, catechin, catechin gallate, tiletamine, ketamine, propofol,
lactic acids, acetic acid, salts of any organic acid and amine
above described, lysine/glutamic acid, lysine acetate, lactobionic
acid/meglumine, lactobionic acid/tromethanemine, lactobionic
acid/diethanolamine, lactic acid/meglumine, lactic
acid/tromethanemine, lactic acid/diethanolamine, gentisic
acid/meglumine, gentisic acid/tromethanemine, gensitic
acid/diethanolamine, vanillic acid/meglumine, vanillic
acid/tromethanemine, vanillic acid/diethanolamine, benzoic
acid/meglumine, benzoic acid/tromethanemine, benzoic
acid/diethanolamine, acetic acid/meglumine, acetic
acid/tromethanemine, acetic acid/diethanolamine, polyglycidol,
glycerols, multiglycerols and a mixture of the additives, and their
derivatives.
43. The method according to claim 33, wherein the water insoluble
drug is chosen from paclitaxel and analogues thereof and rapamycin
and analogues thereof.
44. An aerosol device for delivering a drug to a respiratory
system, the device comprising a pharmaceutical formulation
comprising a water insoluble drug and an additive, wherein the
additive enhances absorption of the drug into tissue of the
respiratory system.
45. The device according to claim 44, wherein the pharmaceutical
formulation is an aqueous, propellant based, or dry powder
formulation.
46. The device according to claim 44, wherein the additive
comprises a hydrophilic part and a drug affinity part, wherein the
drug affinity part is at least one of a hydrophobic part, a part
that has an affinity to the therapeutic agent by hydrogen bonding,
and a part that has an affinity to the therapeutic agent by van der
Waals interactions.
47. The device according to claim 46, wherein the additive is at
least one of a surfactant and a chemical compound.
48. The device according to claim 47, wherein the chemical compound
is chosen from amino alcohols, hydroxyl carboxylic acid, ester,
anhydrides, hydroxyl ketone, hydroxyl lactone, hydroxyl ester,
sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols, amino
acids, peptides, proteins, sorbitan, glycerol, polyalcohol,
phosphates, sulfates, organic acids, esters, salts, vitamins,
combinations of amino alcohol and organic acid, and their
substituted molecules.
49. The device according to claim 47, wherein the surfactant is
chosen from ionic, nonionic, aliphatic, and aromatic surfactants,
PEG fatty esters, PEG omega-3 fatty esters, ether, and alcohols,
glycerol fatty esters, sorbitan fatty esters, PEG glyceryl fatty
esters, PEG sorbitan fatty esters, sugar fatty esters, PEG sugar
esters, and derivatives thereof.
50. The device according to claim 47, wherein the chemical compound
has one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or
ester groups.
51. The device according to claim 50, wherein the chemical compound
having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide
or ester groups is chosen from amino alcohols, hydroxyl carboxylic
acid, ester, anhydrides, hydroxyl ketone, hydroxyl lactone,
hydroxyl ester, sugar phosphate, sugar sulfate, ethyl oxide, ethyl
glycols, amino acids, peptides, proteins, sorbitan, glycerol,
polyalcohol, phosphates, sulfates, organic acids, esters, salts,
vitamins, combinations of amino alcohol and organic acid, and their
substituted molecules.
52. The device according to claim 44, wherein the additive is
chosen from p-isononylphenoxypolyglycidol, PEG laurate, Tween 20,
Tween 40, Tween 60, PEG oleate, PEG stearate, PEG glyceryl laurate,
PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate,
plyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate,
polyglyceryl-6 laurate, plyglyceryl-6 oleate, polyglyceryl-6
myristate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate,
plyglyceryl-10 oleate, polyglyceryl-10 myristate, polyglyceryl-10
palmitate PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG
sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG
laurayl ether, octoxynol, monoxynol, tyloxapol, sucrose
monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,
n-decyl-.beta.-D-glucopyranoside, n-decyl-.beta.-D-maltopyranoside,
n-dodecyl-.beta.-D-glucopyranoside, n-dodecyl-.beta.-D-maltoside,
heptanoyl-N-methylglucamide, n-heptyl-.beta.-D-glucopyranoside,
n-heptyl-.beta.-D-thioglucoside, n-hexyl-.beta.-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-.beta.-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside,
octyl-.beta.-D-thioglucopyranoside; cystine, tyrosine, tryptophan,
leucine, isoleucine, phenylalanine, asparagine, aspartic acid,
glutamic acid, and methionine; acetic anhydride, benzoic anhydride,
ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone
carboxylate, ethylenediaminetetraacetic dianhydride, maleic and
anhydride, succinic anhydride, diglycolic anhydride, glutaric
anhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;
cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal
5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin
phosphate, thiamine, folic acid, menadiol diphosphate, menadione
sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6,
vitamin K6, and vitamin U; albumin, immunoglobulins, caseins,
hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin,
fibronectins, vitronectins, firbinogens, lipases, benzalkonium
chloride, benzethonium chloride, docecyl trimethyl ammonium
bromide, sodium docecylsulfates, dialkyl methylbenzyl ammonium
chloride, and dialkylesters of sodium sulfonsuccinic acid,
L-ascorbic acid and its salt, D-glucoascorbic acid and its salt,
tromethamine, triethanolamine, diethanolamine, meglumine,
glucamine, amine alcohols, glucoheptonic acid, glucomic acid,
hydroxyl ketone, hydroxyl lactone, gluconolactone,
glucoheptonolactone, glucooctanoic lactone, gulonic acid lactone,
mannoic lactone, ribonic acid lactone, lactobionic acid,
glucosamine, glutamic acid, benzyl alcohol, benzoic acid,
hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt,
gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic
acid, vanillin, methyl paraben, propyl paraben, sorbitol, xylitol,
cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,
ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,
catechin gallate, tiletamine, ketamine, propofol, lactic acids,
acetic acid, salts of any organic acid and organic amine,
polyglycidol, glycerol, multiglycerols, galactitol, di(ethylene
glycol), tri(ethylene glycol), tetra(ethylene glycol),
penta(ethylene glycol), poly(ethylene glycol) oligomers,
di(propylene glycol), tri(propylene glycol), tetra(propylene
glycol, and penta(propylene glycol), poly(propylene glycol)
oligomers, a block copolymer of polyethylene glycol and
polypropylene glycol, and derivatives and combinations thereof.
53. The device according to claim 47, wherein the surfactant is
chosen from esters of lauric acid, oleic acid, and stearic acid,
PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10
laurate, PEG-10 oleate, PEG-12 laurate, PEG-12 oleate, PEG-15
oleate, PEG-20 laurate, PEG-20 oleate, PEG-20 dilaurate, PEG-20
dioleate, PEG-20 distearate, PEG-32 dilaurate, PEG-32 dioleate,
PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-40 glyceryl
laurate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-25
trioleate, PEG-60 corn glycerides, PEG-60 almond oil, PEG-40 palm
kernel oil, PEG-8 caprylic/capric glycerides, PEG-6 caprylic/capric
glycerides, PEG-6 corn oil, PEG-6 almond oil, PEG-6 apricot kernel
oil, PEG-6 olive oil, PEG-6 peanut oil, PEG-6 hydrogenated palm
kernel oil, PEG-6 palm kernel oil, PEG-6 triolein, PEG-8 corn oil,
PEG-20 corn glycerides, PEG-20 almond glycerides, polyglyceryl
oleate, polyglyceryl-2 dioleate, polyglyceryl-10 trioleate,
polyglyceryl stearate, polyglyceryl laurate, polyglyceryl
myristate, polyglyceryl palmitate, and polyglyceryl linoleate,
polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10
mono, dioleate, polyglyceryl-10 stearate, polyglyceryl-10 laurate,
polyglyceryl-10 myristate, polyglyceryl-10 palmitate,
polyglyceryl-10 linoleate, polyglyceryl-6 stearate, polyglyceryl-6
laurate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate, and
polyglyceryl-6 linoleate, and polyglyceryl polyricinoleate,
propylene glycol monolaurate, propylene glycol ricinoleate,
propylene glycol monooleate, propylene glycol
dicaprylate/dicaprate, propylene glycol dioctanoate, PEG-20
sorbitan monolaurate, PEG-20 sorbitan monopalmitate, PEG-20
sorbitan monostearate, PEG-20 sorbitan monooleate, PEG-3 oleyl
ether and PEG-4 lauryl ether, sucrose monopalmitate, sucrose
monolaurate, decanoyl-N-methylglucamide,
n-decyl-.beta.-D-glucopyranoside, n-decyl-.beta.-D-maltopyranoside,
n-dodecyl-.beta.-D-glucopyranoside, n-dodecyl-.beta.-D-maltoside,
heptanoyl-N-methylglucamide, n-heptyl-.beta.-D-glucopyranoside,
n-heptyl-.beta.-D-thioglucoside, n-hexyl-.beta.-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-.beta.-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside,
octyl-.beta.-D-thioglucopyranoside, PEG-10-100 nonyl phenol,
PEG-15-100 octyl phenol ether, Tyloxapol, octoxynol, nonoxynol,
sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate,
sorbitan monostearate, benzalkonium chloride, benzethonium
chloride, docecyl trimethyl ammonium bromide, sodium
docecylsulfates, dialkyl methylbenzyl ammonium chloride, and
dialkylesters of sodium sulfonsuccinic acid (ionic surfactants),
n-octyl-.beta.-D-glucopyranoside, octoxynol-9, Polysorbates,
Tyloxapol, octoxynol, nonoxynol, isononylphenylpolyglycidol, PEG
glyceryl monooleate, sorbitan monolaurate, sorbitan monopalmitate,
sorbitan monooleate, sorbitan monostearate, polyglyceryl-10 oleate,
polyglyceryl-10 laurate, polyglyceryl-10 palmitate, polyglyceryl-10
stearate, and their derivatives.
54. The device according to claim 50, wherein the chemical compound
having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide
or ester groups is chosen from cystine, tyrosine, tryptophan,
leucine, isoleucine, phenylalanine, asparagine, aspartic acid,
glutamic acid, and methionine; acetic anhydride, benzoic anhydride,
ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone
carboxylate, ethylenediaminetetraacetic dianhydride, maleic and
anhydride, succinic anhydride, diglycolic anhydride, glutaric
anhydride, acetiamine, benfotiamine, pantothenic acid cetotiamine;
cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal
5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin
phosphate, thiamine, folic acid, menadiol diphosphate, menadione
sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6,
vitamin K6, and vitamin U; albumin, immunoglobulins, caseins,
hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin,
fibronectins, vitronectins, firbinogens, lipases, L-ascorbic acid
and its salt, D-glucoascorbic acid and its salt, tromethamine,
triethanolamine, diethanolamine, meglumine, glucamine, amine
alcohols, glucoheptonic acid, glucomic acid, gluconolactone,
D-glucoheptono-1,4-lactone, glucooctanoic lactone, gulonic acid
lactone, mannoic lactone, erythronic acid lactone, ribonic acid
lactone, glucosamine, glutamic acid, benzyl alcohol, benzoic acid,
hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt,
gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic
acid, vanillin, methyl paraben, propyl paraben, acetaminophen,
ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,
catechin gallate, tiletamine, ketamine, propofol, lactic acids,
acetic acid, salts of any organic acid and amine above described,
lysine/glutamic acid, lysine acetate, lactobionic acid/meglumine,
lactobionic acid/tromethanemine, lactobionic acid/diethanolamine,
lactic acid/meglumine, lactic acid/tromethanemine, lactic
acid/diethanolamine, gentisic acid/meglumine, gentisic
acid/tromethanemine, gensitic acid/diethanolamine, vanillic
acid/meglumine, vanillic acid/tromethanemine, vanillic
acid/diethanolamine, benzoic acid/meglumine, benzoic
acid/tromethanemine, benzoic acid/diethanolamine, acetic
acid/meglumine, acetic acid/tromethanemine, acetic
acid/diethanolamine, polyglycidol, glycerols, multiglycerols and a
mixture of the additives, and their derivatives.
55. The device according to claim 44, wherein the water insoluble
drug is chosen from paclitaxel and analogues thereof and rapamycin
and analogues thereof.
56. The device according to claim 44, wherein the aerosol device is
one of a nebulizer, a hand-held meter dose inhaler, or a dry powder
inhaler.
57. A device sized and configured for insertion into a passage of a
respiratory system, the device comprising a layer overlying an
exterior surface of the device, the layer comprising a water
insoluble drug for the treatment of the respiratory system and an
additive that enhances absorption of the drug into tissue of the
respiratory system.
58. The device according to claim 57, wherein the additive
comprises a hydrophilic part and a drug affinity part, wherein the
drug affinity part is at least one of a hydrophobic part, a part
that has an affinity to the therapeutic agent by hydrogen bonding,
and a part that has an affinity to the therapeutic agent by van der
Waals interactions.
59. The device according to claim 57, wherein the device is a
balloon catheter or a stent.
60. The device according to claim 57, wherein the water insoluble
drug is chosen from paclitaxel and analogues thereof and rapamycin
and analogues thereof.
61. The device according to claim 58, wherein the additive is at
least one of a surfactant and a chemical compound.
62. The device according to claim 61, wherein the chemical compound
is chosen from amino alcohols, hydroxyl carboxylic acid, ester,
anhydrides, hydroxyl ketone, hydroxyl lactone, hydroxyl ester,
sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols, amino
acids, peptides, proteins, sorbitan, glycerol, polyalcohol,
phosphates, sulfates, organic acids, esters, salts, vitamins,
combinations of amino alcohol and organic acid, and their
substituted molecules.
63. The device according to claim 61, wherein the surfactant is
chosen from ionic, nonionic, aliphatic, and aromatic surfactants,
PEG fatty esters, PEG omega-3 fatty esters, ether, and alcohols,
glycerol fatty esters, sorbitan fatty esters, PEG glyceryl fatty
esters, PEG sorbitan fatty esters, sugar fatty esters, PEG sugar
esters, and derivatives thereof.
64. The device according to claim 61, wherein the chemical compound
has one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or
ester groups.
65. The device according to claim 64, wherein the chemical compound
having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide
or ester groups is chosen from amino alcohols, hydroxyl carboxylic
acid, ester, anhydrides, hydroxyl ketone, hydroxyl lactone,
hydroxyl ester, sugar phosphate, sugar sulfate, ethyl oxide, ethyl
glycols, amino acids, peptides, proteins, sorbitan, glycerol,
polyalcohol, phosphates, sulfates, organic acids, esters, salts,
vitamins, combinations of amino alcohol and organic acid, and their
substituted molecules.
66. The device according to claim 57, wherein the additive is
chosen from p-isononylphenoxypolyglycidol, PEG laurate, Tween 20,
Tween 40, Tween 60, PEG oleate, PEG stearate, PEG glyceryl laurate,
PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate,
plyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate,
polyglyceryl-6 laurate, plyglyceryl-6 oleate, polyglyceryl-6
myristate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate,
plyglyceryl-10 oleate, polyglyceryl-10 myristate, polyglyceryl-10
palmitate PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG
sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG
laurayl ether, octoxynol, monoxynol, tyloxapol, sucrose
monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,
n-decyl-.beta.-D-glucopyranoside, n-decyl-.beta.-D-maltopyranoside,
n-dodecyl-.beta.-D-glucopyranoside, n-dodecyl-.beta.-D-maltoside,
heptanoyl-N-methylglucamide, n-heptyl-.beta.-D-glucopyranoside,
n-heptyl-.beta.-D-thioglucoside, n-hexyl-.beta.-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-.beta.-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside,
octyl-.beta.-D-thioglucopyranoside; cystine, tyrosine, tryptophan,
leucine, isoleucine, phenylalanine, asparagine, aspartic acid,
glutamic acid, and methionine; acetic anhydride, benzoic anhydride,
ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone
carboxylate, ethylenediaminetetraacetic dianhydride, maleic and
anhydride, succinic anhydride, diglycolic anhydride, glutaric
anhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;
cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal
5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin
phosphate, thiamine, folic acid, menadiol diphosphate, menadione
sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6,
vitamin K6, and vitamin U; albumin, immunoglobulins, caseins,
hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin,
fibronectins, vitronectins, firbinogens, lipases, benzalkonium
chloride, benzethonium chloride, docecyl trimethyl ammonium
bromide, sodium docecylsulfates, dialkyl methylbenzyl ammonium
chloride, and dialkylesters of sodium sulfonsuccinic acid,
L-ascorbic acid and its salt, D-glucoascorbic acid and its salt,
tromethamine, triethanolamine, diethanolamine, meglumine,
glucamine, amine alcohols, glucoheptonic acid, glucomic acid,
hydroxyl ketone, hydroxyl lactone, gluconolactone,
glucoheptonolactone, glucooctanoic lactone, gulonic acid lactone,
mannoic lactone, ribonic acid lactone, lactobionic acid,
glucosamine, glutamic acid, benzyl alcohol, benzoic acid,
hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt,
gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic
acid, vanillin, methyl paraben, propyl paraben, sorbitol, xylitol,
cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,
ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,
catechin gallate, tiletamine, ketamine, propofol, lactic acids,
acetic acid, salts of any organic acid and organic amine,
polyglycidol, glycerol, multiglycerols, galactitol, di(ethylene
glycol), tri(ethylene glycol), tetra(ethylene glycol),
penta(ethylene glycol), poly(ethylene glycol) oligomers,
di(propylene glycol), tri(propylene glycol), tetra(propylene
glycol, and penta(propylene glycol), poly(propylene glycol)
oligomers, a block copolymer of polyethylene glycol and
polypropylene glycol, and derivatives and combinations thereof.
67. The device according to claim 61, wherein the surfactant is
chosen from esters of lauric acid, oleic acid, and stearic acid,
PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10
laurate, PEG-10 oleate, PEG-12 laurate, PEG-12 oleate, PEG-15
oleate, PEG-20 laurate, PEG-20 oleate, PEG-20 dilaurate, PEG-20
dioleate, PEG-20 distearate, PEG-32 dilaurate, PEG-32 dioleate,
PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-40 glyceryl
laurate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-25
trioleate, PEG-60 corn glycerides, PEG-60 almond oil, PEG-40 palm
kernel oil, PEG-8 caprylic/capric glycerides, PEG-6 caprylic/capric
glycerides, PEG-6 corn oil, PEG-6 almond oil, PEG-6 apricot kernel
oil, PEG-6 olive oil, PEG-6 peanut oil, PEG-6 hydrogenated palm
kernel oil, PEG-6 palm kernel oil, PEG-6 triolein, PEG-8 corn oil,
PEG-20 corn glycerides, PEG-20 almond glycerides, polyglyceryl
oleate, polyglyceryl-2 dioleate, polyglyceryl-10 trioleate,
polyglyceryl stearate, polyglyceryl laurate, polyglyceryl
myristate, polyglyceryl palmitate, and polyglyceryl linoleate,
polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10
mono, dioleate, polyglyceryl-10 stearate, polyglyceryl-10 laurate,
polyglyceryl-10 myristate, polyglyceryl-10 palmitate,
polyglyceryl-10 linoleate, polyglyceryl-6 stearate, polyglyceryl-6
laurate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate, and
polyglyceryl-6 linoleate, and polyglyceryl polyricinoleate,
propylene glycol monolaurate, propylene glycol ricinoleate,
propylene glycol monooleate, propylene glycol
dicaprylate/dicaprate, propylene glycol dioctanoate, PEG-20
sorbitan monolaurate, PEG-20 sorbitan monopalmitate, PEG-20
sorbitan monostearate, PEG-20 sorbitan monooleate, PEG-3 oleyl
ether and PEG-4 lauryl ether, sucrose monopalmitate, sucrose
monolaurate, decanoyl-N-methylglucamide,
n-decyl-.beta.-D-glucopyranoside, n-decyl-.beta.-D-maltopyranoside,
n-dodecyl-.beta.-D-glucopyranoside, n-dodecyl-.beta.-D-maltoside,
heptanoyl-N-methylglucamide, n-heptyl-.beta.-D-glucopyranoside,
n-heptyl-.beta.-D-thioglucoside, n-hexyl-.beta.-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-.beta.-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside,
octyl-.beta.-D-thioglucopyranoside, PEG-10-100 nonyl phenol,
PEG-15-100 octyl phenol ether, Tyloxapol, octoxynol, nonoxynol,
sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate,
sorbitan monostearate, benzalkonium chloride, benzethonium
chloride, docecyl trimethyl ammonium bromide, sodium
docecylsulfates, dialkyl methylbenzyl ammonium chloride, and
dialkylesters of sodium sulfonsuccinic acid (ionic surfactants),
n-octyl-.beta.-D-glucopyranoside, octoxynol-9, Polysorbates,
Tyloxapol, octoxynol, nonoxynol, isononylphenylpolyglycidol, PEG
glyceryl monooleate, sorbitan monolaurate, sorbitan monopalmitate,
sorbitan monooleate, sorbitan monostearate, polyglyceryl-10 oleate,
polyglyceryl-10 laurate, polyglyceryl-10 palmitate, polyglyceryl-10
stearate, and their derivatives.
68. The device according to claim 64, wherein the chemical compound
having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide
or ester groups is chosen from cystine, tyrosine, tryptophan,
leucine, isoleucine, phenylalanine, asparagine, aspartic acid,
glutamic acid, and methionine; acetic anhydride, benzoic anhydride,
ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone
carboxylate, maleic and anhydride, succinic anhydride, diglycolic
anhydride, glutaric anhydride, acetiamine, benfotiamine,
pantothenic acid; cetotiamine; cyclothiamine, dexpanthenol,
niacinamide, nicotinic acid, pyridoxal 5-phosphate, nicotinamide
ascorbate, riboflavin, riboflavin phosphate, thiamine, folic acid,
menadiol diphosphate, menadione sodium bisulfite, menadoxime,
vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitamin U;
albumin, immunoglobulins, caseins, hemoglobins, lysozymes,
immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,
firbinogens, lipases, L-ascorbic acid and its salt, D-glucoascorbic
acid and its salt, tromethamine, triethanolamine, diethanolamine,
meglumine, glucamine, amine alcohols, glucoheptonic acid, glucomic
acid, gluconolactone, D-glucoheptono-1,4-lactone, glucooctanoic
lactone, gulonic acid lactone, mannoic lactone, erythronic acid
lactone, ribonic acid lactone, glucosamine, glutamic acid, benzyl
alcohol, benzoic acid, hydroxybenzoic acid, propyl
4-hydroxybenzoate, lysine acetate salt, gentisic acid, lactobionic
acid, lactitol, sinapic acid, vanillic acid, vanillin, methyl
paraben, propyl paraben, acetaminophen, ibuprofen, retinoic acid,
lysine acetate, gentisic acid, catechin, catechin gallate,
tiletamine, ketamine, propofol, lactic acids, acetic acid, salts of
any organic acid and amine above described, lysine/glutamic acid,
lysine acetate, lactobionic acid/meglumine, lactobionic
acid/tromethanemine, lactobionic acid/diethanolamine, lactic
acid/meglumine, lactic acid/tromethanemine, lactic
acid/diethanolamine, gentisic acid/meglumine, gentisic
acid/tromethanemine, gensitic acid/diethanolamine, vanillic
acid/meglumine, vanillic acid/tromethanemine, vanillic
acid/diethanolamine, benzoic acid/meglumine, benzoic
acid/tromethanemine, benzoic acid/diethanolamine, acetic
acid/meglumine, acetic acid/tromethanemine, acetic
acid/diethanolamine, polyglycidol, glycerols, multiglycerols and a
mixture of the additives, and their derivatives.
69. A method for treating a respiratory system comprising:
inserting a balloon catheter comprising a coating layer into an
airway, wherein the coating layer comprises a drug and an additive;
inflating the balloon catheter and releasing the drug to a wall of
the airway; deflating the balloon; and withdrawing the balloon
catheter from the airway.
70. The method according to claim 69, wherein the additive enhances
absorption of the drug into tissue of the respiratory or sinus
system.
71. The method according to claim 69, wherein the additive
comprises a hydrophilic part and a drug affinity part, wherein the
drug affinity part is at least one of a hydrophobic part, a part
that has an affinity to the therapeutic agent by hydrogen bonding,
and a part that has an affinity to the therapeutic agent by van der
Waals interactions.
72. The method according to claim 69, wherein the drug is chosen
from paclitaxel and analogues thereof and rapamycin and analogues
thereof.
73. The method according to claim 71, wherein the additive is at
least one of a surfactant and a chemical compound.
74. The method according to claim 73, wherein the chemical compound
is chosen from amino alcohols, hydroxyl carboxylic acid, ester,
anhydrides, hydroxyl ketone, hydroxyl lactone, hydroxyl ester,
sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols, amino
acids, peptides, proteins, sorbitan, glycerol, polyalcohol,
phosphates, sulfates, organic acids, esters, salts, vitamins,
combinations of amino alcohol and organic acid, and their
substituted molecules.
75. The method according to claim 73, wherein the surfactant is
chosen from ionic, nonionic, aliphatic, and aromatic surfactants,
PEG fatty esters, PEG omega-3 fatty esters, ether, and alcohols,
glycerol fatty esters, sorbitan fatty esters, PEG glyceryl fatty
esters, PEG sorbitan fatty esters, sugar fatty esters, PEG sugar
esters, and derivatives thereof.
76. The method according to claim 73, wherein the chemical compound
has one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or
ester groups.
77. The method according to claim 76, wherein the chemical compound
having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide
or ester groups is chosen from amino alcohols, hydroxyl carboxylic
acid, ester, anhydrides, hydroxyl ketone, hydroxyl lactone,
hydroxyl ester, sugar phosphate, sugar sulfate, ethyl oxide, ethyl
glycols, amino acids, peptides, proteins, sorbitan, glycerol,
polyalcohol, phosphates, sulfates, organic acids, esters, salts,
vitamins, combinations of amino alcohol and organic acid, and their
substituted molecules.
78. The method according to claim 69, wherein the additive is
chosen from p-isononylphenoxypolyglycidol, PEG laurate, Tween 20,
Tween 40, Tween 60, PEG oleate, PEG stearate, PEG glyceryl laurate,
PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate,
plyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate,
polyglyceryl-6 laurate, plyglyceryl-6 oleate, polyglyceryl-6
myristate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate,
plyglyceryl-10 oleate, polyglyceryl-10 myristate, polyglyceryl-10
palmitate PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG
sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG
laurayl ether, octoxynol, monoxynol, tyloxapol, sucrose
monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,
n-decyl-.beta.-D-glucopyranoside, n-decyl-.beta.-D-maltopyranoside,
n-dodecyl-.beta.-D-glucopyranoside, n-dodecyl-.beta.-D-maltoside,
heptanoyl-N-methylglucamide, n-heptyl-.beta.-D-glucopyranoside,
n-heptyl-.beta.-D-thioglucoside, n-hexyl-.beta.-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-.beta.-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside,
octyl-.beta.-D-thioglucopyranoside; cystine, tyrosine, tryptophan,
leucine, isoleucine, phenylalanine, asparagine, aspartic acid,
glutamic acid, and methionine; acetic anhydride, benzoic anhydride,
ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone
carboxylate, ethylenediaminetetraacetic dianhydride, maleic and
anhydride, succinic anhydride, diglycolic anhydride, glutaric
anhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;
cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal
5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin
phosphate, thiamine, folic acid, menadiol diphosphate, menadione
sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6,
vitamin K6, and vitamin U; albumin, immunoglobulins, caseins,
hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin,
fibronectins, vitronectins, firbinogens, lipases, benzalkonium
chloride, benzethonium chloride, docecyl trimethyl ammonium
bromide, sodium docecylsulfates, dialkyl methylbenzyl ammonium
chloride, and dialkylesters of sodium sulfonsuccinic acid,
L-ascorbic acid and its salt, D-glucoascorbic acid and its salt,
tromethamine, triethanolamine, diethanolamine, meglumine,
glucamine, amine alcohols, glucoheptonic acid, glucomic acid,
hydroxyl ketone, hydroxyl lactone, gluconolactone,
glucoheptonolactone, glucooctanoic lactone, gulonic acid lactone,
mannoic lactone, ribonic acid lactone, lactobionic acid,
glucosamine, glutamic acid, benzyl alcohol, benzoic acid,
hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt,
gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic
acid, vanillin, methyl paraben, propyl paraben, sorbitol, xylitol,
cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,
ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,
catechin gallate, tiletamine, ketamine, propofol, lactic acids,
acetic acid, salts of any organic acid and organic amine,
polyglycidol, glycerol, multiglycerols, galactitol, di(ethylene
glycol), tri(ethylene glycol), tetra(ethylene glycol),
penta(ethylene glycol), poly(ethylene glycol) oligomers,
di(propylene glycol), tri(propylene glycol), tetra(propylene
glycol, and penta(propylene glycol), poly(propylene glycol)
oligomers, a block copolymer of polyethylene glycol and
polypropylene glycol, and derivatives and combinations thereof.
79. The method according to claim 69, wherein the drug can be
released to the wall of the airway prior to, during, or after an
asthma attack.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of application
Ser. No. 11/942,459, filed Nov. 19, 2007, which claims the benefit
of priority of U.S. Provisional Application No. 60/860,084, filed
on Nov. 20, 2006, U.S. Provisional Application No. 60/880,742,
filed Jan. 17, 2007, U.S. Provisional Application No. 60/897,427,
filed on Jan. 25, 2007, U.S. Provisional Application No. 60/903,529
filed on Feb. 26, 2007, U.S. Provisional Application No. 60/904,473
filed Mar. 2, 2007, U.S. Provisional Application No. 60/926,850
filed Apr. 30, 2007, U.S. Provisional Application No. 60/981,380
filed Oct. 19, 2007, and U.S. Provisional Application 60/981,384
filed Oct. 19, 2007, the disclosures of all of which are
incorporated by reference herein.
FIELD OF THE INVENTION
[0002] Embodiments of the present invention relate to a method for
treatment of respiratory disorders such as asthma and chronic
obstructive pulmonary disease, including cystic fibrosis,
interstitial fibrosis, chronic bronchitis, emphysema,
bronchopulmonary dysplasia and neoplasia. The method involves
administration, preferably oral, nasal or pulmonary administration,
of anti-inflammatory and anti-proliferate drugs (rapamycin or
paclitaxel and their analogues).
BACKGROUND OF THE INVENTION
[0003] Chronic obstructive pulmonary disease (COPD) is a term used
to classify two major airflow obstruction disorders: chronic
bronchitis and emphysema. Approximately 16 million Americans have
COPD, 80-90% of them were smokers throughout much of their lives.
COPD is a leading cause of death in the U.S., accounting for
122,283 deaths in 2003. The cost to the USA for COPD was
approximately $20.9 billion in direct health care expenditures in
2003. Chronic bronchitis is inflammation of the bronchial airways.
The bronchial airways connect the trachea with the lungs. When
inflamed, the bronchial tubes secrete mucus, causing a chronic
cough. Emphysema is an overinflation of the alveoli, or air sacs in
the lungs. This condition causes shortness of breath.
[0004] In emphysema, the alveolar sacs are overinflated as a result
of damage to the elastin skeleton of the lung. Inflammatory cells
in emphysematous lung release elastase enzymes, which degrade or
damage elastin fibers within the lung matrix. Emphysema has a
number of causes, including smoking, exposure to environmental
pollutants, alpha-one antitrypsin deficiency, and aging.
[0005] There are no therapies available today to halt the
progression of COPD. Inhaled steroids have recently been studied
(Lung Health Study II) as a potential therapy to prevent loss of
lung function in emphysema patients. The study concluded, however,
that inhaled steroids failed to alter the decline in lung function
over time. As patients lose lung function over time, they may
become dependent on oxygen, and eventually end up on ventilators to
assist with respiration. A relatively new treatment for patients
with emphysema is lung volume reduction surgery. Emphysema patients
suffer from air trapping in the lungs. This flattens the diaphragm,
impairing the ability to inhale and exhale. Patients with emphysema
localized to the upper lung lobes are candidates for lung volume
reduction surgery, where the upper lobes are surgically removed to
restore the natural concavity and function of the diaphragm.
[0006] Acute exacerbation of asthma is often caused by spasm of the
airways, or bronchoconstriction, causing symptoms including sudden
shortness of breath, wheezing, and cough. Bronchospasm is treated
with inhaled bronchodilators (anticholinergics such as ipratropium
and beta-agonists such as albuterol). Patients inhale these
medications into their lungs as a mist, produced by either a
nebulizer or a hand-held meter dose (MDI) or dry powder (DPI)
inhaler. Patients with acute episodes may also be treated with oral
or intravenous steroids that serve to reduce the inflammatory
response that exacerbates the condition.
[0007] Asthma is a chronic respiratory disease characterized by
inflammation of the airways, excess mucus production and airway
hyper responsiveness, and a condition in which airways narrow
excessively or too easily respond to a stimulus. Asthma episodes or
attacks cause narrowing of the airways, which make breathing
difficult. Asthma attacks can have a significant impact on a
patient's life, limiting participation in many activities. In
severe cases, asthma attacks can be life threatening. Presently,
there is no known cure for asthma.
[0008] According to the American Lung Association, there are
approximately 20 million Americans with asthma in 2002. Fourteen
million of them were adults. Asthma resulted in approximately 1.9
million emergency room visits in 2002. The estimated direct cost of
asthma in the U.S. is $11.5 billion, which is spent on asthma
medications, physician office visits, emergency room visits and
hospitalizations.
[0009] The causes of coronary heart disease and asthma are
neointimal proliferation of smooth muscle in arterial vessels and
in walls of airways. One aspect of the invention is to deliver
paclitaxel or rapamycin and their analogues to the wall of airways
to treat the asthma and COPD. Drug coated stents with these drugs
have been approved for inhibiting the growth of the smooth muscle
cells in vascular arterial vessels.
[0010] Chronic sinusitis is an inflammation of the membrane lining
of one or more paranasal sinuses. Chronic sinusitis lasts longer
than three weeks and often continues for months. In cases of
chronic sinusitis, there is usually tissue damage. According to the
Center for Disease Control (CDC), thirty seven million cases of
chronic sinusitis are reported annually.
[0011] Chronic sinusitis is often difficult to treat successfully,
however, as some symptoms persist even after prolonged courses of
antibiotics. Steroid nasal sprays and prescribed steroids are
commonly used to treat inflammation in chronic sinusitis. When
medical treatment fails, surgery may be the only alternative in
treating chronic sinusitis. Presently, the most common surgery done
is functional endoscopic sinus surgery, in which the diseased and
thickened tissues from the sinuses are removed to allow drainage.
However, there is a need for better medicine for chronic
sinusitis.
[0012] The present invention provides a new method for treatment of
respiratory disorders such as asthma, chronic obstructive pulmonary
disease, and chronic sinusitis. The method involves administration,
preferably oral, nasal or pulmonary administration, of
anti-inflammatory and anti-proliferate drugs (rapamycin or
paclitaxel and their analogues) and an additive. Embodiments of the
present invention provide a pharmaceutical formulation comprising a
drug for treatment of the respiratory system, and an additive that
enhances absorption of the drug into tissue of body passages.
SUMMARY OF THE INVENTION
[0013] Embodiments of the present invention are directed to the
treatment of respiratory disorders by intratracheal administration
of an effective amount of anti-inflammatory and anti-proliferate
drugs (rapamycin or paclitaxel and their analogues). Respiratory
disorders such as asthma, chronic obstructive pulmonary disease,
and chronic sinusitis include cystic fibrosis, interstitial
fibrosis, chronic bronchitis, emphysema, nasal and sinus dysplasia,
bronchopulmonary dysplasia and neoplasia. The treatment is intended
for a variety of animals, such as premature neonates to adult
humans. Administration of rapamycin or paclitaxel may be performed
by aerosol, which can be generated by a nebulizer, by inhalation or
by instillation. The rapamycin or paclitaxel may be administered
alone or with an additive carrier in solution such as saline
solution, DMSO, alcohol, or water. It may also be used as
combinations with inhaled bronchodilators (anticholinergics such as
ipratropium and beta-agonists such as albuterol) and oral or
intravenous steroids. Patients inhale these medications into their
lungs as a mist, produced by either a nebulizer or a hand-held
meter dose (MDI) or dry powder (DPI) inhaler.
[0014] The additive has a hydrophilic part and a drug affinity
part. The drug affinity part is a hydrophobic part and/or has an
affinity to the therapeutic agent by hydrogen bonding and/or van
der Waals interactions. The drug affinity part may include
aliphatic and aromatic organic hydrocarbon compounds, such as
benzene, toluene, and alkanes, among others. These parts are not
water soluble. They have no covalently bonded iodine. The
hydrophilic part may include hydroxyl groups, amine groups, amide
groups, carbonyl groups, carboxylic acid and anhydrides, ethyl
oxide, ethyl glycol, polyethylene glycol, ascorbic acid, amino
acid, amino alcohol, glucose, sucrose, sorbitan, glycerol,
polyalcohol, phosphates, sulfates, organic salts and their
substituted molecules, among others. These parts can dissolve in
water and polar solvents. These additives are not oils, lipids, or
polymers. The therapeutic agent is not enclosed in micelles or
liposomes or encapsulated in polymer particles.
[0015] Embodiments of the present invention provide a method for
treating the lung during an acute episode of reversible chronic
obstructive pulmonary disease. The coronary and peripheral diseases
result from smooth muscle cell proliferation. Asthma includes
episodes or attacks of the airway narrowing, contracting and
thickening via smooth muscle cell proliferation. The rapamycin,
paclitaxel, and their analogues can be used for treating asthma in
the lung.
[0016] Embodiments of the present invention provide a method of
treating respiratory disorders such as asthma, chronic obstructive
pulmonary disease and chronic sinusitis in a mammal comprises
administrating an antiproliferative and anti-inflammatory effective
amount of rapamycin, or paclitaxel or their analogues to said
mammal orally, parenterally, intravascularly, intranasally,
intrabronchially, transdermally, rectally, or via an impregnated
vascular stent or balloon catheter.
[0017] In one embodiment, the present invention relates to a method
for treating a respiratory disorder, such as at least one of
asthma, chronic obstructive pulmonary disease, and chronic
sinusitis, in a mammal comprising administering a pharmaceutical
formulation comprising an effective amount of a drug and an
additive to said mammal orally, parenterally, intravascularly,
intranasally, intrabronchially, transdermally, rectally, or via an
impregnated vascular stent or balloon catheter into a body passage,
wherein said drug is chosen from rapamycin and analogues thereof
and paclitaxel and analogues thereof. In one aspect of this
embodiment, the respiratory disorder, such as asthma and chronic
obstructive pulmonary disease, is chosen from chronic bronchitis,
cystic fibrosis, interstitial fibrosis, nasal and sinus dysplasia,
bronchopulmonary dysplasia and neoplasia, and emphysema. In another
aspect of this embodiment, the administering comprises delivery via
a mist route chosen from aerosol inhalation, dry powder inhalation,
liquid inhalation, and liquid instillation. In one embodiment, the
mist is produced by either a nebulizer, a hand-held meter dose
inhaler (MDI), or dry powder (DPI) inhaler.
[0018] In one embodiment of the method, the additive enhances
absorption of the drug into tissue of the body passage of the
respiratory and sinus system. In another embodiment of the method,
the additive comprises a hydrophilic part and a drug affinity part,
wherein the drug affinity part is at least one of a hydrophobic
part, a part that has an affinity to the therapeutic agent by
hydrogen bonding, and a part that has an affinity to the
therapeutic agent by van der Waals interactions. In another
embodiment, the drug is not enclosed in micelles or encapsulated in
polymer particles. In yet another embodiment, the pharmaceutical
formulation does not include oil, a lipid, or a polymer.
[0019] In one embodiment of the method, the additive is at least
one of a surfactant and a chemical compound. In one embodiment, the
chemical compound is chosen from amino alcohols, hydroxyl
carboxylic acid, ester, anhydrides, hydroxyl ketone, hydroxyl
lactone, hydroxyl ester, sugar phosphate, sugar sulfate, ethyl
oxide, ethyl glycols, amino acids, peptides, proteins, sorbitan,
glycerol, polyalcohol, phosphates, sulfates, organic acids, esters,
salts, vitamins, combinations of amino alcohol and organic acid,
and their substituted molecules. In one embodiment, the surfactant
is chosen from ionic, nonionic, aliphatic, and aromatic
surfactants, PEG fatty esters, PEG omega-3 fatty esters, ether, and
alcohols, glycerol fatty esters, sorbitan fatty esters, PEG
glyceryl fatty esters, PEG sorbitan fatty esters, sugar fatty
esters, PEG sugar esters, and derivatives thereof. In another
embodiment, the chemical compound has one or more hydroxyl, amino,
carbonyl, carboxyl, acid, amide or ester groups. In another
embodiment, the chemical compound having one or more hydroxyl,
amino, carbonyl, carboxyl, acid, amide or ester groups is chosen
from amino alcohols, hydroxyl carboxylic acid, ester, anhydrides,
hydroxyl ketone, hydroxyl lactone, hydroxyl ester, sugar phosphate,
sugar sulfate, ethyl oxide, ethyl glycols, amino acids, peptides,
proteins, sorbitan, glycerol, polyalcohol, phosphates, sulfates,
organic acids, esters, salts, vitamins, combinations of amino
alcohol and organic acid, and their substituted molecules.
[0020] In another embodiment, the additive is chosen from
p-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween 40,
Tween 60, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG
glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate,
plyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate,
polyglyceryl-6 laurate, plyglyceryl-6 oleate, polyglyceryl-6
myristate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate,
plyglyceryl-10 oleate, polyglyceryl-10 myristate, polyglyceryl-10
palmitate PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG
sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG
laurayl ether, octoxynol, monoxynol, tyloxapol, sucrose
monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,
n-decyl-.beta.-D-glucopyranoside, n-decyl-.beta.-D-maltopyranoside,
n-dodecyl-.beta.-D-glucopyranoside, n-dodecyl-.beta.-D-maltoside,
heptanoyl-N-methylglucamide, n-heptyl-.beta.-D-glucopyranoside,
n-heptyl-.beta.-D-thioglucoside, n-hexyl-.beta.-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-.beta.-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside,
octyl-.beta.-D-thioglucopyranoside; cystine, tyrosine, tryptophan,
leucine, isoleucine, phenylalanine, asparagine, aspartic acid,
glutamic acid, and methionine; acetic anhydride, benzoic anhydride,
ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone
carboxylate, ethylenediaminetetraacetic dianhydride, maleic and
anhydride, succinic anhydride, diglycolic anhydride, glutaric
anhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;
cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal
5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin
phosphate, thiamine, folic acid, menadiol diphosphate, menadione
sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6,
vitamin K6, and vitamin U; albumin, immunoglobulins, caseins,
hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin,
fibronectins, vitronectins, firbinogens, lipases, benzalkonium
chloride, benzethonium chloride, docecyl trimethyl ammonium
bromide, sodium docecylsulfates, dialkyl methylbenzyl ammonium
chloride, and dialkylesters of sodium sulfonsuccinic acid,
L-ascorbic acid and its salt, D-glucoascorbic acid and its salt,
tromethamine, triethanolamine, diethanolamine, meglumine,
glucamine, amine alcohols, glucoheptonic acid, glucomic acid,
hydroxyl ketone, hydroxyl lactone, gluconolactone,
glucoheptonolactone, glucooctanoic lactone, gulonic acid lactone,
mannoic lactone, ribonic acid lactone, lactobionic acid,
glucosamine, glutamic acid, benzyl alcohol, benzoic acid,
hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt,
gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic
acid, vanillin, methyl paraben, propyl paraben, sorbitol, xylitol,
cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,
ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,
catechin gallate, tiletamine, ketamine, propofol, lactic acids,
acetic acid, salts of any organic acid and organic amine,
polyglycidol, glycerol, multiglycerols, galactitol, di(ethylene
glycol), tri(ethylene glycol), tetra(ethylene glycol),
penta(ethylene glycol), poly(ethylene glycol) oligomers,
di(propylene glycol), tri(propylene glycol), tetra(propylene
glycol, and penta(propylene glycol), poly(propylene glycol)
oligomers, a block copolymer of polyethylene glycol and
polypropylene glycol, and derivatives and combinations thereof.
[0021] In one embodiment, the surfactant is chosen from PEG-fatty
acids and PEG-fatty acid mono and diesters, polyethylene glycol
glycerol fatty acid esters, alcohol-oil transesterification
products, polyglyceryl fatty acids, propylene glycol fatty acid
esters, sterols and derivatives thereof, polyethylene glycol
sorbitan fatty acid esters, polyethylene glycol alkyl ethers,
polyethylene glycol alkyl phenols, polyoxyethylene-polyoxypropylene
block copolymers, and sorbitan fatty acid esters. In another
embodiment, the surfactant is chosen from esters of lauric acid,
oleic acid, and stearic acid, PEG-8 laurate, PEG-8 oleate, PEG-8
stearate, PEG-9 oleate, PEG-10 laurate, PEG-10 oleate, PEG-12
laurate, PEG-12 oleate, PEG-15 oleate, PEG-20 laurate, PEG-20
oleate, PEG-20 dilaurate, PEG-20 dioleate, PEG-20 distearate,
PEG-32 dilaurate, PEG-32 dioleate, PEG-25 trioleate, PEG-60 corn
glycerides, PEG-60 almond oil, PEG-40 palm kernel oil, PEG-8
caprylic/capric glycerides, and PEG-6 caprylic/capric glycerides,
PEG-6 corn oil, PEG-6 almond oil, PEG-6 apricot kernel oil, PEG-6
olive oil, PEG-6 peanut oil, PEG-6 hydrogenated palm kernel oil,
PEG-6 palm kernel oil, PEG-6 triolein, PEG-8 corn oil, PEG-20 corn
glycerides, PEG-20 almond glycerides, polyglyceryl oleate,
polyglyceryl-2 dioleate, polyglyceryl-10 trioleate, polyglyceryl
stearate, polyglyceryl laurate, polyglyceryl myristate,
polyglyceryl palmitate, and polyglyceryl linoleate, polyglyceryl-10
laurate, polyglyceryl-10 oleate, polyglyceryl-10 mono, dioleate,
polyglyceryl-10 stearate, polyglyceryl-10 laurate, polyglyceryl-10
myristate, polyglyceryl-10 palmitate, polyglyceryl-10 linoleate,
polyglyceryl-6 stearate, polyglyceryl-6 laurate, polyglyceryl-6
myristate, polyglyceryl-6 palmitate, and polyglyceryl-6 linoleate,
polyglyceryl polyricinoleate, propylene glycol monolaurate,
propylene glycol ricinoleate, propylene glycol monooleate,
propylene glycol dicaprylate/dicaprate, propylene glycol
dioctanoate, PEG-20 sorbitan monolaurate, PEG-20 sorbitan
monopalmitate, PEG-20 sorbitan monostearate, PEG-20 sorbitan
monooleate, PEG-10-100 nonyl phenol, PEG-15-100 octyl phenol ether,
Tyloxapol, octoxynol, nonoxynol, sucrose monopalmitate, sucrose
monolaurate, decanoyl-N-methylglucamide,
n-decyl-.beta.-D-glucopyranoside, n-decyl-.beta.-D-maltopyranoside,
n-dodecyl-.beta.-D-glucopyranoside, n-dodecyl-.beta.-D-maltoside,
heptanoyl-N-methylglucamide, n-heptyl-.beta.-D-glucopyranoside,
n-heptyl-.beta.-D-thioglucoside, n-hexyl-.beta.-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-.beta.-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside,
octyl-.beta.-D-thioglucopyranoside, sorbitan monolaurate, sorbitan
monopalmitate, sorbitan monooleate, sorbitan monostearate,
benzalkonium chloride, benzethonium chloride, cetylpyridinium
chloride, docecyl trimethyl ammonium bromide, sodium
docecylsulfates, dialkyl methylbenzyl ammonium chloride,
edrophonium chloride, domiphen bromide, dialkylesters of sodium
sulfonsuccinic acid, sodium dioctyl sulfosuccinate, sodium cholate,
sodium taurocholate, and derivatives thereof.
[0022] In one embodiment, the chemical compound having one or more
hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups is
chosen from cystine, tyrosine, tryptophan, leucine, isoleucine,
phenylalanine, asparagine, aspartic acid, glutamic acid, and
methionine (Aminoacids); acetic anhydride, benzoic anhydride,
ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone
carboxylate, ethylenediaminetetraacetic dianhydride, maleic and
anhydride, succinic anhydride, diglycolic anhydride, glutaric
anhydride, acetiamine, benfotiamine, pantothenic acid (organic
acids and anhydrides); cetotiamine; cyclothiamine, dexpanthenol,
niacinamide, nicotinic acid, pyridoxal 5-phosphate, nicotinamide
ascorbate, riboflavin, riboflavin phosphate, thiamine, folic acid,
menadiol diphosphate, menadione sodium bisulfite, menadoxime,
vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitamin U
(vitamins); albumin, immunoglobulins, caseins, hemoglobins,
lysozymes, immunoglobins, a-2-macroglobulin, fibronectins,
vitronectins, firbinogens, lipases, L-ascorbic acid and its salt,
D-glucoascorbic acid and its salt, tromethamine, triethanolamine,
diethanolamine, meglumine, glucamine, amine alcohols, glucoheptonic
acid, glucomic acid, gluconolactone, D-glucoheptono-1,4-lactone,
glucooctanoic lactone, gulonic acid lactone, mannoic lactone,
erythronic acid lactone, ribonic acid lactone, glucosamine,
glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid,
propyl 4-hydroxybenzoate, lysine acetate salt, gentisic acid,
lactobionic acid, lactitol, sinapic acid, vanillic acid, vanillin,
methyl paraben, propyl paraben, acetaminophen, ibuprofen, retinoic
acid, lysine acetate, gentisic acid, catechin, catechin gallate,
tiletamine, ketamine, propofol, lactic acids, acetic acid, salts of
any organic acid and organic amine, lysine/glutamic acid, lysine
acetate, lactobionic acid/meglumine, lactobionic
acid/tromethanemine, lactobionic acid/diethanolamine, lactic
acid/meglumine, lactic acid/tromethanemine, lactic
acid/diethanolamine, gentisic acid/meglumine, gentisic
acid/tromethanemine, gensitic acid/diethanolamine, vanillic
acid/meglumine, vanillic acid/tromethanemine, vanillic
acid/diethanolamine, benzoic acid/meglumine, benzoic
acid/tromethanemine, benzoic acid/diethanolamine, acetic
acid/meglumine, acetic acid/tromethanemine, acetic
acid/diethanolamine, polyglycidol, glycerols, multiglycerols, and
derivatives thereof.
[0023] In one embodiment of the method, the pharmaceutical
formulation further comprises an additional drug. In one aspect of
this embodiment, the additional drug is chosen from
corticosteroids, anticholinergics, beta-agonists, non-steroidal
anti-inflammatory drugs, macrolide antibiotics, bronchodilators,
leukotriene receptor inhibitors, cromolyn sulfate, and combinations
thereof.
[0024] In one embodiment, the additive is chosen from PEG fatty
esters and alcohols, glycerol fatty esters, sorbitan fatty esters,
PEG glyceryl fatty esters, PEG sorbitan fatty esters, sugar fatty
esters, PEG sugar esters, vitamins and derivatives, aminoacids,
multiaminoacids and derivatives, peptides, polypeptides, proteins,
quaternary ammonium salts, organic acids, salts and anhydrides. In
another embodiment, the additive in the coating layer overlying the
surface of the balloon is chosen from
p-isononylphenoxypolyglycidol, PEG laurate, PEG oleate, PEG
stearate, PEG glyceryl laurate, PEG glyceryl oleate, PEG glyceryl
stearate, polyglyceryl laurate, plyglyceryl oleate, polyglyceryl
myristate, polyglyceryl palmitate, polyglyceryl-6 laurate,
plyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6
palmitate, polyglyceryl-10 laurate, plyglyceryl-10 oleate,
polyglyceryl-10 myristate, polyglyceryl-10 palmitate PEG sorbitan
monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEG
sorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol,
monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate,
decanoyl-N-methylglucamide, n-decyl-.beta.-D-glucopyranoside,
n-decyl-.beta.-D-maltopyranoside,
n-dodecyl-.beta.-D-glucopyranoside, n-dodecyl-.beta.-D-maltoside,
heptanoyl-N-methylglucamide, n-heptyl-.beta.-D-glucopyranoside,
n-heptyl-.beta.-D-thioglucoside, n-hexyl-.beta.-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-.beta.-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside,
octyl-.beta.-D-thioglucopyranoside; benzalkonium chloride,
benzethonium chloride, docecyl trimethyl ammonium bromide, sodium
docecylsulfates, dialkyl methylbenzyl ammonium chloride, and
dialkylesters of sodium sulfonsuccinic acid (ionic surfactants),
cystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine,
asparagine, aspartic acid, glutamic acid, and methionine (amino
acids); acetic anhydride, benzoic anhydride, ascorbic acid,
2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone carboxylate,
ethylenediaminetetraacetic dianhydride, maleic and anhydride,
succinic anhydride, diglycolic anhydride, glutaric anhydride,
acetiamine, benfotiamine, pantothenic acid (organic acids and
anhydrides); cetotiamine; cyclothiamine, dexpanthenol, niacinamide,
nicotinic acid, pyridoxal 5-phosphate, nicotinamide ascorbate,
riboflavin, riboflavin phosphate, thiamine, folic acid, menadiol
diphosphate, menadione sodium bisulfite, menadoxime, vitamin B12,
vitamin K5, vitamin K6, vitamin K6, and vitamin U (vitamins);
albumin, immunoglobulins, caseins, hemoglobins, lysozymes,
immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,
firbinogens, lipases, L-ascorbic acid and its salt, D-glucoascorbic
acid and its salt, triethanolamine, diethanolamine, meglumine,
tromethamine, glucamine, glucosamine, glucoheptonic acid, glucomic
acid, gluconolactone, D-glucoheptono-1,4-lactone, glucooctanoic
lactone, gulonic acid lactone, mannoic lactone, erythronic acid
lactone, ribonic acid lactone, glucosamine, glutamic acid, benzyl
alcohol, benzoic acid, hydroxybenzoic acid, vanillin, vanillic
acid, vanillic acid diethylamide, lysine acetate salt, gentisic
acid, lactobionic acid, lactitol, acetaminophen, ibuprofen,
catechin, catechin gallate, methyl paraben, ethyl paraben, propyl
paraben, butyl paraben, tiletamine, ketamine, propofol, lactic
acids, acetic acid, salts of any organic acid and amine above
described, polyglycidol, glycerols and multiglycerols (chemical
compounds with multiple hydroxyl, amino, carbonyl, carboxyl, or
ester moieties).
[0025] In another aspect of this embodiment, the ionic surfactant
is chosen from benzalkonium chloride, benzethonium chloride,
cetylpyridinium chloride, docecyl trimethyl ammonium bromide,
sodium docecylsulfates, dialkyl methylbenzyl ammonium chloride,
edrophonium chloride, domiphen bromide, and dialkylesters of sodium
sulfonsuccinic acid, sodium dioctyl sulfosuccinate, sodium cholate,
and sodium taurocholate.
[0026] In one embodiment of the method, the additive is chosen from
PEG-fatty acids and PEG-fatty acid mono and diesters, polyethylene
glycol glycerol fatty acid esters, alcohol-oil transesterification
products, polyglyceryl fatty acids, propylene glycol fatty acid
esters, sterols and derivatives thereof, polyethylene glycol
sorbitan fatty acid esters, polyethylene glycol alkyl ethers,
sugars and derivatives thereof, polyethylene glycol alkyl phenols,
polyoxyethylene-polyoxypropylene block copolymers, sorbitan fatty
acid esters, fat-soluble vitamins and salts thereof, water-soluble
vitamins and amphiphilic derivatives thereof, amino acid and salts
thereof, oligopeptides, peptides and proteins, and organic acids
and esters and anhydrides thereof.
[0027] In another embodiment of the method, the additive is chosen
from esters of lauric acid, oleic acid, and stearic acid, PEG-8
laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10
laurate, PEG-10 oleate, PEG-12 laurate, PEG-12 oleate, PEG-15
oleate, PEG-20 laurate, and PEG-20 oleate. In another embodiment,
the additive is chosen from PEG-20 dilaurate, PEG-20 dioleate,
PEG-20 distearate, PEG-32 dilaurate and PEG-32 dioleate. In another
embodiment of the method, the additive is chosen from PEG-20
glyceryl laurate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate,
PEG-20 glyceryl oleate, and PEG-30 glyceryl oleate. In another
embodiment of the method, the additive is chosen from PEG-25
trioleate, PEG-60 corn glycerides, PEG-60 almond oil, PEG-40 palm
kernel oil, PEG-8 caprylic/capric glycerides, and PEG-6
caprylic/capric glycerides, PEG-6 corn oil, PEG-6 almond oil, PEG-6
apricot kernel oil, PEG-6 olive oil, PEG-6 peanut oil, PEG-6
hydrogenated palm kernel oil, PEG-6 palm kernel oil, PEG-6
triolein, PEG-8 corn oil, PEG-20 corn glycerides, and PEG-20 almond
glycerides.
[0028] In another embodiment of the method, the additive is chosen
from polyglyceryl oleate, polyglyceryl-2 dioleate, polyglyceryl-10
trioleate, polyglyceryl stearate, polyglyceryl laurate,
polyglyceryl myristate, polyglyceryl palmitate, and polyglyceryl
linoleate, polyglyceryl-10 laurate, polyglyceryl-10 oleate,
polyglyceryl-10 mono, dioleate, polyglyceryl-10 stearate,
polyglyceryl-10 laurate, polyglyceryl-10 myristate, polyglyceryl-10
palmitate, polyglyceryl-10 linoleate, polyglyceryl-6 stearate,
polyglyceryl-6 laurate, polyglyceryl-6 myristate, polyglyceryl-6
palmitate, and polyglyceryl-6 linoleate, and polyglyceryl
polyricinoleate. In another embodiment of the method, the additive
is chosen from propylene glycol monolaurate, propylene glycol
ricinoleate, propylene glycol monooleate, propylene glycol
dicaprylate/dicaprate, and propylene glycol dioctanoate. In another
embodiment of the method, the additive is PEG-24 cholesterol ether.
In another embodiment of the method, the additive is chosen from
sterol polyethylene glycol derivatives.
[0029] In another embodiment of the method, the additive is chosen
from PEG-20 sorbitan monolaurate, PEG-20 sorbitan monopalmitate,
PEG-20 sorbitan monostearate, and PEG-20 sorbitan monooleate. In
another embodiment of the method, the additive is chosen from PEG-3
oleyl ether and PEG-4 lauryl ether. In another embodiment of the
method, the additive is chosen from sucrose monopalmitate, sucrose
monolaurate, decanoyl-N-methylglucamide,
n-decyl-.beta.-D-glucopyranoside, n-decyl-.beta.-D-maltopyranoside,
n-dodecyl-.beta.-D-glucopyranoside, n-dodecyl-.beta.-D-maltoside,
heptanoyl-N-methylglucamide, n-heptyl-.beta.-D-glucop-yranoside,
n-heptyl-.beta.-D-thioglucoside, n-hexyl-.beta.-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-.beta.-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside, and
octyl-.beta.-D-thioglucopyranoside.
[0030] In another embodiment of the method, the additive is chosen
from PEG-10-100 nonyl phenol, PEG-15-100 octyl phenol ether,
Tyloxapol, octoxynol, and nonoxynol. In another embodiment of the
method, the additive is chosen from poloxamer 108, poloxamer 188,
poloxamer 217, poloxamer 238, poloxamer 288, poloxamer 338, and
poloxamer 407. In another embodiment of the method, the additive is
chosen from poloxamer 124, poloxamer 182, poloxamer 183, poloxamer
212, poloxamer 331, and poloxamer 335. In another embodiment of the
method, the additive is chosen from sorbitan monolaurate, sorbitan
monopalmitate, sorbitan monooleate, and sorbitan monostearate. In
another embodiment of the method, the additive is chosen from
alpha-tocopherol, beta-tocopherol, gamma-tocopherol,
delta-tocopherol, tocopherol acetate, ergosterol,
1-alpha-hydroxycholecal-ciferol, vitamin D2, vitamin D3,
alpha-carotene, beta-carotene, gamma-carotene, vitamin A,
fursultiamine, methylolriboflavin, octotiamine, prosultiamine,
riboflavine, vintiamol, dihydrovitamin K1, menadiol diacetate,
menadiol dibutyrate, menadiol disulfate, menadiol, vitamin K1,
vitamin K1 oxide, vitamins K2, and vitamin K-S(II), and folic
acid.
[0031] In another embodiment of the method, the additive is chosen
from acetiamine, benfotiamine, pantothenic acid, cetotiamine,
cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal
5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin
phosphate, thiamine, folic acid, menadiol diphosphate, menadione
sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6,
vitamin K6, and vitamin U. In another embodiment of the method, the
additive is chosen from alanine, arginine, asparagines, aspartic
acid, cysteine, glutamic acid, glutamine, glycine, histidine,
proline, isoleucine, leucine, lysine, methionine, phenylalanine,
serine, threonine, tryptophan, tyrosine, and valine, and salts of
any of the foregoing. In another embodiment of the method, the
additive is albumin. In another embodiment of the method, the
additive is chosen from n-octyl-.beta.-D-glucopyranoside,
octoxynol-9, Polysorbates, Tyloxapol, octoxynol, nonoxynol,
isononylphenylpolyglycidol, PEG glyceryl monooleate, sorbitan
monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan
monostearate, polyglyceryl-10 oleate, polyglyceryl-10 laurate,
polyglyceryl-10 palmitate, polyglyceryl-10 stearate, L-ascorbic
acid, thiamine, maleic anhydride, niacinamide, and
2-pyrrolidone-5-carboxylic acid.
[0032] In another embodiment of the method, the additive is chosen
from riboflavin, riboflavin-phosphate sodium, Vitamin D3, folic
acid, vitamin 12, diethylenetriaminepentaacetic acid dianhydride,
ethylenediaminetetraacetic dianhydride, maleic acid and anhydride,
succinic acid and anhydride, diglycolic anhydride, glutaric
anhydride, L-ascorbic acid, thiamine, nicotinamide, nicotinic acid,
2-pyrrolidone-5-carboxylic acid, cystine, tyrosine, tryptophan,
leucine, isoleucine, phenylalanine, asparagine, aspartic acid,
glutamic acid, and methionine.
[0033] In another embodiment of the method, the additive is chosen
from isononylphenylpolyglycidol, PEG glyceryl monooleate, sorbitan
monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan
monostearate, polyglyceryl-10 oleate, polyglyceryl-10 laurate,
polyglyceryl-10 palmitate, and polyglyceryl-10 stearate. In another
embodiment of the method, the additive is chosen from L-ascorbic
acid, thiamine, maleic acids, niacinamide, and
2-pyrrolidone-5-carboxylic acid. In another embodiment of the
method, the additive is chosen from Vitamin D2 and D3.
[0034] In one embodiment, the present invention relates to a
pharmaceutical formulation comprising an effective amount of a drug
for treatment of a respiratory or sinus system, and an additive
that enhances absorption of the drug into tissue of the respiratory
system. In one aspect of this embodiment, the additive comprises a
hydrophilic part and a drug affinity part, wherein the drug
affinity part is at least one of a hydrophobic part, a part that
has an affinity to the therapeutic agent by hydrogen bonding, and a
part that has an affinity to the therapeutic agent by van der Waals
interactions. In another aspect of this embodiment, the drug is not
enclosed in micelles or encapsulated in polymer particles. In
another aspect of this embodiment, the formulation does not include
oil, a lipid, or a polymer. In yet another aspect of this
embodiment, the formulation is an aqueous aerosol formulation, a
dry powder aerosol formulation, or a propellant-based
formulation.
[0035] In one embodiment of the pharmaceutical formulation, the
drug is chosen from paclitaxel and analogues thereof and rapamycin
and analogues thereof. In one aspect of this embodiment, the drug
is present in a concentration of about 0.05 mg/ml to about 600
mg/ml.
[0036] In one embodiment of the pharmaceutical formulation, the
additive is at least one of a surfactant and a chemical compound.
In one embodiment, the chemical compound is chosen from amino
alcohols, hydroxyl carboxylic acid, ester, anhydrides, hydroxyl
ketone, hydroxyl lactone, hydroxyl ester, sugar phosphate, sugar
sulfate, ethyl oxide, ethyl glycols, amino acids, peptides,
proteins, sorbitan, glycerol, polyalcohol, phosphates, sulfates,
organic acids, esters, salts, vitamins, combinations of amino
alcohol and organic acid, and their substituted molecules. In one
embodiment, the surfactant is chosen from ionic, nonionic,
aliphatic, and aromatic surfactants, PEG fatty esters, PEG omega-3
fatty esters, ether, and alcohols, glycerol fatty esters, sorbitan
fatty esters, PEG glyceryl fatty esters, PEG sorbitan fatty esters,
sugar fatty esters, PEG sugar esters, and derivatives thereof. In
one embodiment, the chemical compound has one or more hydroxyl,
amino, carbonyl, carboxyl, acid, amide or ester groups. In one
aspect of this embodiment, the chemical compound having one or more
hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups is
chosen from amino alcohols, hydroxyl carboxylic acid, ester,
anhydrides, hydroxyl ketone, hydroxyl lactone, hydroxyl ester,
sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols, amino
acids, peptides, proteins, sorbitan, glycerol, polyalcohol,
phosphates, sulfates, organic acids, esters, salts, vitamins,
combinations of amino alcohol and organic acid, and their
substituted molecules. In another aspect of this embodiment, the
chemical compound having one or more hydroxyl, amino, carbonyl,
carboxyl, acid, amide or ester groups is chosen from cystine,
tyrosine, tryptophan, leucine, isoleucine, phenylalanine,
asparagine, aspartic acid, glutamic acid, and methionine; acetic
anhydride, benzoic anhydride, ascorbic acid,
2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone carboxylate,
ethylenediaminetetraacetic dianhydride, maleic and anhydride,
succinic anhydride, diglycolic anhydride, glutaric anhydride,
acetiamine, benfotiamine, pantothenic acid cetotiamine;
cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal
5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin
phosphate, thiamine, folic acid, menadiol diphosphate, menadione
sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6,
vitamin K6, and vitamin U; albumin, immunoglobulins, caseins,
hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin,
fibronectins, vitronectins, firbinogens, lipases, L-ascorbic acid
and its salt, D-glucoascorbic acid and its salt, tromethamine,
triethanolamine, diethanolamine, meglumine, glucamine, amine
alcohols, glucoheptonic acid, glucomic acid, gluconolactone,
D-glucoheptono-1,4-lactone, glucooctanoic lactone, gulonic acid
lactone, mannoic lactone, erythronic acid lactone, ribonic acid
lactone, glucosamine, glutamic acid, benzyl alcohol, benzoic acid,
hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt,
gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic
acid, vanillin, methyl paraben, propyl paraben, acetaminophen,
ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,
catechin gallate, tiletamine, ketamine, propofol, lactic acids,
acetic acid, salts of any organic acid and amine above described,
lysine/glutamic acid, lysine acetate,_lactobionic acid/meglumine,
lactobionic acid/tromethanemine, lactobionic acid/diethanolamine,
lactic acid/meglumine, lactic acid/tromethanemine, lactic
acid/diethanolamine, gentisic acid/meglumine, gentisic
acid/tromethanemine, gensitic acid/diethanolamine, vanillic
acid/meglumine, vanillic acid/tromethanemine, vanillic
acid/diethanolamine, benzoic acid/meglumine, benzoic
acid/tromethanemine, benzoic acid/diethanolamine, acetic
acid/meglumine, acetic acid/tromethanemine, and acetic
acid/diethanolamine, polyglycidol, glycerols, multiglycerols and a
mixture of the additives, and their derivatives.
[0037] In one embodiment of the pharmaceutical formulation, the
additive is chosen from p-isononylphenoxypolyglycidol, PEG laurate,
Tween 20, Tween 40, Tween 60, PEG oleate, PEG stearate, PEG
glyceryl laurate, PEG glyceryl oleate, PEG glyceryl stearate,
polyglyceryl laurate, plyglyceryl oleate, polyglyceryl myristate,
polyglyceryl palmitate, polyglyceryl-6 laurate, plyglyceryl-6
oleate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate,
polyglyceryl-10 laurate, plyglyceryl-10 oleate, polyglyceryl-10
myristate, polyglyceryl-10 palmitate PEG sorbitan monolaurate, PEG
sorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan
stearate, PEG oleyl ether, PEG laurayl ether, octoxynol, monoxynol,
tyloxapol, sucrose monopalmitate, sucrose monolaurate,
decanoyl-N-methylglucamide, n-decyl-.beta.-D-glucopyranoside,
n-decyl-.beta.-D-maltopyranoside,
n-dodecyl-.beta.-D-glucopyranoside, n-dodecyl-.beta.-D-maltoside,
heptanoyl-N-methylglucamide, n-heptyl-.beta.-D-glucopyranoside,
n-heptyl-.beta.-D-thioglucoside, n-hexyl-.beta.-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-.beta.-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside,
octyl-.beta.-D-thioglucopyranoside; cystine, tyrosine, tryptophan,
leucine, isoleucine, phenylalanine, asparagine, aspartic acid,
glutamic acid, and methionine; acetic anhydride, benzoic anhydride,
ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone
carboxylate, ethylenediaminetetraacetic dianhydride, maleic and
anhydride, succinic anhydride, diglycolic anhydride, glutaric
anhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;
cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal
5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin
phosphate, thiamine, folic acid, menadiol diphosphate, menadione
sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6,
vitamin K6, and vitamin U; albumin, immunoglobulins, caseins,
hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin,
fibronectins, vitronectins, firbinogens, lipases, benzalkonium
chloride, benzethonium chloride, docecyl trimethyl ammonium
bromide, sodium docecylsulfates, dialkyl methylbenzyl ammonium
chloride, and dialkylesters of sodium sulfonsuccinic acid,
L-ascorbic acid and its salt, D-glucoascorbic acid and its salt,
tromethamine, triethanolamine, diethanolamine, meglumine,
glucamine, amine alcohols, glucoheptonic acid, glucomic acid,
hydroxyl ketone, hydroxyl lactone, gluconolactone,
glucoheptonolactone, glucooctanoic lactone, gulonic acid lactone,
mannoic lactone, ribonic acid lactone, lactobionic acid,
glucosamine, glutamic acid, benzyl alcohol, benzoic acid,
hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt,
gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic
acid, vanillin, methyl paraben, propyl paraben, sorbitol, xylitol,
cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,
ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,
catechin gallate, tiletamine, ketamine, propofol, lactic acids,
acetic acid, salts of any organic acid and organic amine,
polyglycidol, glycerol, multiglycerols, galactitol, di(ethylene
glycol), tri(ethylene glycol), tetra(ethylene glycol),
penta(ethylene glycol), poly(ethylene glycol) oligomers,
di(propylene glycol), tri(propylene glycol), tetra(propylene
glycol, and penta(propylene glycol), poly(propylene glycol)
oligomers, a block copolymer of polyethylene glycol and
polypropylene glycol, and derivatives and combinations thereof.
[0038] In one embodiment of the pharmaceutical formulation, the
surfactant is chosen from esters of lauric acid, oleic acid, and
stearic acid, PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-9
oleate, PEG-10 laurate, PEG-10 oleate, PEG-12 laurate, PEG-12
oleate, PEG-15 oleate, PEG-20 laurate, PEG-20 oleate, PEG-20
dilaurate, PEG-20 dioleate, PEG-20 distearate, PEG-32 dilaurate,
PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate,
PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, PEG-30 glyceryl
oleate, PEG-25 trioleate, PEG-60 corn glycerides, PEG-60 almond
oil, PEG-40 palm kernel oil, PEG-8 caprylic/capric glycerides,
PEG-6 caprylic/capric glycerides, PEG-6 corn oil, PEG-6 almond oil,
PEG-6 apricot kernel oil, PEG-6 olive oil, PEG-6 peanut oil, PEG-6
hydrogenated palm kernel oil, PEG-6 palm kernel oil, PEG-6
triolein, PEG-8 corn oil, PEG-20 corn glycerides, PEG-20 almond
glycerides, polyglyceryl oleate, polyglyceryl-2 dioleate,
polyglyceryl-10 trioleate, polyglyceryl stearate, polyglyceryl
laurate, polyglyceryl myristate, polyglyceryl palmitate, and
polyglyceryl linoleate, polyglyceryl-10 laurate, polyglyceryl-10
oleate, polyglyceryl-10 mono, dioleate, polyglyceryl-10 stearate,
polyglyceryl-10 laurate, polyglyceryl-10 myristate, polyglyceryl-10
palmitate, polyglyceryl-10 linoleate, polyglyceryl-6 stearate,
polyglyceryl-6 laurate, polyglyceryl-6 myristate, polyglyceryl-6
palmitate, and polyglyceryl-6 linoleate, and polyglyceryl
polyricinoleate, propylene glycol monolaurate, propylene glycol
ricinoleate, propylene glycol monooleate, propylene glycol
dicaprylate/dicaprate, propylene glycol dioctanoate, PEG-20
sorbitan monolaurate, PEG-20 sorbitan monopalmitate, PEG-20
sorbitan monostearate, PEG-20 sorbitan monooleate, PEG-3 oleyl
ether and PEG-4 lauryl ether, sucrose monopalmitate, sucrose
monolaurate, decanoyl-N-methylglucamide,
n-decyl-.beta.-D-glucopyranoside, n-decyl-.beta.-D-maltopyranoside,
n-dodecyl-.beta.-D-glucopyranoside, n-dodecyl-.beta.-D-maltoside,
heptanoyl-N-methylglucamide, n-heptyl-.beta.-D-glucopyranoside,
n-heptyl-.beta.-D-thioglucoside, n-hexyl-.beta.-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-.beta.-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside,
octyl-.beta.-D-thioglucopyranoside, PEG-10-100 nonyl phenol,
PEG-15-100 octyl phenol ether, Tyloxapol, octoxynol, nonoxynol,
sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate,
sorbitan monostearate, benzalkonium chloride, benzethonium
chloride, docecyl trimethyl ammonium bromide, sodium
docecylsulfates, dialkyl methylbenzyl ammonium chloride, and
dialkylesters of sodium sulfonsuccinic acid (ionic surfactants),
n-octyl-.beta.-D-glucopyranoside, octoxynol-9, Polysorbates,
Tyloxapol, octoxynol, nonoxynol, isononylphenylpolyglycidol, PEG
glyceryl monooleate, sorbitan monolaurate, sorbitan monopalmitate,
sorbitan monooleate, sorbitan monostearate, polyglyceryl-10 oleate,
polyglyceryl-10 laurate, polyglyceryl-10 palmitate, polyglyceryl-10
stearate, and their derivatives.
[0039] In one embodiment of the pharmaceutical formulation, the
additive is chosen from PEG-fatty acids and PEG-fatty acid mono and
diesters, polyethylene glycol glycerol fatty acid esters,
alcohol-oil transesterification products, polyglyceryl fatty acids,
propylene glycol fatty acid esters, sterol and derivatives thereof,
polyethylene glycol sorbitan fatty acid esters, polyethylene glycol
alkyl ethers, sugars and derivatives thereof, polyethylene glycol
alkyl phenols, polyoxyethylene-polyoxypropylene block copolymers,
sorbitan fatty acid esters, fat-soluble vitamins and salts thereof,
water-soluble vitamins and amphiphilic derivatives thereof, amino
acid and salts thereof, oligopeptides, peptides and proteins, and
organic acids and esters and anhydrides thereof. In another
embodiment of the pharmaceutical formulation, the additive is
chosen from esters of lauric acid, oleic acid, and stearic acid,
PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10
laurate, PEG-10 oleate, PEG-12 laurate, PEG-12 oleate, PEG-15
oleate, PEG-20 laurate, and PEG-20 oleate.
[0040] In one embodiment of the pharmaceutical formulation, the
additive is chosen from PEG-20 dilaurate, PEG-20 dioleate, PEG-20
distearate, PEG-32 dilaurate and PEG-32 dioleate. In another
embodiment of the pharmaceutical formulation, the additive is
chosen from PEG-20 glyceryl laurate, PEG-30 glyceryl laurate,
PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, and PEG-30
glyceryl oleate. In another embodiment of the pharmaceutical
formulation, the additive is chosen from PEG-25 trioleate, PEG-60
corn glycerides, PEG-60 almond oil, PEG-40 palm kernel oil, PEG-8
caprylic/capric glycerides, PEG-6 caprylic/capric glycerides, PEG-6
corn oil, PEG-6 almond oil, PEG-6 apricot kernel oil, PEG-6 olive
oil, PEG-6 peanut oil, PEG-6 hydrogenated palm kernel oil, PEG-6
palm kernel oil, PEG-6 triolein, PEG-8 corn oil, PEG-20 corn
glycerides, and PEG-20 almond glycerides.
[0041] In one embodiment of the pharmaceutical formulation, the
additive is chosen from polyglyceryl oleate, polyglyceryl-2
dioleate, polyglyceryl-10 trioleate, polyglyceryl stearate,
polyglyceryl laurate, polyglyceryl myristate, polyglyceryl
palmitate, and polyglyceryl linoleate, polyglyceryl-10 laurate,
polyglyceryl-10 oleate, polyglyceryl-10 mono, dioleate,
polyglyceryl-10 stearate, polyglyceryl-10 laurate, polyglyceryl-10
myristate, polyglyceryl-10 palmitate, polyglyceryl-10 linoleate,
polyglyceryl-6 stearate, polyglyceryl-6 laurate, polyglyceryl-6
myristate, polyglyceryl-6 palmitate, and polyglyceryl-6 linoleate,
and polyglyceryl polyricinoleate. In another embodiment of the
pharmaceutical formulation, the additive is chosen from propylene
glycol monolaurate, propylene glycol ricinoleate, propylene glycol
monooleate, propylene glycol dicaprylate/dicaprate, and propylene
glycol dioctanoate.
[0042] In one embodiment of the pharmaceutical formulation, the
additive is PEG-24 cholesterol ether. In another embodiment of the
pharmaceutical formulation, the additive is chosen from sterol
polyethylene glycol derivatives. In another embodiment of the
pharmaceutical formulation, the additive is chosen from PEG-20
sorbitan monolaurate, PEG-20 sorbitan monopalmitate, PEG-20
sorbitan monostearate, and PEG-20 sorbitan monooleate. In another
embodiment of the pharmaceutical formulation, the additive is
chosen from PEG-3 oleyl ether and PEG-4 lauryl ether.
[0043] In one embodiment of the pharmaceutical formulation, the
additive is chosen from sucrose monopalmitate, sucrose monolaurate,
decanoyl-N-methylglucamide, n-decyl-.beta.-D-glucopyranoside,
n-decyl-.beta.-D-maltopyranoside,
n-dodecyl-.beta.-D-glucopyranoside, n-dodecyl-.beta.-D-maltoside,
heptanoyl-N-methylglucamide, n-heptyl-.beta.-D-glucopyranoside,
n-heptyl-.beta.-D-thioglucoside, n-hexyl-.beta.-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-.beta.-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside, and
octyl-.beta.-D-thioglucopyranoside. In another embodiment of the
pharmaceutical formulation, the additive is chosen from PEG-10-100
nonyl phenol, PEG-15-100 octyl phenol ether, Tyloxapol, octoxynol,
and nonoxynol. In another embodiment of the pharmaceutical
formulation, the additive is chosen from poloxamer 108, poloxamer
188, poloxamer 217, poloxamer 238, poloxamer 288, poloxamer 338,
and poloxamer 407. In another embodiment of the pharmaceutical
formulation, the additive is chosen from poloxamer 124, poloxamer
182, poloxamer 183, poloxamer 212, poloxamer 331, and poloxamer
335.
[0044] In one embodiment of the pharmaceutical formulation, the
additive is chosen from sorbitan monolaurate, sorbitan
monopalmitate, sorbitan monooleate, and sorbitan monostearate. In
another embodiment of the pharmaceutical formulation, the additive
is chosen from alpha-tocopherol, beta-tocopherol, gamma-tocopherol,
delta-tocopherol, tocopherol acetate, ergosterol,
1-alpha-hydroxycholecal-ciferol, vitamin D2, vitamin D3,
alpha-carotene, beta-carotene, gamma-carotene, vitamin A,
fursultiamine, methylolriboflavin, octotiamine, prosultiamine,
riboflavine, vintiamol, dihydrovitamin K1, menadiol diacetate,
menadiol dibutyrate, menadiol disulfate, menadiol, vitamin K1,
vitamin K1 oxide, vitamins K2, and vitamin K--S(II), and folic
acid.
[0045] In another embodiment of the pharmaceutical formulation, the
additive is chosen from acetiamine, benfotiamine, pantothenic acid,
cetotiamine, cyclothiamine, dexpanthenol, niacinamide, nicotinic
acid, pyridoxal 5-phosphate, nicotinamide ascorbate, riboflavin,
riboflavin phosphate, thiamine, folic acid, menadiol diphosphate,
menadione sodium bisulfite, menadoxime, vitamin B12, vitamin K5,
vitamin K6, vitamin K6, and vitamin U. In another embodiment of the
pharmaceutical formulation, the additive is chosen from alanine,
arginine, asparagines, aspartic acid, cysteine, cystine, glutamic
acid, glutamine, glycine, histidine, proline, isoleucine, leucine,
lysine, methionine, phenylalanine, serine, threonine, tryptophan,
tyrosine, and valine, and salts of any of the foregoing. In another
embodiment of the pharmaceutical formulation, the additive is
albumin.
[0046] In one embodiment of the pharmaceutical formulation, the
additive is chosen from n-octyl-.beta.-D-glucopyranoside,
octoxynol-9, Polysorbates, Tyloxapol, octoxynol, nonoxynol,
isononylphenylpolyglycidol, PEG glyceryl monooleate, sorbitan
monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan
monostearate, polyglyceryl-10 oleate, polyglyceryl-10 laurate,
polyglyceryl-10 palmitate, polyglyceryl-10 stearate, L-ascorbic
acid, thiamine, maleic anhydride, niacinamide, and
2-pyrrolidone-5-carboxylic acid. In another embodiment of the
pharmaceutical formulation, the additive is chosen from riboflavin,
riboflavin-phosphate sodium, Vitamin D3, folic acid, vitamin 12,
diethylenetriaminepentaacetic acid dianhydride,
ethylenediaminetetraacetic dianhydride, maleic acid and anhydride,
succinic acid and anhydride, diglycolic anhydride, glutaric
anhydride, L-ascorbic acid, thiamine, nicotinamide, nicotinic acid,
2-pyrrolidone-5-carboxylic acid, cystine, tyrosine, tryptophan,
leucine, isoleucine, phenylalanine, asparagine, aspartic acid,
glutamic acid, and methionine.
[0047] In one embodiment of the pharmaceutical formulation, the
additive is chosen from isononylphenylpolyglycidol, PEG glyceryl
monooleate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan
monooleate, sorbitan monostearate, polyglyceryl-10 oleate,
polyglyceryl-10 laurate, polyglyceryl-10 palmitate, and
polyglyceryl-10 stearate. In another embodiment of the
pharmaceutical formulation, the additive is chosen from L-ascorbic
acid, thiamine, maleic acids, niacinamide, and
2-pyrrolidone-5-carboxylic acid. In another embodiment of the
pharmaceutical formulation, the additive is chosen from Vitamin D2
and D3.
[0048] In one embodiment of the pharmaceutical formulation, the
drug is present in a concentration of about 0.05 mg/g to about 990
mg/g. In another embodiment of the pharmaceutical formulation, the
formulation further comprises an additional drug. In one aspect of
this embodiment, the additional drug is chosen from
corticosteroids, anticholinergics, beta-agonists, non-steroidal
anti-inflammatory drugs, macrolide antibiotics, bronchodilators,
leukotriene receptor inhibitors, cromolyn sulfate, and combinations
thereof.
[0049] In one embodiment, the present invention relates to a method
for treating a respiratory system in a mammal comprising (1)
forming an aerosol of a dispersion of particles, wherein the
particles comprise a water insoluble drug and an additive that
enhances absorption of the drug into tissue of the respiratory
system, and (2) administering the aerosol to the respiratory system
of the mammal. In one aspect of this embodiment, the additive
comprises a hydrophilic part and a drug affinity part, wherein the
drug affinity part is at least one of a hydrophobic part, a part
that has an affinity to the therapeutic agent by hydrogen bonding,
and a part that has an affinity to the therapeutic agent by van der
Waals interactions. In another aspect of this embodiment, the drug
is not enclosed in micelles or encapsulated in polymer particles.
In another aspect of this embodiment, the dispersion does not
include oil, a lipid, or a polymer. In another aspect of this
embodiment, the dispersion does not include a purely hydrophobic
additive.
[0050] In one embodiment, the additive is at least one of a
surfactant and a chemical compound. In one embodiment, the chemical
compound is chosen from amino alcohols, hydroxyl carboxylic acid,
ester, anhydrides, hydroxyl ketone, hydroxyl lactone, hydroxyl
ester, sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols,
amino acids, peptides, proteins, sorbitan, glycerol, polyalcohol,
phosphates, sulfates, organic acids, esters, salts, vitamins,
combinations of amino alcohol and organic acid, and their
substituted molecules. In one embodiment, the surfactant is chosen
from ionic, nonionic, aliphatic, and aromatic surfactants, PEG
fatty esters, PEG omega-3 fatty esters, ether, and alcohols,
glycerol fatty esters, sorbitan fatty esters, PEG glyceryl fatty
esters, PEG sorbitan fatty esters, sugar fatty esters, PEG sugar
esters, and derivatives thereof. In one embodiment, the chemical
compound has one or more hydroxyl, amino, carbonyl, carboxyl, acid,
amide or ester groups. In one aspect of this embodiment, the
chemical compound having one or more hydroxyl, amino, carbonyl,
carboxyl, acid, amide or ester groups is chosen from amino
alcohols, hydroxyl carboxylic acid, ester, anhydrides, hydroxyl
ketone, hydroxyl lactone, hydroxyl ester, sugar phosphate, sugar
sulfate, ethyl oxide, ethyl glycols, amino acids, peptides,
proteins, sorbitan, glycerol, polyalcohol, phosphates, sulfates,
organic acids, esters, salts, vitamins, combinations of amino
alcohol and organic acid, and their substituted molecules. In
another aspect of this embodiment, the chemical compound having one
or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester
groups is chosen from cystine, tyrosine, tryptophan, leucine,
isoleucine, phenylalanine, asparagine, aspartic acid, glutamic
acid, and methionine; acetic anhydride, benzoic anhydride, ascorbic
acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone
carboxylate, ethylenediaminetetraacetic dianhydride, maleic and
anhydride, succinic anhydride, diglycolic anhydride, glutaric
anhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;
cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal
5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin
phosphate, thiamine, folic acid, menadiol diphosphate, menadione
sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6,
vitamin K6, and vitamin U; albumin, immunoglobulins, caseins,
hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin,
fibronectins, vitronectins, firbinogens, lipases, benzalkonium
chloride, L-ascorbic acid and its salt, D-glucoascorbic acid and
its salt, tromethamine, triethanolamine, diethanolamine, meglumine,
glucamine, amine alcohols, glucoheptonic acid, glucomic acid,
gluconolactone, D-glucoheptono-1,4-lactone, glucooctanoic lactone,
gulonic acid lactone, mannoic lactone, erythronic acid lactone,
ribonic acid lactone, glucosamine, glutamic acid, benzyl alcohol,
benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine
acetate salt, gentisic acid, lactobionic acid, lactitol, sinapic
acid, vanillic acid, vanillin, methyl paraben, propyl paraben,
acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic
acid, catechin, catechin gallate, tiletamine, ketamine, propofol,
lactic acids, acetic acid, salts of any organic acid and amine
above described, lysine/glutamic acid, lysine acetate, lactobionic
acid/meglumine, lactobionic acid/tromethanemine, lactobionic
acid/diethanolamine, lactic acid/meglumine, lactic
acid/tromethanemine, lactic acid/diethanolamine, gentisic
acid/meglumine, gentisic acid/tromethanemine, gensitic
acid/diethanolamine, vanillic acid/meglumine, vanillic
acid/tromethanemine, vanillic acid/diethanolamine, benzoic
acid/meglumine, benzoic acid/tromethanemine, benzoic
acid/diethanolamine, acetic acid/meglumine, acetic
acid/tromethanemine, acetic acid/diethanolamine, polyglycidol,
glycerols, multiglycerols and a mixture of the additives, and their
derivatives.
[0051] In one embodiment, the additive is chosen from
p-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween 40,
Tween 60, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG
glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate,
plyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate,
polyglyceryl-6 laurate, plyglyceryl-6 oleate, polyglyceryl-6
myristate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate,
plyglyceryl-10 oleate, polyglyceryl-10 myristate, polyglyceryl-10
palmitate PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG
sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG
laurayl ether, octoxynol, monoxynol, tyloxapol, sucrose
monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,
n-decyl-.beta.-D-glucopyranoside, n-decyl-.beta.-D-maltopyranoside,
n-dodecyl-.beta.-D-glucopyranoside, n-dodecyl-.beta.-D-maltoside,
heptanoyl-N-methylglucamide, n-heptyl-.beta.-D-glucopyranoside,
n-heptyl-.beta.-D-thioglucoside, n-hexyl-.beta.-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-.beta.-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside,
octyl-.beta.-D-thioglucopyranoside; cystine, tyrosine, tryptophan,
leucine, isoleucine, phenylalanine, asparagine, aspartic acid,
glutamic acid, and methionine; acetic anhydride, benzoic anhydride,
ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone
carboxylate, ethylenediaminetetraacetic dianhydride, maleic and
anhydride, succinic anhydride, diglycolic anhydride, glutaric
anhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;
cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal
5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin
phosphate, thiamine, folic acid, menadiol diphosphate, menadione
sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6,
vitamin K6, and vitamin U; albumin, immunoglobulins, caseins,
hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin,
fibronectins, vitronectins, firbinogens, lipases, benzalkonium
chloride, benzethonium chloride, docecyl trimethyl ammonium
bromide, sodium docecylsulfates, dialkyl methylbenzyl ammonium
chloride, and dialkylesters of sodium sulfonsuccinic acid,
L-ascorbic acid and its salt, D-glucoascorbic acid and its salt,
tromethamine, triethanolamine, diethanolamine, meglumine,
glucamine, amine alcohols, glucoheptonic acid, glucomic acid,
hydroxyl ketone, hydroxyl lactone, gluconolactone,
glucoheptonolactone, glucooctanoic lactone, gulonic acid lactone,
mannoic lactone, ribonic acid lactone, lactobionic acid,
glucosamine, glutamic acid, benzyl alcohol, benzoic acid,
hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt,
gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic
acid, vanillin, methyl paraben, propyl paraben, sorbitol, xylitol,
cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,
ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,
catechin gallate, tiletamine, ketamine, propofol, lactic acids,
acetic acid, salts of any organic acid and organic amine,
polyglycidol, glycerol, multiglycerols, galactitol, di(ethylene
glycol), tri(ethylene glycol), tetra(ethylene glycol),
penta(ethylene glycol), poly(ethylene glycol) oligomers,
di(propylene glycol), tri(propylene glycol), tetra(propylene
glycol, and penta(propylene glycol), poly(propylene glycol)
oligomers, a block copolymer of polyethylene glycol and
polypropylene glycol, and derivatives and combinations thereof.
[0052] In one embodiment, the additive is chosen from PEG-fatty
acids and PEG-fatty acid mono and diesters, polyethylene glycol
glycerol fatty acid esters, alcohol-oil transesterification
products, polyglyceryl fatty acids, propylene glycol fatty acid
esters, sterol and derivatives thereof, polyethylene glycol
sorbitan fatty acid esters, polyethylene glycol alkyl ethers,
sugars and derivatives thereof, polyethylene glycol alkyl phenols,
polyoxyethylene-polyoxypropylene block copolymers, sorbitan fatty
acid esters, fat-soluble vitamins and salts thereof, water-soluble
vitamins and amphiphilic derivatives thereof, amino acid and salts
thereof, oligopeptides, peptides and proteins, and organic acids
and esters and anhydrides thereof. In yet another aspect of this
embodiment, the water insoluble drug is chosen from paclitaxel and
analogues thereof and rapamycin and analogues thereof.
[0053] In one embodiment, the surfactant is chosen from esters of
lauric acid, oleic acid, and stearic acid, PEG-8 laurate, PEG-8
oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate, PEG-10
oleate, PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20
laurate, PEG-20 oleate, PEG-20 dilaurate, PEG-20 dioleate, PEG-20
distearate, PEG-32 dilaurate, PEG-32 dioleate, PEG-20 glyceryl
laurate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-20
glyceryl oleate, PEG-30 glyceryl oleate, PEG-25 trioleate, PEG-60
corn glycerides, PEG-60 almond oil, PEG-40 palm kernel oil, PEG-8
caprylic/capric glycerides, PEG-6 caprylic/capric glycerides, PEG-6
corn oil, PEG-6 almond oil, PEG-6 apricot kernel oil, PEG-6 olive
oil, PEG-6 peanut oil, PEG-6 hydrogenated palm kernel oil, PEG-6
palm kernel oil, PEG-6 triolein, PEG-8 corn oil, PEG-20 corn
glycerides, PEG-20 almond glycerides, polyglyceryl oleate,
polyglyceryl-2 dioleate, polyglyceryl-10 trioleate, polyglyceryl
stearate, polyglyceryl laurate, polyglyceryl myristate,
polyglyceryl palmitate, and polyglyceryl linoleate, polyglyceryl-10
laurate, polyglyceryl-10 oleate, polyglyceryl-10 mono, dioleate,
polyglyceryl-10 stearate, polyglyceryl-10 laurate, polyglyceryl-10
myristate, polyglyceryl-10 palmitate, polyglyceryl-10 linoleate,
polyglyceryl-6 stearate, polyglyceryl-6 laurate, polyglyceryl-6
myristate, polyglyceryl-6 palmitate, and polyglyceryl-6 linoleate,
and polyglyceryl polyricinoleate, propylene glycol monolaurate,
propylene glycol ricinoleate, propylene glycol monooleate,
propylene glycol dicaprylate/dicaprate, propylene glycol
dioctanoate, PEG-20 sorbitan monolaurate, PEG-20 sorbitan
monopalmitate, PEG-20 sorbitan monostearate, PEG-20 sorbitan
monooleate, PEG-3 oleyl ether and PEG-4 lauryl ether, sucrose
monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,
n-decyl-.beta.-D-glucopyranoside, n-decyl-.beta.-D-maltopyranoside,
n-dodecyl-.beta.-D-glucopyranoside, n-dodecyl-.beta.-D-maltoside,
heptanoyl-N-methylglucamide, n-heptyl-.beta.-D-glucopyranoside,
n-heptyl-.beta.-D-thioglucoside, n-hexyl-.beta.-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-.beta.-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside,
octyl-.beta.-D-thioglucopyranoside, PEG-10-100 nonyl phenol,
PEG-15-100 octyl phenol ether, Tyloxapol, octoxynol, nonoxynol,
sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate,
sorbitan monostearate, benzalkonium chloride, benzethonium
chloride, docecyl trimethyl ammonium bromide, sodium
docecylsulfates, dialkyl methylbenzyl ammonium chloride, and
dialkylesters of sodium sulfonsuccinic acid (ionic surfactants),
n-octyl-.beta.-D-glucopyranoside, octoxynol-9, Polysorbates,
Tyloxapol, octoxynol, nonoxynol, isononylphenylpolyglycidol, PEG
glyceryl monooleate, sorbitan monolaurate, sorbitan monopalmitate,
sorbitan monooleate, sorbitan monostearate, polyglyceryl-10 oleate,
polyglyceryl-10 laurate, polyglyceryl-10 palmitate, polyglyceryl-10
stearate, and their derivatives.
[0054] In one embodiment, the water insoluble drug is chosen from
paclitaxel and analogues thereof and rapamycin and analogues
thereof.
[0055] In one embodiment, the present invention relates to an
aerosol device for delivering a drug to a respiratory system, the
device comprising a pharmaceutical formulation comprising a water
insoluble drug and an additive, wherein the additive enhances
absorption of the drug into tissue of the respiratory system. In
one aspect of this embodiment, the pharmaceutical formulation is an
aqueous, propellant based, or dry powder formulation. In another
aspect of this embodiment, the additive comprises a hydrophilic
part and a drug affinity part, wherein the drug affinity part is at
least one of a hydrophobic part, a part that has an affinity to the
therapeutic agent by hydrogen bonding, and a part that has an
affinity to the therapeutic agent by van der Waals interactions. In
another aspect of this embodiment, the drug is not enclosed in
micelles or encapsulated in polymer particles. In another aspect of
this embodiment, the formulation does not include oil, a lipid, or
a polymer. In another aspect of this embodiment, the additive is
chosen from PEG-fatty acids and PEG-fatty acid mono and diesters,
polyethylene glycol glycerol fatty acid esters, alcohol-oil
transesterification products, polyglyceryl fatty acids, propylene
glycol fatty acid esters, sterol and derivatives thereof,
polyethylene glycol sorbitan fatty acid esters, polyethylene glycol
alkyl ethers, sugars and derivatives thereof, polyethylene glycol
alkyl phenols, polyoxyethylene-polyoxypropylene block copolymers,
sorbitan fatty acid esters, fat-soluble vitamins and salts thereof,
water-soluble vitamins and amphiphilic derivatives thereof, amino
acid and salts thereof, oligopeptides, peptides and proteins, and
organic acids and esters and anhydrides thereof. In another aspect
of this embodiment, the water insoluble drug is chosen from
paclitaxel and analogues thereof and rapamycin and analogues
thereof. In yet another aspect of this embodiment, the aerosol
device is one of a nebulizer, a hand-held meter dose inhaler, or a
dry powder inhaler.
[0056] In another embodiment, the additive is at least one of a
surfactant and a chemical compound. In one embodiment, the chemical
compound is chosen from amino alcohols, hydroxyl carboxylic acid,
ester, anhydrides, hydroxyl ketone, hydroxyl lactone, hydroxyl
ester, sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols,
amino acids, peptides, proteins, sorbitan, glycerol, polyalcohol,
phosphates, sulfates, organic acids, esters, salts, vitamins,
combinations of amino alcohol and organic acid, and their
substituted molecules. In one embodiment, the surfactant is chosen
from ionic, nonionic, aliphatic, and aromatic surfactants, PEG
fatty esters, PEG omega-3 fatty esters, ether, and alcohols,
glycerol fatty esters, sorbitan fatty esters, PEG glyceryl fatty
esters, PEG sorbitan fatty esters, sugar fatty esters, PEG sugar
esters, and derivatives thereof.
[0057] In one embodiment, the chemical compound has one or more
hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups.
In one aspect of this embodiment, the chemical compound having one
or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester
groups is chosen from amino alcohols, hydroxyl carboxylic acid,
ester, anhydrides, hydroxyl ketone, hydroxyl lactone, hydroxyl
ester, sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols,
amino acids, peptides, proteins, sorbitan, glycerol, polyalcohol,
phosphates, sulfates, organic acids, esters, salts, vitamins,
combinations of amino alcohol and organic acid, and their
substituted molecules. In another aspect of this embodiment, the
chemical compound having one or more hydroxyl, amino, carbonyl,
carboxyl, acid, amide or ester groups is chosen from cystine,
tyrosine, tryptophan, leucine, isoleucine, phenylalanine,
asparagine, aspartic acid, glutamic acid, and methionine; acetic
anhydride, benzoic anhydride, ascorbic acid,
2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone carboxylate,
ethylenediaminetetraacetic dianhydride, maleic and anhydride,
succinic anhydride, diglycolic anhydride, glutaric anhydride,
acetiamine, benfotiamine, pantothenic acid cetotiamine;
cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal
5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin
phosphate, thiamine, folic acid, menadiol diphosphate, menadione
sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6,
vitamin K6, and vitamin U; albumin, immunoglobulins, caseins,
hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin,
fibronectins, vitronectins, firbinogens, lipases, L-ascorbic acid
and its salt, D-glucoascorbic acid and its salt, tromethamine,
triethanolamine, diethanolamine, meglumine, glucamine, amine
alcohols, glucoheptonic acid, glucomic acid, gluconolactone,
D-glucoheptono-1,4-lactone, glucooctanoic lactone, gulonic acid
lactone, mannoic lactone, erythronic acid lactone, ribonic acid
lactone, glucosamine, glutamic acid, benzyl alcohol, benzoic acid,
hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt,
gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic
acid, vanillin, methyl paraben, propyl paraben, acetaminophen,
ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,
catechin gallate, tiletamine, ketamine, propofol, lactic acids,
acetic acid, salts of any organic acid and amine above described,
lysine/glutamic acid, lysine acetate, lactobionic acid/meglumine,
lactobionic acid/tromethanemine, lactobionic acid/diethanolamine,
lactic acid/meglumine, lactic acid/tromethanemine, lactic
acid/diethanolamine, gentisic acid/meglumine, gentisic
acid/tromethanemine, gensitic acid/diethanolamine, vanillic
acid/meglumine, vanillic acid/tromethanemine, vanillic
acid/diethanolamine, benzoic acid/meglumine, benzoic
acid/tromethanemine, benzoic acid/diethanolamine, acetic
acid/meglumine, acetic acid/tromethanemine, acetic
acid/diethanolamine, polyglycidol, glycerols, multiglycerols and a
mixture of the additives, and their derivatives.
[0058] In one embodiment, the additive is chosen from
p-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween 40,
Tween 60, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG
glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate,
plyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate,
polyglyceryl-6 laurate, plyglyceryl-6 oleate, polyglyceryl-6
myristate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate,
plyglyceryl-10 oleate, polyglyceryl-10 myristate, polyglyceryl-10
palmitate PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG
sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG
laurayl ether, octoxynol, monoxynol, tyloxapol, sucrose
monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,
n-decyl-.beta.-D-glucopyranoside, n-decyl-.beta.-D-maltopyranoside,
n-dodecyl-.beta.-D-glucopyranoside, n-dodecyl-.beta.-D-maltoside,
heptanoyl-N-methylglucamide, n-heptyl-.beta.-D-glucopyranoside,
n-heptyl-.beta.-D-thioglucoside, n-hexyl-.beta.-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-.beta.-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside,
octyl-.beta.-D-thioglucopyranoside; cystine, tyrosine, tryptophan,
leucine, isoleucine, phenylalanine, asparagine, aspartic acid,
glutamic acid, and methionine; acetic anhydride, benzoic anhydride,
ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone
carboxylate, ethylenediaminetetraacetic dianhydride, maleic and
anhydride, succinic anhydride, diglycolic anhydride, glutaric
anhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;
cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal
5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin
phosphate, thiamine, folic acid, menadiol diphosphate, menadione
sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6,
vitamin K6, and vitamin U; albumin, immunoglobulins, caseins,
hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin,
fibronectins, vitronectins, firbinogens, lipases, benzalkonium
chloride, benzethonium chloride, docecyl trimethyl ammonium
bromide, sodium docecylsulfates, dialkyl methylbenzyl ammonium
chloride, and dialkylesters of sodium sulfonsuccinic acid,
L-ascorbic acid and its salt, D-glucoascorbic acid and its salt,
tromethamine, triethanolamine, diethanolamine, meglumine,
glucamine, amine alcohols, glucoheptonic acid, glucomic acid,
hydroxyl ketone, hydroxyl lactone, gluconolactone,
glucoheptonolactone, glucooctanoic lactone, gulonic acid lactone,
mannoic lactone, ribonic acid lactone, lactobionic acid,
glucosamine, glutamic acid, benzyl alcohol, benzoic acid,
hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt,
gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic
acid, vanillin, methyl paraben, propyl paraben, sorbitol, xylitol,
cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,
ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,
catechin gallate, tiletamine, ketamine, propofol, lactic acids,
acetic acid, salts of any organic acid and organic amine,
polyglycidol, glycerol, multiglycerols, galactitol, di(ethylene
glycol), tri(ethylene glycol), tetra(ethylene glycol),
penta(ethylene glycol), poly(ethylene glycol) oligomers,
di(propylene glycol), tri(propylene glycol), tetra(propylene
glycol, and penta(propylene glycol), poly(propylene glycol)
oligomers, a block copolymer of polyethylene glycol and
polypropylene glycol, and derivatives and combinations thereof.
[0059] In one embodiment, the surfactant is chosen from esters of
lauric acid, oleic acid, and stearic acid, PEG-8 laurate, PEG-8
oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate, PEG-10
oleate, PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20
laurate, PEG-20 oleate, PEG-20 dilaurate, PEG-20 dioleate, PEG-20
distearate, PEG-32 dilaurate, PEG-32 dioleate, PEG-20 glyceryl
laurate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-20
glyceryl oleate, PEG-30 glyceryl oleate, PEG-25 trioleate, PEG-60
corn glycerides, PEG-60 almond oil, PEG-40 palm kernel oil, PEG-8
caprylic/capric glycerides, PEG-6 caprylic/capric glycerides, PEG-6
corn oil, PEG-6 almond oil, PEG-6 apricot kernel oil, PEG-6 olive
oil, PEG-6 peanut oil, PEG-6 hydrogenated palm kernel oil, PEG-6
palm kernel oil, PEG-6 triolein, PEG-8 corn oil, PEG-20 corn
glycerides, PEG-20 almond glycerides, polyglyceryl oleate,
polyglyceryl-2 dioleate, polyglyceryl-10 trioleate, polyglyceryl
stearate, polyglyceryl laurate, polyglyceryl myristate,
polyglyceryl palmitate, and polyglyceryl linoleate, polyglyceryl-10
laurate, polyglyceryl-10 oleate, polyglyceryl-10 mono, dioleate,
polyglyceryl-10 stearate, polyglyceryl-10 laurate, polyglyceryl-10
myristate, polyglyceryl-10 palmitate, polyglyceryl-10 linoleate,
polyglyceryl-6 stearate, polyglyceryl-6 laurate, polyglyceryl-6
myristate, polyglyceryl-6 palmitate, and polyglyceryl-6 linoleate,
and polyglyceryl polyricinoleate, propylene glycol monolaurate,
propylene glycol ricinoleate, propylene glycol monooleate,
propylene glycol dicaprylate/dicaprate, propylene glycol
dioctanoate, PEG-20 sorbitan monolaurate, PEG-20 sorbitan
monopalmitate, PEG-20 sorbitan monostearate, PEG-20 sorbitan
monooleate, PEG-3 oleyl ether and PEG-4 lauryl ether, sucrose
monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,
n-decyl-.beta.-D-glucopyranoside, n-decyl-.beta.-D-maltopyranoside,
n-dodecyl-.beta.-D-glucopyranoside, n-dodecyl-.beta.-D-maltoside,
heptanoyl-N-methylglucamide, n-heptyl-.beta.-D-glucopyranoside,
n-heptyl-.beta.-D-thioglucoside, n-hexyl-.beta.-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-.beta.-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside,
octyl-.beta.-D-thioglucopyranoside, PEG-10-100 nonyl phenol,
PEG-15-100 octyl phenol ether, Tyloxapol, octoxynol, nonoxynol,
sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate,
sorbitan monostearate, benzalkonium chloride, benzethonium
chloride, docecyl trimethyl ammonium bromide, sodium
docecylsulfates, dialkyl methylbenzyl ammonium chloride, and
dialkylesters of sodium sulfonsuccinic acid (ionic surfactants),
n-octyl-.beta.-D-glucopyranoside, octoxynol-9, Polysorbates,
Tyloxapol, octoxynol, nonoxynol, isononylphenylpolyglycidol, PEG
glyceryl monooleate, sorbitan monolaurate, sorbitan monopalmitate,
sorbitan monooleate, sorbitan monostearate, polyglyceryl-10 oleate,
polyglyceryl-10 laurate, polyglyceryl-10 palmitate, polyglyceryl-10
stearate, and their derivatives.
[0060] In one embodiment, the water insoluble drug is chosen from
paclitaxel and analogues thereof and rapamycin and analogues
thereof. In one embodiment, the aerosol device is one of a
nebulizer, a hand-held meter dose inhaler, or a dry powder
inhaler.
[0061] In one embodiment, the present invention relates to a device
sized and configured for insertion into a passage of a respiratory
system, the device comprising a layer overlying an exterior surface
of the device, the layer comprising a water insoluble drug for the
treatment of the respiratory system and an additive that enhances
absorption of the drug into tissue of the respiratory system. In
one aspect of this embodiment, the additive comprises a hydrophilic
part and a drug affinity part, wherein the drug affinity part is at
least one of a hydrophobic part, a part that has an affinity to the
therapeutic agent by hydrogen bonding, and a part that has an
affinity to the therapeutic agent by van der Waals interactions. In
another aspect of this embodiment, the drug is not enclosed in
micelles or encapsulated in polymer particles. In another aspect of
this embodiment, the layer does not include oil, a lipid, or a
polymer. In another aspect of this embodiment, the layer does not
include a purely hydrophobic additive. In another aspect of this
embodiment, the device is a balloon catheter or a stent. In another
aspect of this embodiment, the water insoluble drug is chosen from
paclitaxel and analogues thereof and rapamycin and analogues
thereof. In another aspect of this embodiment, the additive is
chosen from PEG-fatty acids and PEG-fatty acid mono and diesters,
polyethylene glycol glycerol fatty acid esters, alcohol-oil
transesterification products, polyglyceryl fatty acids, propylene
glycol fatty acid esters, sterol and derivatives thereof,
polyethylene glycol sorbitan fatty acid esters, polyethylene glycol
alkyl ethers, sugars and derivatives thereof, polyethylene glycol
alkyl phenols, polyoxyethylene-polyoxypropylene block copolymers,
sorbitan fatty acid esters, fat-soluble vitamins and salts thereof,
water-soluble vitamins and amphiphilic derivatives thereof, amino
acid and salts thereof, oligopeptides, peptides and proteins, and
organic acids and esters and anhydrides thereof.
[0062] In one embodiment, the additive is at least one of a
surfactant and a chemical compound. In one embodiment, the chemical
compound is chosen from amino alcohols, hydroxyl carboxylic acid,
ester, anhydrides, hydroxyl ketone, hydroxyl lactone, hydroxyl
ester, sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols,
amino acids, peptides, proteins, sorbitan, glycerol, polyalcohol,
phosphates, sulfates, organic acids, esters, salts, vitamins,
combinations of amino alcohol and organic acid, and their
substituted molecules. In one embodiment, the surfactant is chosen
from ionic, nonionic, aliphatic, and aromatic surfactants, PEG
fatty esters, PEG omega-3 fatty esters, ether, and alcohols,
glycerol fatty esters, sorbitan fatty esters, PEG glyceryl fatty
esters, PEG sorbitan fatty esters, sugar fatty esters, PEG sugar
esters, and derivatives thereof.
[0063] In one embodiment, the chemical compound has one or more
hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups.
In one aspect of this embodiment, the chemical compound having one
or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester
groups is chosen from amino alcohols, hydroxyl carboxylic acid,
ester, anhydrides, hydroxyl ketone, hydroxyl lactone, hydroxyl
ester, sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols,
amino acids, peptides, proteins, sorbitan, glycerol, polyalcohol,
phosphates, sulfates, organic acids, esters, salts, vitamins,
combinations of amino alcohol and organic acid, and their
substituted molecules. In another aspect of this embodiment, the
chemical compound having one or more hydroxyl, amino, carbonyl,
carboxyl, acid, amide or ester groups is chosen from cystine,
tyrosine, tryptophan, leucine, isoleucine, phenylalanine,
asparagine, aspartic acid, glutamic acid, and methionine; acetic
anhydride, benzoic anhydride, ascorbic acid,
2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone carboxylate,
maleic and anhydride, succinic anhydride, diglycolic anhydride,
glutaric anhydride, acetiamine, benfotiamine, pantothenic acid;
cetotiamine; cyclothiamine, dexpanthenol, niacinamide, nicotinic
acid, pyridoxal 5-phosphate, nicotinamide ascorbate, riboflavin,
riboflavin phosphate, thiamine, folic acid, menadiol diphosphate,
menadione sodium bisulfite, menadoxime, vitamin B12, vitamin K5,
vitamin K6, vitamin K6, and vitamin U; albumin, immunoglobulins,
caseins, hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin,
fibronectins, vitronectins, firbinogens, lipases, L-ascorbic acid
and its salt, D-glucoascorbic acid and its salt, tromethamine,
triethanolamine, diethanolamine, meglumine, glucamine, amine
alcohols, glucoheptonic acid, glucomic acid, gluconolactone,
D-glucoheptono-1,4-lactone, glucooctanoic lactone, gulonic acid
lactone, mannoic lactone, erythronic acid lactone, ribonic acid
lactone, glucosamine, glutamic acid, benzyl alcohol, benzoic acid,
hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt,
gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic
acid, vanillin, methyl paraben, propyl paraben, acetaminophen,
ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,
catechin gallate, tiletamine, ketamine, propofol, lactic acids,
acetic acid, salts of any organic acid and amine above described,
lysine/glutamic acid, lysine acetate, lactobionic acid/meglumine,
lactobionic acid/tromethanemine, lactobionic acid/diethanolamine,
lactic acid/meglumine, lactic acid/tromethanemine, lactic
acid/diethanolamine, gentisic acid/meglumine, gentisic
acid/tromethanemine, gensitic acid/diethanolamine, vanillic
acid/meglumine, vanillic acid/tromethanemine, vanillic
acid/diethanolamine, benzoic acid/meglumine, benzoic
acid/tromethanemine, benzoic acid/diethanolamine, acetic
acid/meglumine, acetic acid/tromethanemine, acetic
acid/diethanolamine, polyglycidol, glycerols, multiglycerols and a
mixture of the additives, and their derivatives.
[0064] In one embodiment, the additive is chosen from
p-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween 40,
Tween 60, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG
glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate,
plyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate,
polyglyceryl-6 laurate, plyglyceryl-6 oleate, polyglyceryl-6
myristate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate,
plyglyceryl-10 oleate, polyglyceryl-10 myristate, polyglyceryl-10
palmitate PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG
sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG
laurayl ether, octoxynol, monoxynol, tyloxapol, sucrose
monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,
n-decyl-.beta.-D-glucopyranoside, n-decyl-.beta.-D-maltopyranoside,
n-dodecyl-.beta.-D-glucopyranoside, n-dodecyl-.beta.-D-maltoside,
heptanoyl-N-methylglucamide, n-heptyl-.beta.-D-glucopyranoside,
n-heptyl-.beta.-D-thioglucoside, n-hexyl-.beta.-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-.beta.-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside,
octyl-.beta.-D-thioglucopyranoside; cystine, tyrosine, tryptophan,
leucine, isoleucine, phenylalanine, asparagine, aspartic acid,
glutamic acid, and methionine; acetic anhydride, benzoic anhydride,
ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone
carboxylate, ethylenediaminetetraacetic dianhydride, maleic and
anhydride, succinic anhydride, diglycolic anhydride, glutaric
anhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;
cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal
5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin
phosphate, thiamine, folic acid, menadiol diphosphate, menadione
sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6,
vitamin K6, and vitamin U; albumin, immunoglobulins, caseins,
hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin,
fibronectins, vitronectins, firbinogens, lipases, benzalkonium
chloride, benzethonium chloride, docecyl trimethyl ammonium
bromide, sodium docecylsulfates, dialkyl methylbenzyl ammonium
chloride, and dialkylesters of sodium sulfonsuccinic acid,
L-ascorbic acid and its salt, D-glucoascorbic acid and its salt,
tromethamine, triethanolamine, diethanolamine, meglumine,
glucamine, amine alcohols, glucoheptonic acid, glucomic acid,
hydroxyl ketone, hydroxyl lactone, gluconolactone,
glucoheptonolactone, glucooctanoic lactone, gulonic acid lactone,
mannoic lactone, ribonic acid lactone, lactobionic acid,
glucosamine, glutamic acid, benzyl alcohol, benzoic acid,
hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt,
gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic
acid, vanillin, methyl paraben, propyl paraben, sorbitol, xylitol,
cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,
ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,
catechin gallate, tiletamine, ketamine, propofol, lactic acids,
acetic acid, salts of any organic acid and organic amine,
polyglycidol, glycerol, multiglycerols, galactitol, di(ethylene
glycol), tri(ethylene glycol), tetra(ethylene glycol),
penta(ethylene glycol), poly(ethylene glycol) oligomers,
di(propylene glycol), tri(propylene glycol), tetra(propylene
glycol, and penta(propylene glycol), poly(propylene glycol)
oligomers, a block copolymer of polyethylene glycol and
polypropylene glycol, and derivatives and combinations thereof.
[0065] In one embodiment, the surfactant is chosen from esters of
lauric acid, oleic acid, and stearic acid, PEG-8 laurate, PEG-8
oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate, PEG-10
oleate, PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20
laurate, PEG-20 oleate, PEG-20 dilaurate, PEG-20 dioleate, PEG-20
distearate, PEG-32 dilaurate, PEG-32 dioleate, PEG-20 glyceryl
laurate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-20
glyceryl oleate, PEG-30 glyceryl oleate, PEG-25 trioleate, PEG-60
corn glycerides, PEG-60 almond oil, PEG-40 palm kernel oil, PEG-8
caprylic/capric glycerides, PEG-6 caprylic/capric glycerides, PEG-6
corn oil, PEG-6 almond oil, PEG-6 apricot kernel oil, PEG-6 olive
oil, PEG-6 peanut oil, PEG-6 hydrogenated palm kernel oil, PEG-6
palm kernel oil, PEG-6 triolein, PEG-8 corn oil, PEG-20 corn
glycerides, PEG-20 almond glycerides, polyglyceryl oleate,
polyglyceryl-2 dioleate, polyglyceryl-10 trioleate, polyglyceryl
stearate, polyglyceryl laurate, polyglyceryl myristate,
polyglyceryl palmitate, and polyglyceryl linoleate, polyglyceryl-10
laurate, polyglyceryl-10 oleate, polyglyceryl-10 mono, dioleate,
polyglyceryl-10 stearate, polyglyceryl-10 laurate, polyglyceryl-10
myristate, polyglyceryl-10 palmitate, polyglyceryl-10 linoleate,
polyglyceryl-6 stearate, polyglyceryl-6 laurate, polyglyceryl-6
myristate, polyglyceryl-6 palmitate, and polyglyceryl-6 linoleate,
and polyglyceryl polyricinoleate, propylene glycol monolaurate,
propylene glycol ricinoleate, propylene glycol monooleate,
propylene glycol dicaprylate/dicaprate, propylene glycol
dioctanoate, PEG-20 sorbitan monolaurate, PEG-20 sorbitan
monopalmitate, PEG-20 sorbitan monostearate, PEG-20 sorbitan
monooleate, PEG-3 oleyl ether and PEG-4 lauryl ether, sucrose
monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,
n-decyl-.beta.-D-glucopyranoside, n-decyl-.beta.-D-maltopyranoside,
n-dodecyl-.beta.-D-glucopyranoside, n-dodecyl-.beta.-D-maltoside,
heptanoyl-N-methylglucamide, n-heptyl-.beta.-D-glucopyranoside,
n-heptyl-.beta.-D-thioglucoside, n-hexyl-.beta.-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-.beta.-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside,
octyl-.beta.-D-thioglucopyranoside, PEG-10-100 nonyl phenol,
PEG-15-100 octyl phenol ether, Tyloxapol, octoxynol, nonoxynol,
sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate,
sorbitan monostearate, benzalkonium chloride, benzethonium
chloride, docecyl trimethyl ammonium bromide, sodium
docecylsulfates, dialkyl methylbenzyl ammonium chloride, and
dialkylesters of sodium sulfonsuccinic acid (ionic surfactants),
n-octyl-.beta.-D-glucopyranoside, octoxynol-9, Polysorbates,
Tyloxapol, octoxynol, nonoxynol, isononylphenylpolyglycidol, PEG
glyceryl monooleate, sorbitan monolaurate, sorbitan monopalmitate,
sorbitan monooleate, sorbitan monostearate, polyglyceryl-10 oleate,
polyglyceryl-10 laurate, polyglyceryl-10 palmitate, polyglyceryl-10
stearate, and their derivatives.
[0066] In one embodiment, the present invention relates to a method
for treating a respiratory system comprising inserting a balloon
catheter comprising a coating layer into an airway, wherein the
coating layer comprises a drug and an additive, inflating the
balloon catheter and releasing the drug to a wall of the airway,
deflating the balloon; and withdrawing the balloon catheter from
the airway. In one aspect of this embodiment, the additive enhances
absorption of the drug into tissue of the respiratory or sinus
system. In another aspect of this embodiment, the additive
comprises a hydrophilic part and a drug affinity part, wherein the
drug affinity part is at least one of a hydrophobic part, a part
that has an affinity to the therapeutic agent by hydrogen bonding,
and a part that has an affinity to the therapeutic agent by van der
Waals interactions. In another aspect of this embodiment, the drug
is not enclosed in micelles or encapsulated in polymer particles.
In another aspect of this embodiment, the coating layer does not
include oil, a lipid, or a polymer. In another aspect of this
embodiment, the coating layer does not include a purely hydrophobic
additive. In another aspect of this embodiment, the drug is chosen
from paclitaxel and analogues thereof and rapamycin and analogues
thereof. In another aspect of this embodiment, the additive is
chosen from PEG-fatty acids and PEG-fatty acid mono and diesters,
polyethylene glycol glycerol fatty acid esters, alcohol-oil
transesterification products, polyglyceryl fatty acids, propylene
glycol fatty acid esters, sterol and derivatives thereof,
polyethylene glycol sorbitan fatty acid esters, polyethylene glycol
alkyl ethers, sugars and derivatives thereof, polyethylene glycol
alkyl phenols, polyoxyethylene-polyoxypropylene block copolymers,
sorbitan fatty acid esters, fat-soluble vitamins and salts thereof,
water-soluble vitamins and amphiphilic derivatives thereof, amino
acid and salts thereof, oligopeptides, peptides and proteins, and
organic acids and esters and anhydrides thereof. In yet another
aspect of this embodiment, the drug can be released to the wall of
the airway prior to, during, or after an asthma attack.
[0067] In one embodiment, the additive is at least one of a
surfactant and a chemical compound. In one embodiment, the chemical
compound is chosen from amino alcohols, hydroxyl carboxylic acid,
ester, anhydrides, hydroxyl ketone, hydroxyl lactone, hydroxyl
ester, sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols,
amino acids, peptides, proteins, sorbitan, glycerol, polyalcohol,
phosphates, sulfates, organic acids, esters, salts, vitamins,
combinations of amino alcohol and organic acid, and their
substituted molecules. In one embodiment, the surfactant is chosen
from ionic, nonionic, aliphatic, and aromatic surfactants, PEG
fatty esters, PEG omega-3 fatty esters, ether, and alcohols,
glycerol fatty esters, sorbitan fatty esters, PEG glyceryl fatty
esters, PEG sorbitan fatty esters, sugar fatty esters, PEG sugar
esters, and derivatives thereof.
[0068] In one embodiment, the chemical compound has one or more
hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups.
In one aspect of this embodiment, the chemical compound having one
or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester
groups is chosen from amino alcohols, hydroxyl carboxylic acid,
ester, anhydrides, hydroxyl ketone, hydroxyl lactone, hydroxyl
ester, sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols,
amino acids, peptides, proteins, sorbitan, glycerol, polyalcohol,
phosphates, sulfates, organic acids, esters, salts, vitamins,
combinations of amino alcohol and organic acid, and their
substituted molecules.
[0069] In one embodiment, the additive is chosen from
p-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween 40,
Tween 60, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG
glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate,
plyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate,
polyglyceryl-6 laurate, plyglyceryl-6 oleate, polyglyceryl-6
myristate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate,
plyglyceryl-10 oleate, polyglyceryl-10 myristate, polyglyceryl-10
palmitate PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG
sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG
laurayl ether, octoxynol, monoxynol, tyloxapol, sucrose
monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,
n-decyl-.beta.-D-glucopyranoside, n-decyl-.beta.-D-maltopyranoside,
n-dodecyl-.beta.-D-glucopyranoside, n-dodecyl-.beta.-D-maltoside,
heptanoyl-N-methylglucamide, n-heptyl-.beta.-D-glucopyranoside,
n-heptyl-.beta.-D-thioglucoside, n-hexyl-.beta.-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-.beta.-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside,
octyl-.beta.-D-thioglucopyranoside; cystine, tyrosine, tryptophan,
leucine, isoleucine, phenylalanine, asparagine, aspartic acid,
glutamic acid, and methionine; acetic anhydride, benzoic anhydride,
ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone
carboxylate, ethylenediaminetetraacetic dianhydride, maleic and
anhydride, succinic anhydride, diglycolic anhydride, glutaric
anhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;
cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal
5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin
phosphate, thiamine, folic acid, menadiol diphosphate, menadione
sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6,
vitamin K6, and vitamin U; albumin, immunoglobulins, caseins,
hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin,
fibronectins, vitronectins, firbinogens, lipases, benzalkonium
chloride, benzethonium chloride, docecyl trimethyl ammonium
bromide, sodium docecylsulfates, dialkyl methylbenzyl ammonium
chloride, and dialkylesters of sodium sulfonsuccinic acid,
L-ascorbic acid and its salt, D-glucoascorbic acid and its salt,
tromethamine, triethanolamine, diethanolamine, meglumine,
glucamine, amine alcohols, glucoheptonic acid, glucomic acid,
hydroxyl ketone, hydroxyl lactone, gluconolactone,
glucoheptonolactone, glucooctanoic lactone, gulonic acid lactone,
mannoic lactone, ribonic acid lactone, lactobionic acid,
glucosamine, glutamic acid, benzyl alcohol, benzoic acid,
hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt,
gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic
acid, vanillin, methyl paraben, propyl paraben, sorbitol, xylitol,
cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,
ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,
catechin gallate, tiletamine, ketamine, propofol, lactic acids,
acetic acid, salts of any organic acid and organic amine,
polyglycidol, glycerol, multiglycerols, galactitol, di(ethylene
glycol), tri(ethylene glycol), tetra(ethylene glycol),
penta(ethylene glycol), poly(ethylene glycol) oligomers,
di(propylene glycol), tri(propylene glycol), tetra(propylene
glycol, and penta(propylene glycol), poly(propylene glycol)
oligomers, a block copolymer of polyethylene glycol and
polypropylene glycol, and derivatives and combinations thereof.
[0070] It is understood that both the foregoing general description
and the following detailed description are exemplary and
explanatory only and are not restrictive of the present invention
as claimed.
DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS
[0071] Embodiments of the present invention provide a method for
treatment of respiratory disorders such as asthma, chronic
obstructive pulmonary disease and chronic sinusitis, including
cystic fibrosis, interstitial fibrosis, chronic bronchitis,
emphysema, nasal and sinus dysplasia, bronchopulmonary dysplasia
and neoplasia. According to embodiments, the method involves
administration, preferably oral or pulmonary administration, of
anti-inflammatory and anti-proliferate drugs (rapamycin or
paclitaxel and their analogues). The anti-inflammatory and
anti-proliferate drugs can be administered alone or with one or
more additives.
[0072] The anti-inflammatory and anti-proliferate drugs intended
for intranasal delivery (systemic and local) for treatment of
respiratory disorders such as asthma, COPD and chronic sinusitis
can be, administered as aqueous solutions or suspensions, as
solutions or suspensions in halogenated hydrocarbon propellants
(pressurized metered-dose inhalers), or as dry powders.
Metered-dose spray pumps for aqueous formulations, pMDIs, and DPIs
for nasal delivery, are available from, for example, Valois of
America or Pfeiffer of America.
[0073] The drugs intended for pulmonary delivery can also be
administered as aqueous formulations, as suspensions or solutions
in halogenated hydrocarbon propellants, or as dry powders. Aqueous
formulations must be aerosolized by liquid nebulizers employing
either hydraulic or ultrasonic atomization, propellant-based
systems require suitable pressurized metered-dose inhalers (pMDIs),
and dry powders require dry powder inhaler devices (DPIs), which
are capable of dispersing the drug substance effectively. For
aqueous and other non-pressurized liquid systems, a variety of
nebulizers (including small volume nebulizers) are available to
aerosolize the formulations. Compressor-driven nebulizers
incorporate jet technology and use compressed air to generate the
liquid aerosol. Such devices are commercially available from, for
example, Healthdyne Technologies, Inc.; Invacare, Inc.; Mountain
Medical Equipment, Inc.; Pari Respiratory, Inc.; Mada Medical,
Inc.; Puritan-Bennet; Schuco, Inc., DeVilbiss Health Care, Inc.;
and Hospitak, Inc. Ultrasonic nebulizers rely on mechanical energy
in the form of vibration of a piezoelectric crystal to generate
respirable liquid droplets and are commercially available from, for
example, Omron Heathcare, Inc. and DeVilbiss Health Care, Inc.
[0074] A propellant driven inhaler (pMDI) releases a metered dose
of medicine upon each actuation. The medicine is formulated as a
suspension or solution of a drug substance in a suitable propellant
such as a halogenated hydrocarbon. pMDIs are described in, for
example, Newman, S. P., Aerosols and the Lung, Clarke et al., eds.,
pp. 197-224 (Butterworths, London, England, 1984).
[0075] Dry powder inhalers (DPIs), which involve disaggregation and
aerosolization of dry powders, normally rely upon a burst of
inspired air that is drawn through the unit to deliver a drug
dosage. Such devices are described in, for example, U.S. Pat. No.
4,807,814, which is directed to a pneumatic powder ejector having a
suction stage and an injection stage; SU 628930 (Abstract),
describing a hand-held powder disperser having an axial air flow
tube; Fox et al., Powder and Bulk Engineering, pages 33-36 (March
1988), describing a venturi eductor having an axial air inlet tube
upstream of a venturi restriction; EP 347 779, describing a
hand-held powder disperser having a collapsible expansion chamber;
and U.S. Pat. No. 5,785,049 directed to dry powder delivery devices
for drugs.
[0076] Droplet/particle size determines deposition site. In
developing the therapeutic aerosol of the anti-inflammatory and
anti-proliferate drugs, the aerodynamic size distribution of the
inhaled particles is the single most important variable in defining
the site of droplet or particle deposition in the patient; in
short, it will determine whether drug targeting succeeds or fails.
See P. Byron, "Aerosol Formulation, Generation, and Delivery Using
Nonmetered Systems," Respiratory Drug Delivery, 144-151, 144 (CRC
Press, 1989). Thus, a prerequisite in developing a therapeutic
aerosol is a preferential particle size. The deposition of inhaled
aerosols involves different mechanisms for different size
particles. D. Swift (1980); Parodi et al., "Airborne Particles and
Their Pulmonary Deposition," in Scientific Foundations of
Respiratory Medicine, Scaddings et al. (eds.), pp. 545-557 (W.B.
Saunders, Philadelphia, 1981); J. Heyder, "Mechanism of Aerosol
Particle Deposition," Chest, 80:820-823 (1981).
[0077] Generally, inhaled particles are subject to deposition by
one of two mechanisms: impaction, which usually predominates for
larger particles, and sedimentation, which is prevalent for smaller
particles. Impaction occurs when the momentum of an inhaled
particle is large enough that the particle does not follow the air
stream and encounters a physiological surface. In contrast,
sedimentation occurs primarily in the deep lung when very small
particles which have traveled with the inhaled air stream encounter
physiological surfaces as a result of random diffusion within the
air stream. For intranasally administered drug compounds which are
inhaled through the nose, it is desirable for the drug to impact
directly on the nasal mucosa; thus, large (ca. 5 to 100 microns)
particles or droplets are generally preferred for targeting of
nasal delivery.
[0078] Pulmonary drug delivery of the anti-inflammatory and
anti-proliferative drugs is accomplished by inhalation of an
aerosol through the mouth and throat. Particles having aerodynamic
diameters of greater than about 5 microns generally do not reach
the lung; instead, they tend to impact the back of the throat and
are swallowed and possibly orally absorbed. Particles having
diameters of about 2 to about 5 microns are small enough to reach
the upper- to mid-pulmonary region (conducting airways), but are
too large to reach the alveoli. Even smaller particles, i.e., about
0.5 to about 2 microns, are capable of reaching the alveolar
region. Particles having diameters smaller than about 0.5 microns
can also be deposited in the alveolar region by sedimentation,
although very small particles may be exhaled.
[0079] Embodiments of the present invention are directed to
aqueous, propellant-based, and dry powder aerosols of
anti-inflammatory and anti-proliferate drug compositions, for
pulmonary delivery, in which essentially every inhaled particle
contains at least one anti-inflammatory and anti-proliferate drug
particle. The drug is highly water-insoluble. Preferably, the
anti-inflammatory and anti-proliferate drug has an effective
average particle size of about 5 micron or less.
[0080] A. Aqueous Aerosol Formulations
[0081] Embodiments of the present invention encompass aqueous
formulations comprising drug particles and an additive. For aqueous
aerosol formulations, the anti-inflammatory and anti-proliferate
drug may be present at a concentration of about 0.05 mg/ml up to
about 600 mg/ML. Such formulations provide effective delivery to
appropriate areas of the lung. In addition, the more concentrated
aerosol formulations (i.e., for aqueous aerosol formulations, about
10 mg/ml up to about 600 mg/ml) have the additional advantage of
enabling large quantities of drug substance to be delivered to the
lung in a very short period of time.
[0082] B. Dry Powder Aerosol Formulations
[0083] Another embodiment of the invention is directed to dry
powder aerosol formulations comprising anti-inflammatory and
anti-proliferate drug particles and an additive for pulmonary and
nasal administration. Dry powders, which can be used in both DPIs
and pMDIs, can be made by spray drying aqueous drug dispersions.
Alternatively, dry powders containing anti-inflammatory and
anti-proliferate drug can be made by freeze-drying drug
dispersions. Combinations of spray-dried and freeze-dried drug
powders can be used in DPIs and pMDIs. For dry powder aerosol
formulations, the anti-inflammatory and anti-proliferate drug may
be present at a concentration of about 0.05 mg/g up to about 990
mg/g.
[0084] 1. Spray-Dried Powders Containing Anti-inflammatory and
Anti-proliferate Drug
[0085] Powders comprising anti-inflammatory and anti-proliferate
drug can be made by spray-drying aqueous dispersions of a drug and
an additive to form a dry powder which consists of aggregated drug
particles having an additive. The aggregates can have a size of
about 1 to about 2 microns, which is suitable for deep lung
delivery. The aggregate particle size can be increased to target
alternative delivery sites, such as the upper bronchial region or
nasal mucosa by increasing the concentration of drug in the
spray-dried dispersion or by increasing the droplet size generated
by the spray dryer.
[0086] Alternatively, the aqueous dispersion of the
anti-inflammatory and anti-proliferate drug and additive can
contain a dissolved diluent such as lactose or mannitol which, when
spray dried, forms respirable diluent particles, each of which
contains at least one embedded drug particle and additive. The
diluent particles with embedded drug can have a particle size of
about 1 to about 2 microns, suitable for deep lung delivery. In
addition, the diluent particle size can be increased to target
alternate delivery sites, such as the upper bronchial region or
nasal mucosa by increasing the concentration of dissolved diluent
in the aqueous dispersion prior to spray drying, or by increasing
the droplet size generated by the spray dryer.
[0087] Spray-dried powders can be used in DPIs or pMDIs, either
alone or combined with freeze-dried particulate powder. In
addition, spray-dried powders containing drug particles can be
reconstituted and used in either jet or ultrasonic nebulizers to
generate aqueous dispersions having respirable droplet sizes, where
each droplet contains at least one drug particle. Concentrated
particulate dispersions may also be used in these aspects of the
invention.
[0088] 2. Freeze-Dried Powders Containing Anti-inflammatory and
Anti-proliferative Particulate Drug
[0089] The particulate drug dispersions can also be freeze-dried to
obtain powders suitable for nasal or pulmonary delivery. Such
powders may contain aggregated particulate drug particles having an
additive. Such aggregates may have sizes within a respirable range,
i.e., about 2 to about 5 microns.
[0090] Freeze dried powders of the appropriate particle size can
also be obtained by freeze drying aqueous dispersions of the
anti-inflammatory and anti-proliferative drug and additive, which
additionally contain a dissolved diluent such as lactose or
mannitol. In these instances the freeze dried powders consist of
respirable particles of diluent, each of which contains at least
one embedded drug particle.
[0091] Freeze-dried powders can be used in DPIs or pMDIs, either
alone or combined with spray-dried particulate powder. In addition,
freeze-dried powders containing drug particles can be reconstituted
and used in either jet or ultrasonic nebulizers to generate aqueous
dispersions having respirable droplet sizes, where each droplet
contains at least one drug particle. Concentrated particulate
dispersions may also be used in these aspects of the invention.
[0092] C. Propellant-Based Formulations
[0093] Yet another embodiment of the invention is directed to a
process and composition for propellant-based systems comprising
anti-inflammatory and anti-proliferative drug particles and an
additive. Such formulations may be prepared by wet milling the
coarse drug substance and additive in liquid propellant, either at
ambient pressure or under high pressure conditions. Alternatively,
dry powders containing drug particles may be prepared by
spray-drying or freeze-drying aqueous dispersions of drug particles
and additive; the resultant powders are dispersed into suitable
propellants for use in conventional pMDIs. Such particulate pMDI
formulations can be used for either nasal or pulmonary delivery.
For pulmonary administration, such formulations afford increased
delivery to the deep lung regions because of the small (i.e., about
1 to about 2 microns) particle sizes available from these methods.
Concentrated aerosol formulations can also be employed in
pMDIs.
[0094] D. Methods of Making Aerosol Formulations
[0095] In embodiments, the invention also provides methods for
making an aerosol comprising a drug particulate composition
comprising an anti-inflammatory and anti-proliferate and an
additive. The particulate dispersions used in making aqueous
aerosol compositions can be made by wet milling or by precipitation
methods known in the art. Dry powders containing the drug particles
and additive can be made by spray-drying or freeze-drying aqueous
dispersions of the anti-inflammatory and anti-proliferate drug
particles and the additive. The dispersions used in these systems
may or may not contain dissolved diluent material prior to drying.
Additionally, both pressurized and non-pressurized milling
operations can be employed to make particulate drug compositions in
non-aqueous systems.
[0096] In a non-aqueous, non-pressurized milling system, a
non-aqueous liquid which has a vapor pressure of 1 atm or less at
room temperature is used as a milling medium and may be evaporated
to yield dry particulate drug and additive. The non-aqueous liquid
may be, for example, a high-boiling halogenated hydrocarbon. The
dry particulate drug composition thus produced may then be mixed
with a suitable propellant or propellants and used in a
conventional pMDI.
[0097] Alternatively, in a pressurized milling operation, a
non-aqueous liquid which has a vapor pressure >1 atm at room
temperature is used as a milling medium for making a particulate
drug and additive composition. Such a liquid may be, for example, a
halogenated hydrocarbon propellant which has a low boiling point.
The resultant particulate composition can then be used in a
conventional pMDI without further modification, or can be blended
with other suitable propellants. Concentrated aerosols may also be
made via such methods.
[0098] E. Methods of Using particulate Aerosol Formulations
[0099] In yet another aspect of the invention, there is provided a
method of treating asthma and COPD of mammals comprising: (1)
forming an aerosol of a dispersion (either aqueous or powder) of
the anti-inflammatory and anti-proliferate drug particles, wherein
the particles comprise an insoluble drug having an additive on the
surface thereof, and (2) administering the aerosol to the pulmonary
or nasal cavities of the mammal. Concentrated aerosol formulations
may also be used in such methods.
[0100] Drugs and Drug Combinations
[0101] The therapeutic drug or agent in the invention comprises one
or more drugs or agents chosen from an anti-thrombosis agent, an
anti-proliferate agent, an anti-inflammatory agent, an
anti-coagulant, an agent affecting extra cellular matrix production
and organization, and a vasodilating agent.
[0102] Examples of the therapeutic agents or drugs that are
suitable for use in accordance with the present invention include
sirolimus, everolimus, actinomycin D (ActD), taxol, paclitaxel, or
derivatives and analogs thereof. Examples of agents include other
antiproliferative substances as well as antineoplastic,
antiinflammatory, antiplatelet, anticoagulant, antifibrin,
antithrombin, antimitotic, antibiotic, and antioxidant substances.
Examples of antineoplastics include taxol (paclitaxel and
docetaxel). Further examples of therapeutic drugs or agents include
antiplatelets, anticoagulants, antifibrins, antiinflammatories,
antithrombins, and antiproliferatives. Examples of antiplatelets,
anticoagulants, antifibrins, and antithrombins include, but are not
limited to, sodium heparin, low molecular weight heparin, hirudin,
argatroban, forskolin, vapiprost, prostacyclin and prostacyclin
analogs, dextran, D-phe-pro-arg-chloromethylketone (synthetic
antithrombin), dipyridamole, glycoprotein IIb/IIIa platelet
membrane receptor antagonist, recombinant hirudin, thrombin
inhibitor (available from Biogen located in Cambridge, Mass.), and
7E-3B.RTM. (An antiplatelet drug from Centocor located in Malvern,
Pa.). Examples of antimitotic agents include methotrexate,
azathioprine, vincristine, vinblastine, fluorouracil, adriamycin,
and mutamycin. Examples of cytostatic or antiproliferative agents
include angiopeptin (a somatostatin analog from Ibsen located in
the United Kingdom), angiotensin converting enzyme inhibitors such
as Captopril.RTM. (available from Squibb located in New York,
N.Y.), Cilazapril.RTM. (available from Hoffman-LaRoche located in
Basel, Switzerland), or Lisinopril.RTM. (available from Merck
located in Whitehouse Station, N.J.); calcium channel blockers
(such as Nifedipine), colchicine, fibroblast growth factor (FGF)
antagonists, fish oil (omega 3-fatty acid), histamine antagonists,
Lovastatin.RTM. (an inhibitor of HMG-CoA reductase, a cholesterol
lowering drug from Merck), methotrexate, monoclonal antibodies
(such as PDGF receptors), nitroprusside, phosphodiesterase
inhibitors, prostaglandin inhibitor (available from GlaxoSmithKline
located in United Kingdom), Seramin (a PDGF antagonist), serotonin
blockers, steroids, thioprotease inhibitors, triazolopyrimidine (a
PDGF antagonist), and nitric oxide. Other therapeutic drugs or
agents which may be appropriate include alpha-interferon,
genetically engineered epithelial cells, and dexamethasone.
[0103] An anti-thrombosis agent, an anti-proliferate agent, an
anti-inflammatory agent, especially rapamycin or paclitaxel and
their analogues, as discussed above, can be used in combination
with other drugs, such as inhaled corticosteroids, inhaled
anticholinergics such as ipratropium and beta-agonists such as
albuterol, inhaled leukotriene inhibitors, and inhaled
epinephrine.
[0104] Some drugs that are considered particularly suitable for the
combination are inhaled corticosteroids such as, Budesonide,
Flunisolide, Triamcinolone, Beclomethasone, Fluticasone,
Mometasone, Dexamethasone, Hydrocortisone, Methylprednisolone,
Prednisone, Cotisone, Betamethasone, or the like. Some other
suitable drugs are bronchodilators such as Terbutaline, Albuterol,
Ipratropium, Pirbuterol, Epinephrine, Salmeterol, Levalbuterol,
Formoterol, or the like.
[0105] Other drugs that are also considered to be suitably
administered in the combinations include, but are not limited to,
Leukotriene inhibitors such as Montelukast, Zafirlukast, Zileuton,
or the like; antihistamines such as Loratadine, Cetirizine or the
like; Anti-Tuberculosis drugs for M TB or atypical mycobacteria
such as, Isoniazid, Ethambutol, Pyrazinamide, Rifamycin; Rifampin,
Streptomycin, Clarithromycin, or the like; other drugs; such as the
Serine lung protease inhibitors Azelastine, and Theophylline; and
other peptides, such as those that relate to Allergy Immunotherapy
for indoor and outdoor allergens, or the like. Additionally,
amikacin, gentamicin, tobramicin, rifabutin, rifapentine,
sparfloxacin, ciprofloxacin, quinolones, azithromycin,
erythromycin, isoniazid, or the like, can be considered to be
useful.
[0106] According to embodiments of the invention preferred,
.beta..sub.2 agonists in the combinations according to the
invention are selected from the group consisting of albuterol,
bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol,
fenoterol, formoterol, hexoprenaline, ibuterol, isoetharine,
isoprenaline, levosalbutamol, mabuterol, meluadrine,
metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol,
TD 3327, ritodrine, salmeterol, salmefamol, soterenot,
sulphonterol, tiaramide, terbutaline, and tolubuterol.
[0107] Additive
[0108] The additive according to embodiments of the present
invention has two parts. One part is hydrophilic and the other part
is a drug affinity part. The drug affinity part is a hydrophobic
part, and/or has an affinity to the therapeutic agent by hydrogen
bonding and/or van der Waals interactions. The drug affinity part
of the additive may bind the hydrophobic or lipophilic drug, such
as rapamycin or paclitaxel, with which they share structural
similiraties, and lipids of cell membranes. The hydrophilic portion
accelerates diffusion and increases permeation of the drug into
tissue. In some embodiments, such as coatings for medical devices,
the additive may facilitate rapid movement of drug off a medical
device during deployment at the target site by preventing
hydrophobic drug molecules from clumping to each other and to the
device, increasing drug solubility in interstitial spaces, and/or
accelerating drug passage through polar head groups to the lipid
bilayer of cell membranes of target tissues.
[0109] The additive according to embodiments of the present
invention has a drug affinity part and a hydrophilic part. The drug
affinity part is a hydrophobic part and/or has an affinity to the
therapeutic agent by hydrogen bonding and/or van der Waals
interactions. The hydrophobic part may include aliphatic and
aromatic organic hydrocarbon compounds, such as benzene, toluene,
and alkanes, among others. These parts are not water soluble. They
may bind both hydrophobic drug, with which they share structural
similarities, and lipids of cell membranes. They have no covalently
bonded iodine. The drug affinity part may include functional groups
that can form hydrogen bonds with drug and with itself. The
hydrophilic part may include hydroxyl groups, amine groups, amide
groups, carbonyl groups, carboxylic acid and anhydrides, ethyl
oxide, ethyl glycol, polyethylene glycol, ascorbic acid amino acid,
amino alcohol, glucose, sucrose, sorbitan, glycerol, polyalcohol,
phosphates, sulfates, organic salts and their substituted
molecules, among others. Hydroxyl, carboxyl, acid, amide or amine
groups, for example, may be advantageous since they easily displace
water molecules that are hydrogen-bound to polar head groups and
surface proteins of cell membranes and may function to remove this
barrier between hydrophobic drug and cell membrane lipid. These
parts can dissolve in water and polar solvents. These additives are
not oils, lipids, or polymers. The therapeutic agent is not
enclosed in micelles or liposomes or encapsulated in polymer
particles. The additive of embodiments of the present invention
have hydrophobic and hydrophilic components to both bind drug and
facilitate its rapid movement off a medical device during
deployment and into target tissues.
[0110] The additives in embodiments of the present invention are
surfactants and chemical compounds with one or more hydroxyl,
amino, carbonyl, carboxyl, acid, amide or ester moieties. The
surfactants include ionic, nonionic, aliphatic, and aromatic
surfactants. The chemical compounds with one or more hydroxyl,
amino, carbonyl, carboxyl, acid, amide or ester moieties are amino
alcohols, hydroxyl carboxylic acid and anhydrides, ethyl oxide,
ethyl glycols, amino acids, peptides, proteins, sugars, glucose,
sucrose, sorbitan, glycerol, polyalcohol, phosphates, sulfates,
organic acids, esters, salts, vitamins, and their substituted
molecules.
[0111] As is well known in the art, the terms "hydrophilic" and
"hydrophobic" are relative terms. To function as an additive in
exemplary embodiments of the present invention, the compound
includes polar or charged hydrophilic moieties as well as non-polar
hydrophobic (lipophilic) moieties.
[0112] An empirical parameter commonly used in medicinal chemistry
to characterize the relative hydrophilicity and hydrophobicity of
pharmaceutical compounds is the partition coefficient, P, the ratio
of concentrations of unionized compound in the two phases of a
mixture of two immiscible solvents, usually octanol and water, such
that P=([solute]octanol/[solute]water). Compounds with higher log
Ps are more hydrophobic, while compounds with lower log Ps are more
hydrophilic. Lipinski's rule suggests that pharmaceutical compounds
having log P<5 are typically more membrane permeable. For
purposes of certain embodiments of the present invention, it is
preferable that the additive has log P less than log P of the drug
to be formulated (as an example, log P of paclitaxel is 7.4). A
greater log P difference between the drug and the additive can
facilitate phase separation of drug. For example, if log P of the
additive is much lower than log P of the drug, the additive may
accelerate the release of drug in an aqueous environment from the
surface of a device to which drug might otherwise tightly adhere,
thereby accelerating drug delivery to tissue. In certain
embodiments of the present invention, log P of the additive is
negative. In other embodiments, log P of the additive is less than
log P of the drug. While a compound's octanol-water partition
coefficient P or log P is useful as a measurement of relative
hydrophilicity and hydrophobicity, it is merely a rough guide that
may be useful in defining suitable additives for use in embodiments
of the present invention.
[0113] Suitable additives that can be used in embodiments of the
present invention include, without limitation, organic and
inorganic pharmaceutical excipients, natural products and
derivatives thereof (such as sugars, vitamins, amino acids,
peptides, proteins, and fatty acids), low molecular weight
oligomers, surfactants (anionic, cationic, non-ionic, and ionic),
and mixtures thereof. The following detailed list of additives
useful in the present invention is provided for exemplary purposes
only and is not intended to be comprehensive. Many other additives
may be useful for purposes of the present invention.
[0114] Surfactants
[0115] The surfactant can be any surfactant suitable for use in
pharmaceutical compositions. Such surfactants can be anionic,
cationic, zwitterionic or non-ionic. Mixtures of surfactants are
also within the scope of the invention, as are combinations of
surfactant and other additives. Surfactants often have one or more
long aliphatic chains such as fatty acids that may insert directly
into the lipid bilayers of cell membranes to form part of the lipid
structure of the cells, while other components of the surfactants
loosen the lipid structure and enhance drug penetration and
absorption. The contrast agent, such as iopromide, does not have
these properties.
[0116] An empirical parameter commonly used to characterize the
relative hydrophilicity and hydrophobicity of surfactants is the
hydrophilic-lipophilic balance ("HLB" value). Surfactants with
lower HLB values are more hydrophobic, and have greater solubility
in oils, while surfactants with higher HLB values are more
hydrophilic, and have greater solubility in aqueous solutions.
Using HLB values as a rough guide, hydrophilic surfactants are
generally considered to be those compounds having an HLB value
greater than about 10, as well as anionic, cationic, or
zwitterionic compounds for which the HLB scale is not generally
applicable. Similarly, hydrophobic surfactants are compounds having
an HLB value less than about 10.
[0117] It should be understood that the HLB value of a surfactant
is merely a rough guide generally used to enable formulation of
industrial, pharmaceutical and cosmetic emulsions, for example. For
many important surfactants, including several polyethoxylated
surfactants, it has been reported that HLB values can differ by as
much as about 8 HLB units, depending upon the empirical method
chosen to determine the HLB value (Schott, J. Pharm. Sciences,
79(1), 87-88 (1990)). Keeping these inherent difficulties in mind,
and using HLB values as a guide, surfactants may be identified that
have suitable hydrophilicity or hydrophobicity for use in
embodiments of the present invention, as described herein.
[0118] PEG-Fatty Acids and PEG-Fatty Acid Mono and Diesters
[0119] Although polyethylene glycol (PEG) itself does not function
as a surfactant, a variety of PEG-fatty acid esters have useful
surfactant properties. Among the PEG-fatty acid monoesters, esters
of lauric acid, oleic acid, and stearic acid are most useful in
embodiments of the present invention. Preferred hydrophilic
surfactants include PEG-8 laurate, PEG-8 oleate, PEG-8 stearate,
PEG-9 oleate, PEG-10 laurate, PEG-10 oleate, PEG-12 laurate, PEG-12
oleate, PEG-15 oleate, PEG-20 laurate and PEG-20 oleate. The HLB
values are in the range of 4-20.
[0120] Polyethylene glycol fatty acid diesters are also suitable
for use as surfactants in the compositions of embodiments of the
present invention. Most preferred hydrophilic surfactants include
PEG-20 dilaurate, PEG-20 dioleate, PEG-20 distearate, PEG-32
dilaurate and PEG-32 dioleate. The HLB values are in the range of
5-15.
[0121] In general, mixtures of surfactants are also useful in
embodiments of the present invention, including mixtures of two or
more commercial surfactants as well as mixtures of surfactants with
another additive or additives. Several PEG-fatty acid esters are
marketed commercially as mixtures or mono- and diesters.
[0122] Polyethylene Glycol Glycerol Fatty Acid Esters
[0123] Preferred hydrophilic surfactants are PEG-20 glyceryl
laurate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-20
glyceryl oleate, and PEG-30 glyceryl oleate.
[0124] Alcohol-Oil Transesterification Products
[0125] A large number of surfactants of different degrees of
hydrophobicity or hydrophilicity can be prepared by reaction of
alcohols or polyalcohol with a variety of natural and/or
hydrogenated oils. Most commonly, the oils used are castor oil or
hydrogenated castor oil, or an edible vegetable oil such as corn
oil, olive oil, peanut oil, palm kernel oil, apricot kernel oil, or
almond oil. Preferred alcohols include glycerol, propylene glycol,
ethylene glycol, polyethylene glycol, sorbitol, and
pentaerythritol. Among these alcohol-oil transesterified
surfactants, preferred hydrophilic surfactants are PEG-35 castol
oil (Incrocas 35), PEG 40 hydrogenated castor oil (Cremophor RH
40), PEG-25 trioleate (TAGAT.RTM. TO), PEG-60 corn glycerides
(Crovol M70), PEG-60 almond oil (Crovol A70), PEG-40 palm kernel
oil (Crovol PK70), PEG-50 castor oil (Emalex C-50), PEG-50
hydrogenated castor oil (Emalex HC-50), PEG-8 caprylic/capric
glycerides (Labrasol), and PEG-5 hydrogenated castor oil, PEG-7
hydrogenated castor oil, PEG-9 hydrogenated castor oil, PEG-6
caprylic/capric glycerides (Softigen 767). Preferred hydrophobic
surfactants in this class include PEG-6 corn oil (Labrafil.RTM. M
2125 CS), PEG-6 almond oil (Labrafil.RTM. M 1966 CS), PEG-6 apricot
kernel oil (Labrafil.RTM. M 1944 CS), PEG-6 olive oil
(Labrafil.RTM. M 1980 CS), PEG-6 peanut oil (Labrafil.RTM. M 1969
CS), PEG-6 hydrogenated palm kernel oil (Labrafil.RTM. M 2130 BS),
PEG-6 palm kernel oil (Labrafil.RTM. M 2130 CS), PEG-6 triolein
(Labrafil.RTM. b M 2735 CS), PEG-8 corn oil (Labrafil.RTM. WL 2609
BS), PEG-20 corn glycerides (Crovol M40), and PEG-20 almond
glycerides (Crovol A40).
[0126] Polyglyceryl Fatty Acids
[0127] Polyglycerol esters of fatty acids are also suitable
surfactants for use in embodiments of the present invention. Among
the polyglyceryl fatty acid esters, preferred hydrophobic
surfactants include polyglyceryl oleate (Plurol Oleique),
polyglyceryl-2 dioleate (Nikkol DGDO), polyglyceryl-10 trioleate,
polyglyceryl stearate, polyglyceryl laurate, polyglyceryl
myristate, polyglyceryl palmitate, and polyglyceryl linoleate.
Preferred hydrophilic surfactants include polyglyceryl-10 laurate
(Nikkol Decaglyn 1-L), polyglyceryl-10 oleate (Nikkol Decaglyn
1-0), and polyglyceryl-10 mono, dioleate (Caprol.RTM. PEG 860),
polyglyceryl-10 stearate, polyglyceryl-10 laurate, polyglyceryl-10
myristate, polyglyceryl-10 palmitate, polyglyceryl-10 linoleate,
polyglyceryl-6 stearate, polyglyceryl-6 laurate, polyglyceryl-6
myristate, polyglyceryl-6 palmitate, and polyglyceryl-6 linoleate.
Polyglyceryl polyricinoleates (Polymuls) are also preferred
surfactants.
[0128] Propylene Glycol Fatty Acid Esters
[0129] Esters of propylene glycol and fatty acids are suitable
surfactants for use in embodiments of the present invention. In
this surfactant class, preferred hydrophobic surfactants include
propylene glycol monolaurate (Lauroglycol FCC), propylene glycol
ricinoleate (Propymuls), propylene glycol monooleate (Myverol
P-O6), propylene glycol dicaprylate/dicaprate (Captex.RTM. 200),
and propylene glycol dioctanoate (Captex.RTM. 800).
[0130] Sterol and Sterol Derivatives
[0131] Sterols and derivatives of sterols are suitable surfactants
for use in embodiments of the present invention. Preferred
derivatives include the polyethylene glycol derivatives. A
preferred surfactant in this class is PEG-24 cholesterol ether
(Solulan C-24).
[0132] Polyethylene Glycol Sorbitan Fatty Acid Esters
[0133] A variety of PEG-sorbitan fatty acid esters are available
and are suitable for use as surfactants in embodiments of the
present invention. Among the PEG-sorbitan fatty acid esters,
preferred surfactants include PEG-20 sorbitan monolaurate
(Tween-20), PEG-20 sorbitan monopalmitate (Tween-40), PEG-20
sorbitan monostearate (Tween-60), and PEG-20 sorbitan monooleate
(Tween-80). In some embodiments, laurate esters are preferred
because they have a short lipid compared with oleate esters,
increasing drug absorption.
[0134] Polyethylene Glycol Alkyl Ethers
[0135] Ethers of polyethylene glycol and alkyl alcohols are
suitable surfactants for use in embodiments of the present
invention. Preferred ethers include PEG-3 oleyl ether (Volpo 3) and
PEG-4 lauryl ether (Brij 30).
[0136] Sugar and Its Derivatives
[0137] Sugar derivatives are suitable surfactants for use in
embodiments of the present invention. Preferred surfactants in this
class include sucrose monopalmitate, sucrose monolaurate,
decanoyl-N-methylglucamide, n-decyl-.beta.-D-glucopyranoside,
n-decyl-.beta.-D-maltopyranoside,
n-dodecyl-.beta.-D-glucopyranoside, n-dodecyl-.beta.-D-maltoside,
heptanoyl-N-methylglucamide, n-heptyl-.beta.-D-glucopyranoside,
n-heptyl-.beta.-D-thioglucoside, n-hexyl-.beta.-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-nonyl-.beta.-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside, and
octyl-.beta.-D-thioglucopyranoside.
[0138] Polyethylene Glycol Alkyl Phenols
[0139] Several PEG-alkyl phenol surfactants are available, such as
PEG-10-100 nonyl phenol and PEG-15-100 octyl phenol ether,
Tyloxapol, octoxynol, nonoxynol, and are suitable for use in
embodiments of the present invention.
[0140] Polyoxyethylene-Polyoxypropylene (POE-POP) Block
Copolymers
[0141] The POE-POP block copolymers are a unique class of polymeric
surfactants. The unique structure of the surfactants, with
hydrophilic POE and hydrophobic POP moieties in well-defined ratios
and positions, provides a wide variety of surfactants suitable for
use in embodiments of the present invention. These surfactants are
available under various trade names, including Synperonic PE series
(ICI); Pluronic.RTM. series (BASF), Emkalyx, Lutrol (BASF),
Supronic, Monolan, Pluracare, and Plurodac. The generic term for
these polymers is "poloxamer" (CAS 9003-11-6). These polymers have
the formula:
HO(C.sub.2H.sub.4O).sub.a(C.sub.3H.sub.6O).sub.b(C.sub.2H.sub.4O).sub.aH
where "a" and "b" denote the number of polyoxyethylene and
polyoxypropylene units, respectively.
[0142] Preferred hydrophilic surfactants of this class include
Poloxamers 108, 188, 217, 238, 288, 338, and 407. Preferred
hydrophobic surfactants in this class include Poloxamers 124, 182,
183, 212, 331, and 335.
[0143] Sorbitan Fatty Acid Esters Sorbitan esters of fatty acids
are suitable surfactants for use in embodiments of the present
invention. Among these esters, preferred hydrophobic surfactants
include sorbitan monolaurate (Arlacel 20), sorbitan monopalmitate
(Span-40), and sorbitan monooleate (Span-80), sorbitan
monostearate.
[0144] The sorbitan monopalmitate, an amphiphilic derivative of
Vitamin C (which has Vitamin C activity), can serve two important
functions in solubilization systems. First, it possesses effective
polar groups that can modulate the microenvironment. These polar
groups are the same groups that make vitamin C itself (ascorbic
acid) one of the most water-soluble organic solid compounds
available: ascorbic acid is soluble to about 30 wt/wt % in water
(very close to the solubility of sodium chloride, for example). And
second, when the pH increases so as to convert a fraction of the
ascorbyl palmitate to a more soluble salt, such as sodium ascorbyl
palmitate.
[0145] Ionic Surfactants
[0146] Ionic surfactants, including cationic, anionic and
zwitterionic surfactants, are suitable hydrophilic surfactants for
use in embodiments of the present invention. Preferred ionic
surfactants include quaternary ammonium salts, fatty acid salts and
bile salts. Specifically, preferred ionic surfactants include
benzalkonium chloride, benzethonium chloride, cetylpyridinium
chloride, docecyl trimethyl ammonium bromide, sodium
docecylsulfates, dialkyl methylbenzyl ammonium chloride,
edrophonium chloride, domiphen bromide, dialkylesters of sodium
sulfonsuccinic acid, sodium dioctyl sulfosuccinate, sodium cholate,
and sodium taurocholate. These quaternary ammonium salts are
preferred additives. They can be dissolved in both organic solvents
(such as ethanol, acetone, and toluene) and water. This is
especially useful for medical device coatings because it simplifies
the preparation and coating process and has good adhesive
properties. Water insoluble drugs are commonly dissolved in organic
solvents.
[0147] Chemical Compounds With One or More Hydroxyl, Amino,
Carbonyl, Carboxyl, Acid, Amide or Ester Moieties
[0148] The chemical compounds with one or more hydroxyl, amino,
carbonyl, carboxyl, acid, amide or ester moieties include amino
alcohols, hydroxyl carboxylic acid, ester, and anhydrides, hydroxyl
ketone, hydroxyl lactone, hydroxyl ester, sugar phosphate, sugar
sulfate, ethyl oxide, ethyl glycols, amino acids, peptides,
proteins, sugars, glucose, sucrose, sorbitan, glycerol,
polyalcohol, phosphates, sulfates, organic acids, esters, salts,
vitamins, combinations of amino alcohol and organic acids, and
their substituted molecules. Hydrophilic chemical compounds with
one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide, or
ester moieties having a molecular weight less than 5,000-10,000,
are preferred in certain embodiments. In other embodiments,
molecular weight of the additive with one or more hydroxyl, amino,
carbonyl, carboxyl, acid, amide, or ester moieties is preferably
less than 1000-5,000, or more preferably less than 700-1,000, or
most preferably less than 750. In these embodiments, molecular
weight of the additive is preferred to be less than that of the
drug to be delivered. Further, in some embodiments, the molecular
weight of the additive is preferred to be higher than 80 since
molecules with molecular weight less than 80 very easily evaporate
and do not stay in coatings of a medical device. Small molecules
can diffuse quickly. They can release themselves easily from the
delivery balloon, accelerating release of drug, and they can
diffuse away from drug when the drug binds tissue of the body
lumen.
[0149] In certain embodiments, for example, in a coating for a
medical device, more than four hydroxyl groups are preferred, for
example in the case of a high molecular weight additive. Large
molecules diffuse slowly. If the molecular weight of the additive
or the chemical compound is high, for example if the molecular
weight is above 800, above 1000, above 1200, above 1500, or above
2000; large molecules may elute off of the surface of a medical
device too slowly to release drug under 2 minutes. If these large
molecules contain more than four hydroxyl groups they have
increased hydrophilic properties, which is necessary for relatively
large molecules to release drug quickly. The increased
hydrophilicity helps elute the coating off the balloon, accelerates
release of drug, and improves or facilitates drug movement through
water barrier and polar head groups of lipid bilayers to penetrate
tissues. The hydroxyl group is preferred as the hydrophilic moiety
because it is unlikely to react with water insoluble drug, such as
paclitaxel or rapamycin. In some embodiments, the chemical compound
having more than four hydroxyl groups has a melting point of
120.degree. C. or less. In some embodiments, the chemical compound
having more than four hydroxyl groups has three adjacent hydroxyl
groups that in stereo configuration are all on one side of the
molecule. For example, sorbitol and xylitol have three adjacent
hydroxyl groups that in stereoconfiguration are all on one side of
the molecule, while galactitol does not. The difference impacts the
physical properties of the isomers such as the melting temperature.
The stereoconfiguration of the three adjacent hydroxyl groups may
enhance drug binding. This will lead to improved compatibility of
the water insoluble drug and hydrophilic additive, and improved
tissue uptake and absorption of drug.
[0150] Some of the chemical compounds with one or more hydroxyl,
amine, carbonyl, carboxyl, or ester moieties described herein are
very stable under heating. They survive an ethylene oxide
sterilization process and do not react with the water insoluble
drug paclitaxel or rapamycin during sterilization. L-ascorbic acid
and its salt and diethanolamine, on the other hand, do not
necessarily survive such a sterilization process, and they react
with paclitaxel. A different sterilization method is therefore
preferred for L-ascorbic acid and diethanolamine. Hydroxyl, ester,
and amide groups are preferred because they are unlikely to react
with therapeutic agents such as paclitaxel or rapamycin. Sometimes,
amine and acid groups do react with paclitaxel, for example,
experimentally, benzoic acid, gentisic acid, diethanolamine, and
ascorbic acid were not stable under ethylene oxide sterilization,
heating, and aging process and reacted with paclitaxel. When the
chemical compounds described herein are formulated with paclitaxel,
a top coat layer may be advantageous in order to prevent premature
drug loss during the device delivery process before deployment at
the target site, since hydrophilic small molecules sometimes
release drug too easily. The chemical compounds herein rapidly
elute drug off the balloon during deployment at the target site.
Surprisingly, even though some drug is lost during transit of the
device to the target site when the coating contains these
additives, experimentally drug absorption by tissue is unexpectedly
high after only 0.2-2 minutes of deployment, for example, with the
additive hydroxyl lactones such as ribonic acid lactone and
gluconolactone.
[0151] Fat-soluble Vitamins and Salts Thereof
[0152] Vitamins A, D, E and K in many of their various forms and
provitamin forms are considered as fat-soluble vitamins and in
addition to these a number of other vitamins and vitamin sources or
close relatives are also fat-soluble and have polar groups, and
relatively high octanol-water partition coefficients. Clearly, the
general class of such compounds has a history of safe use and high
benefit to risk ratio, making them useful as additives in
embodiments of the present invention.
[0153] The following examples of fat-soluble vitamin derivatives
and/or sources are also useful as additives: Alpha-tocopherol,
beta-tocopherol, gamma-tocopherol, delta-tocopherol, tocopherol
acetate, ergosterol, 1-alpha-hydroxycholecal-ciferol, vitamin D2,
vitamin D3, alpha-carotene, beta-carotene, gamma-carotene, vitamin
A, fursultiamine, methylolriboflavin, octotiamine, prosultiamine,
riboflavine, vintiamol, dihydrovitamin K1, menadiol diacetate,
menadiol dibutyrate, menadiol disulfate, menadiol, vitamin K1,
vitamin K1 oxide, vitamins K2, and vitamin K--S(II). Folic acid is
also of this type, and although it is water-soluble at
physiological pH, it can be formulated in the free acid form. Other
derivatives of fat-soluble vitamins useful in embodiments of the
present invention may easily be obtained via well known chemical
reactions with hydrophilic molecules.
[0154] Water-soluble Vitamins and Their Amphiphilic Derivatives
[0155] Vitamins B, C, U, pantothenic acid, folic acid, and some of
the menadione-related vitamins/provitamins in many of their various
forms are considered water-soluble vitamins. These may also be
conjugated or complexed with hydrophobic moieties or multivalent
ions into amphiphilic forms having relatively high octanol-water
partition coefficients and polar groups. Again, such compounds can
be of low toxicity and high benefit to risk ratio, making them
useful as additives in embodiments of the present invention. Salts
of these can also be useful as additives in the present invention.
Examples of water-soluble vitamins and derivatives include, without
limitation, acetiamine, benfotiamine, pantothenic acid,
cetotiamine, cyclothiamine, dexpanthenol, niacinamide, nicotinic
acid, pyridoxal 5-phosphate, nicotinamide ascorbate, riboflavin,
riboflavin phosphate, thiamine, folic acid, menadiol diphosphate,
menadione sodium bisulfite, menadoxime, vitamin B12, vitamin K5,
vitamin K6, vitamin K6, and vitamin U. Also, as mentioned above,
folic acid is, over a wide pH range including physiological pH,
water-soluble, as a salt.
[0156] Compounds in which an amino or other basic group is present
can easily be modified by simple acid-base reaction with a
hydrophobic group-containing acid such as a fatty acid (especially
lauric, oleic, myristic, palmitic, stearic, or 2-ethylhexanoic
acid), low-solubility amino acid, benzoic acid, salicylic acid, or
an acidic fat-soluble vitamin (such as riboflavin). Other compounds
might be obtained by reacting such an acid with another group on
the vitamin such as a hydroxyl group to form a linkage such as an
ester linkage, etc. Derivatives of a water-soluble vitamin
containing an acidic group can be generated in reactions with a
hydrophobic group-containing reactant such as stearylamine or
riboflavine, for example, to create a compound that is useful in
embodiments of the present invention. The linkage of a palmitate
chain to vitamin C yields ascorbyl palmitate.
[0157] Amino Acids and Their Salts
[0158] Alanine, arginine, asparagines, aspartic acid, cysteine,
cystine, glutamic acid, glutamine, glycine, histidine, proline,
isoleucine, leucine, lysine, methionine, phenylalanine, serine,
threonine, tryptophan, tyrosine, valine, and their derivatives are
other useful additives in embodiments of the invention.
[0159] Certain amino acids, in their zwitterionic form and/or in a
salt form with a monovalent or multivalent ion, have polar groups,
relatively high octanol-water partition coefficients, and are
useful in embodiments of the present invention. In the context of
the present disclosure we take "low-solubility amino acid" to mean
an amino acid which has solubility in unbuffered water of less than
about 4% (40 mg/ml). These include Cystine, tyrosine, tryptophan,
leucine, isoleucine, phenylalanine, asparagine, aspartic acid,
glutamic acid, and methionine.
[0160] Amino acid dimers, sugar-conjugates, and other derivatives
are also useful, such as dopamine hydrochloride, DOPA, LOVADOPA,
and carbidopa. Through simple reactions well known in the art
hydrophilic molecules may be joined to hydrophobic amino acids, or
hydrophobic molecules to hydrophilic amino acids, to make
additional additives useful in embodiments of the present
invention. Catecholamines, such as dopamine, levodopa, carbidopa,
and DOPA, are also useful as additives.
[0161] Oligopeptides, Peptides and Proteins
[0162] Oligopeptides and peptides are useful as additives, since
hydrophobic and hydrophilic amino acids may be easily coupled and
various sequences of amino acids may be tested to maximally
facilitate permeation of tissue by drug.
[0163] Proteins are also useful as additives in embodiments of the
present invention. Serum albumin, for example, is a particularly
preferred additive since it is water soluble and contains
significant hydrophobic parts to bind drug: paclitaxel is 89% to
98% protein-bound after human intravenous infusion, and rapamycin
is 92% protein bound, primarily (97%) to albumin. Furthermore,
paclitaxel solubility in PBS increases over 20-fold with the
addition of BSA. Albumin is naturally present at high
concentrations in serum and is thus very safe for human
intravascular use.
[0164] Other useful proteins include, without limitation, other
albumins, immunoglobulins, caseins, hemoglobins, lysozymes,
immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,
firbinogens, lipases, and the like.
[0165] Organic Acids and Their Esters and Anhydrides
[0166] Examples are acetic acid and anhydride, benzoic acid and
anhydride, acetylsalicylic acid, diflunisal, 2-hydroxyethyl
salicylate, diethylenetriaminepentaacetic acid dianhydride,
ethylenediaminetetraacetic dianhydride, maleic acid and anhydride,
succinic acid and anhydride, diglycolic anhydride, glutaric
anhydride, ascorbic acid, citric acid, tartaric acid, lactic acid,
oxalic acid aspartic acid, nicotinic acid,
2-pyrrolidone-5-carboxylic acid, and 2-pyrrolidone.
[0167] These esters and anhydrides are soluble in organic solvents
such as ethanol, acetone, methylethylketone, ethyl acetate. The
water insoluble drugs can be dissolved in organic solvent with
these esters and anhydrides, then coated easily on to the medical
device, then hydrolyzed under high pH conditions. The hydrolyzed
anhydrides or esters are acids or alcohols, which are water soluble
and can effectively carry the drugs off the device into the vessel
walls.
[0168] Other Chemical Compounds with One or More Hydroxyl, Amine,
Carbonyl, Carboxyl, or Ester Moieties
[0169] The additives according to embodiments include amino
alcohols, alcohols, amines, acids, amides and hydroxyl acids in
both cyclo and linear aliphatic and aromatic group. Examples are
L-ascorbic acid and its salt, D-glucoascorbic acid and its salt,
tromethamine, triethanolamine, diethanolamine, meglumine,
glucamine, amine alcohols, glucoheptonic acid, glucomic acid,
hydroxyl ketone, hydroxyl lactone, gluconolactone,
glucoheptonolactrone, D-glucoheptono-1,4-lactone, glucooctanoic
lactone, gulonic acid lactone, mannoic lactone, erythronic acid
lactone, ribonic acid lactone, lactobionic acid, glucosamine,
glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid,
propyl 4-hydroxybenzoate, lysine acetate salt, gentisic acid,
lactobionic acid, lactitol, sorbitol, glucose, sucrose, lactose,
maltose, ribose, arabinose, lyxose, xylose, fructose, mannose,
glucitol, sugars, sugar phosphates, glucopyranose phosphate, sugar
sulphates, sinapic acid, vanillic acid, vanillin, methyl paraben,
propyl paraben, xylitol, 2-ethoxyethanol, cyclodextrin,
(2-hydroxypropyl)cyclodextrin, acetaminophen, ibuprofen, retinoic
acid, lysine acetate, gentisic acid, catechin, catechin gallate,
tiletamine, ketamine, propofol, lactic acids, acetic acid, salts of
any organic acid and amine described, polyglycidol, glycerol,
multiglycerols, galactitol, di(ethylene glycol), tri(ethylene
glycol), tetra(ethylene glycol), penta(ethylene glycol),
poly(ethylene glycol) oligomers, di(propylene glycol),
tri(propylene glycol), tetra(propylene glycol, and penta(propylene
glycol), poly(propylene glycol) oligomers, a block copolymer of
polyethylene glycol and polypropylene glycol, and derivatives and
combinations thereof.
[0170] Combinations of additives are also useful for purposes of
the present invention.
[0171] One embodiment comprises the combination or mixture of two
additives, for example, a first additive comprising a surfactant
and a second additive comprising a chemical compound with one or
more hydroxyl, amine, carbonyl, carboxyl, or ester moieties.
[0172] The combination or mixture of the surfactant and the small
water-soluble molecule (the chemical compounds with one or more
hydroxyl, amine, carbonyl, carboxyl, or ester moieties) has
advantages. Formulations comprising mixtures of the two additives
with water-insoluble drug are in certain cases superior to mixtures
including either additive alone. The hydrophobic drugs bind
extremely water-soluble small molecules more poorly than they do
surfactants. The water-insoluble drug has Log P higher than both
that of the surfactant and that of small water-soluble molecules.
However, Log P of the surfactant is typically higher than Log P of
the chemical compounds with one or more hydroxyl, amine, carbonyl,
carboxyl, or ester moieties. The surfactant has a relatively high
Log P (usually above 0) and the water soluble molecules have low
Log P (usually below 0). Some surfactants, when used as additives
in embodiments of the present invention, such as in coatings of
medical devices, adhere so strongly to the water-insoluble drug and
the surface of the medical device that drug is not able to rapidly
release from the surface of the medical device at the target site.
On the other hand, some of the water-soluble small molecules (with
one or more hydroxyl, amine, carbonyl, carboxyl, or ester moieties)
adhere so poorly to the medical device that they release drug
before it reaches the target site, for example, into serum during
the transit of a coated balloon catheter to the site targeted for
intervention. Suprisingly, by adjusting the ratio of the
concentrations of the small hydrophilic molecule and the surfactant
in the formulation, the inventor has found that the coating
stability during transit and rapid drug release when inflated and
pressed against tissues of the lumen wall at the target site of
therapeutic intervention in certain cases is superior to a
formulation comprising either additive alone. Furthermore, the
miscibility and compatibility of the water-insoluble drug and the
highly water-soluble molecules is improved by the presence of the
surfactant. The surfactant also improves coating uniformity and
integrity by its good adhesion to the drug and the small molecules.
The long chain hydrophobic part of the surfactant binds drug
tightly while the hydrophilic part of the surfactant binds the
water-soluble small molecules.
[0173] The surfactants in the mixture or the combination include
all of the surfactants described herein for use in embodiments of
the invention. The surfactant in the mixture may be chosen from PEG
fatty esters, PEG omega-3 fatty esters and alcohols, glycerol fatty
esters, sorbitan fatty esters, PEG glyceryl fatty esters, PEG
sorbitan fatty esters, sugar fatty esters, PEG sugar esters, Tween
20, Tween 40, Tween 60, p-isononylphenoxypolyglycidol, PEG laurate,
PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryl
oleate, PEG glyceryl stearate, polyglyceryl laurate, plyglyceryl
oleate, polyglyceryl myristate, polyglyceryl palmitate,
polyglyceryl-6 laurate, plyglyceryl-6 oleate, polyglyceryl-6
myristate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate,
plyglyceryl-10 oleate, polyglyceryl-10 myristate, polyglyceryl-10
palmitate, PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG
sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG
laurayl ether, Tween 20, Tween 40, Tween 60, Tween 80, octoxynol,
monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate,
decanoyl-N-methylglucamide, n-decyl-.beta.-D-glucopyranoside,
n-decyl-.beta.-D-maltopyranoside,
n-dodecyl-.beta.-D-glucopyranoside, n-dodecyl-.beta.-D-maltoside,
heptanoyl-N-methylglucamide, n-heptyl-.beta.-D-glucopyranoside,
n-heptyl-.beta.-D-thioglucoside, n-hexyl-.beta.-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-.beta.-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside,
octyl-.beta.-D-thioglucopyranoside and their derivatives.
[0174] The chemical compound with one or more hydroxyl, amine,
carbonyl, carboxyl, or ester moieties in the mixture or the
combination include all of the chemical compounds with one or more
hydroxyl, amine, carbonyl, carboxyl, or ester moieties described
herein for use in embodiments of the invention. The chemical
compound with one or more hydroxyl, amine, carbonyl, carboxyl, or
ester moieties in the mixture has at least one hydroxyl group in
one of the embodiments in the inventions. In certain embodiments,
more than four hydroxyl groups are preferred, for example in the
case of a high molecular weight additive. In some embodiments, the
chemical compound having more than four hydroxyl groups has a
melting point of 120.degree. C. or less. Large molecules diffuse
slowly. If the molecular weight of the additive or the chemical
compound is high, for example if the molecular weight is above 800,
above 1000, above 1200, above 1500, or above 2000; large molecules
may elute off of the surface of the medical device too slowly to
release drug under 2 minutes. If these large molecules contain more
than four hydroxyl groups they have increased hydrophilic
properties, which is necessary for relatively large molecules to
release drug quickly. The increased hydrophilicity helps elute the
coating off the balloon, accelerates release of drug, and improves
or facilitates drug movement through water barrier and polar head
groups of lipid bilayers to penetrate tissues. The hydroxyl group
is preferred as the hydrophilic moiety because it is unlikely to
react with water insoluble drug, such as paclitaxel or
rapamycin.
[0175] The chemical compound with one or more hydroxyl, amine,
carbonyl, carboxyl, or ester moieties in the mixture is chosen from
L-ascorbic acid and its salt, D-glucoascorbic acid and its salt,
tromethamine, triethanolamine, diethanolamine, meglumine,
glucamine, amine alcohols, glucoheptonic acid, glucomic acid,
hydroxyl ketone, hydroxyl lactone, gluconolactone,
D-glucoheptono-1,4-lactone, glucooctanoic lactone, gulonic acid
lactone, mannoic lactone, erythronic acid lactone, ribonic acid
lactone, lactobionic acid, glucosamine, glutamic acid, benzyl
alcohol, benzoic acid, hydroxybenzoic acid, propyl
4-hydroxybenzoate, lysine acetate salt, gentisic acid, lactobionic
acid, lactitol, sorbitol, glucitol sugar phosphates, glucopyranose
phophate, sugar sulfates, sinapic acid, vanillic acid, vanillin,
methyl paraben, propyl paraben, xylitol, 2-ethoxyethanol, sugars,
galactose, glucose, ribose, mannose, xylose, sucrose, lactose,
maltose, arabinose, lyxose, fructose, cyclodextrin,
(2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic
acid, lysine acetate, gentisic acid, catechin, catechin gallate,
tiletamine, ketamine, propofol, lactic acids, acetic acid, salts of
any organic acid and amine described above, polyglycidol, glycerol,
multiglycerols, galactitol, di(ethylene glycol), tri(ethylene
glycol), tetra(ethylene glycol), penta(ethylene glycol),
poly(ethylene glycol) oligomers, di(propylene glycol),
tri(propylene glycol), tetra(propylene glycol, and penta(propylene
glycol), poly(propylene glycol) oligomers, a block copolymer of
polyethylene glycol and polypropylene glycol, and derivatives and
combinations thereof.
[0176] Mixtures or combinations of a surfactant and a water-soluble
small molecule confer the advantages of both additives. The water
insoluble drug often has a poor compatibility with highly
water-soluble chemical compounds, and the surfactant improves
compatibility. The surfactant also improves the coating quality,
uniformity, and integrity, and particles do not fall off the
balloon during handling. The surfactant reduces drug loss during
transit to a target site. The water-soluble chemical compound
improves the release of drug off the balloon and absorption of the
drug in the tissue. Experimentally, the combination was
surprisingly effective at preventing drug release during transit
and achieving high drug levels in tissue after very brief 0.2-2
minute deployment. Furthermore, in animal studies it effectively
reduced stenosis and late lumen loss.
[0177] Some of the mixtures or combinations of surfactants and
water-soluble small molecules are very stable under heating. They
survived an ethylene oxide sterilization process and do not react
with the water insoluble drug paclitaxel or rapamycin during
sterilization. The hydroxyl, ester, amide groups are preferred
because they are unlikely to react with therapeutic agents such as
paclitaxel or rapamycin. Sometimes amine and acid groups do react
with paclitaxel and are not stable under ethylene oxide
sterilization, heating, and aging. When the mixtures or
combinations described herein are formulated with paclitaxel, a top
coat layer may be advantageous in order to protect the drug layer
and from premature drug loss during the device.
[0178] Preferred additives include p-isononylphenoxypolyglycidol,
PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate,
plyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate,
polyglyceryl-6 laurate, plyglyceryl-6 oleate, polyglyceryl-6
myristate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate,
plyglyceryl-10 oleate, polyglyceryl-10 myristate, polyglyceryl-10
palmitate, PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG
sorbitan monooleate, PEG sorbitan stearate, octoxynol, monoxynol,
tyloxapol, sucrose monopalmitate, sucrose monolaurate,
decanoyl-N-methylglucamide, n-decyl-.beta.-D-glucopyranoside,
n-decyl-.beta.-D-maltopyranoside,
n-dodecyl-.beta.-D-glucopyranoside, n-dodecyl-.beta.-D-maltoside,
heptanoyl-N-methylglucamide, n-heptyl-.beta.-D-glucopyranoside,
n-heptyl-.beta.-D-thioglucoside, n-hexyl-.beta.-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-.beta.-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside,
octyl-.beta.-D-thioglucopyranoside; cystine, tyrosine, tryptophan,
leucine, isoleucine, phenylalanine, asparagine, aspartic acid,
glutamic acid, and methionine (amino acids); cetotiamine;
cyclothiamine, dexpanthenol, niacinamide, nicotinic acid and its
salt, pyridoxal 5-phosphate, nicotinamide ascorbate, riboflavin,
riboflavin phosphate, thiamine, folic acid, menadiol diphosphate,
menadione sodium bisulfite, menadoxime, vitamin B12, vitamin K5,
vitamin K6, vitamin K6, and vitamin U (vitamins); albumin,
immunoglobulins, caseins, hemoglobins, lysozymes, immunoglobins,
a-2-macroglobulin, fibronectins, vitronectins, firbinogens,
lipases, benzalkonium chloride, benzethonium chloride, docecyl
trimethyl ammonium bromide, sodium docecylsulfates, dialkyl
methylbenzyl ammonium chloride, and dialkylesters of sodium
sulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic
acid and its salt, tromethamine, triethanolamine, diethanolamine,
meglumine, glucamine, amine alcohols, glucoheptonic acid, glucomic
acid, hydroxyl ketone, hydroxyl lactone, gluconolactone,
glucoheptonolactone, glucooctanoic lactone, gulonic acid lactone,
mannoic lactone, ribonic acid lactone, lactobionic acid,
glucosamine, glutamic acid, benzyl alcohol, benzoic acid,
hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt,
gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic
acid, vanillin, methyl paraben, propyl paraben, sorbitol, xylitol,
cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,
ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,
catechin gallate, tiletamine, ketamine, propofol, lactic acids,
acetic acid, salts of any organic acid and organic amine,
polyglycidol, glycerol, multiglycerols, galactitol, di(ethylene
glycol), tri(ethylene glycol), tetra(ethylene glycol),
penta(ethylene glycol), poly(ethylene glycol) oligomers,
di(propylene glycol), tri(propylene glycol), tetra(propylene
glycol, and penta(propylene glycol), poly(propylene glycol)
oligomers, a block copolymer of polyethylene glycol and
polypropylene glycol, and derivatives and combinations thereof.
(chemical compounds with one or more hydroxyl, amino, carbonyl,
carboxyl, or ester moieties). Some of these additives are both
water-soluble and organic solvent-soluble. They have good adhesive
properties and adhere to the surface of polyamide medical devices,
such as balloon catheters. They may therefore be used in the
adherent layer, top layer, and/or in the drug layer of embodiments
of the present invention. The aromatic and aliphatic groups
increase the solubility of water insoluble drugs in the coating
solution, and the polar groups of alcohols and acids accelerate
drug permeation of tissue.
[0179] Other preferred additives in embodiments of the invention
include the combination of a surfactant and a chemical compounds
with one or more hydroxyl, amine, carbonyl, carboxyl, or ester
moieties. Examples are Tween 20/sorbitol, Tween 20/glucose, Tween
20/sucrose, Tween 20/lactobionic acid, Tween 20/gluconolactone,
Tween 20/meglumine/lactic acid, Tween 20/meglumine/gentisic acid,
Tween 80/sorbitol, Tween 80/glucose, Tween 80/sucrose, Tween
80/lactobionic acid, Tween 80/gluconolactone, Tween
80/meglumine/lactic acid, Tween 80/meglumine/gentisic acid,
N-octanoyl N-methylglucamine/sorbitol, N-octanoyl
N-methylglucamine/glucose, N-octanoyl N-methylglucamine/sucrose,
N-octanoyl N-methylglucamine/lactobionic acid, N-octanoyl
N-methylglucamine/gluconolactone, N-octanoyl
N-methylglucamine/meglumine/lactic acid, and N-octanoyl
N-methylglucamine/meglumine/gentisic acid.
[0180] Other preferred additives according to embodiments of the
invention include the combination or mixture or amide reaction
products of an amino alcohol and an organic acid. Examples are
lysine/glutamic acid, lysine acetate, lactobionic acid/meglumine,
lactobionic acid/tromethanemine, lactobionic acid/diethanolamine,
lactic acid/meglumine, lactic acid/tromethanemine, lactic
acid/diethanolamine, gentisic acid/meglumine, gentisic
acid/tromethanemine, gensitic acid/diethanolamine, vanillic
acid/meglumine, vanillic acid/tromethanemine, vanillic
acid/diethanolamine, benzoic acid/meglumine, benzoic
acid/tromethanemine, benzoic acid/diethanolamine, acetic
acid/meglumine, acetic acid/tromethanemine, and acetic
acid/diethanolamine. Other preferred additives according to
embodiments of the invention include hydroxyl ketone, hydroxyl
lactone, hydroxyl acid, hydroxyl ester, and hydroxyl amide.
Examples are gluconolactone, D-glucoheptono-1,4-lactone,
glucooctanoic lactone, gulonic acid lactone, mannoic lactone,
erythronic acid lactone, ribonic acid lactone, glucuronic acid,
gluconic acid, gentisic acid, lactobionic acid, lactic acid,
acetaminophen, vanillic acid, sinapic acid, hydroxybenzoic acid,
methyl paraben, propyl paraben, and derivatives thereof.
[0181] Other preferred additives include
n-octyl-.beta.-D-glucopyranoside, octoxynol-9 (Triton X-100),
Polysorbates (such as 20, 21, 40, 60, 80 and 81), Tyloxapol,
octoxynol, nonoxynol, isononylphenylpolyglycidol (Olin-10 G and
Surfactant-10G), PEG glyceryl monooleate, sorbitan monolaurate
(Arlacel 20), sorbitan monopalmitate (Span-40), sorbitan monooleate
(Span-80), sorbitan monostearate, polyglyceryl-10 oleate,
polyglyceryl-10 laurate, polyglyceryl-10 palmitate, polyglyceryl-10
stearate, L-ascorbic acid, thiamine, maleic anhydride, niacinamide,
2-pyrrolidone-5-carboxylic acid, and the like. These additives are
both water soluble and organic solvent soluble. They have good
adhesive properties and adhere to the surface of polyamide medical
devices, such as balloon catheters. They may therefore be used in
both the adherent layer and in the drug layer of embodiments of the
present invention. The aromatic and aliphatic groups increase the
solubility of water insoluble drugs in the coating solution, and
the polar groups of alcohols and acids accelerate drug permeation
of tissue.
[0182] Other preferred additives that may be useful in embodiments
of the present invention include riboflavin, riboflavin-phosphate
sodium, Vitamin D3, folic acid (vitamin B9), vitamin 12,
diethylenetriaminepentaacetic acid dianhydride,
ethylenediaminetetraacetic dianhydride, maleic acid and anhydride,
succinic acid and anhydride, diglycolic anhydride, glutaric
anhydride, L-ascorbic acid, thiamine, nicotinamide, nicotinic acid,
2-pyrrolidone-5-carboxylic acid, cystine, tyrosine, tryptophan,
leucine, isoleucine, phenylalanine, asparagine, aspartic acid,
glutamic acid, and methionine.
[0183] From a structural point of view, these additives share
structural similarities and are compatible with water insoluble
drugs (such as paclitaxel and rapamycin). They often contain double
bonds such as C.dbd.C, C.dbd.N, C.dbd.O in aromatic or aliphatic
structures. These additives also contain amine, alcohol, ester,
amide, anhydride, carboxylic acid, and/or hydroxyl groups. They may
form hydrogen bonds and van der Waals interactions with drug.
Compounds containing one or more hydroxyl, carboxyl, or amine
groups, for example, are especially useful as additives because
these additives have a good affinity to the vessel wall. These
molecules are polyglyceryl fatty esters, ascorbic ester of fatty
acids, sugar ester, alcohol and ether of fatty acids. The fatty
chains can insert into the lipid structure of target tissue
membranes carrying drug to lipid structures. Some of the amino
acids, vitamins and organic acids have aromatic C.dbd.N groups as
well as amino, hydroxyl, and carboxylic components to their
structure. These structure can bind or complex with hydrophobic
drug, such as paclitaxel or rapamycin, and they also have
structural parts that facilitate tissue penetration by removing
barriers between hydrophobic drug and lipid structure of cell
membranes.
[0184] For example, isononylphenylpolyglycidol (Olin-10 G and
Surfactant-10G), PEG glyceryl monooleate, sorbitan monolaurate
(Arlacel 20), sorbitan monopalmitate (Span-40), sorbitan monooleate
(Span-80), sorbitan monostearate, polyglyceryl-10 oleate,
polyglyceryl-10 laurate, polyglyceryl-10 palmitate, and
polyglyceryl-10 stearate all have more than four hydroxyl groups in
their hydrophilic part. These hydroxyl groups have very good
affinity to the vessel wall and can displace hydrogen bound water
molecules. At the same time they have long chains of fatty acid,
alcohol, ether and ester that can both complex with hydrophobic
drug and integrate into the lipid structure of the cell membranes
to form the part of the lipid structure. This deformation or
loosening of the lipid membrane of target cells may further
accelerate permeation of hydrophobic drug into tissue.
[0185] For another example, L-ascorbic acid, thiamine, maleic
acids, niacinamide, and 2-pyrrolidone-5-carboxylic acid, all have a
very high water and ethanol solubility and a low molecular weight
and small size; therefore they can penetrate into the tissue
easily. They also have structural components including aromatic
C.dbd.N, amino, hydroxyl, and carboxylic groups. These structures
have very good compatibility with paclitaxel and rapamycin and can
increase the solubility of the water-insoluble drugs in water and
enhance their absorption into tissues.
[0186] Representative examples of additives include cetyl
pyridinium chloride, gelatin, casein, lecithin (phosphatides),
dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic
acid, calcium stearate, glycerol monostearate, cetostearyl alcohol,
cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene
alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000),
polyoxyethylene sorbitan fatty acid esters (e.g., the commercially
available Tweens.RTM. such as e.g., Tween 20.RTM. and Tween 80.RTM.
(ICI Specialty Chemicals)); polyethylene glycols (e.g., Carbowaxs
3350.RTM. and 1450.RTM., and Carbopol 934.RTM. (Union Carbide)),
dodecyl trimethyl ammonium bromide, polyoxyethylene stearates,
colloidal silicon dioxide, phosphates, sodium dodecylsulfate,
carboxymethylcellulose calcium, hydroxypropyl cellulose (HPC,
HPC-SL, and HPC-L), hydroxypropyl methylcellulose (HPMC),
carboxymethylcellulose sodium, methylcellulose,
hydroxyethylcellulose, hydroxypropylcellulose,
hydroxypropylmethyl-cellulose phthalate, noncrystalline cellulose,
magnesium aluminum silicate, triethanolamine, polyvinyl alcohol
(PVA), polyvinylpyrrolidone (PVP),
4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and
formaldehyde (also known as tyloxapol, superione, and triton),
poloxamers (e.g., Pluronics F68.RTM. and F108.RTM., which are block
copolymers of ethylene oxide and propylene oxide); poloxamines
(e.g., Tetronic 908.RTM., also known as Poloxamine 908.RTM., which
is a tetrafunctional block copolymer derived from sequential
addition of propylene oxide and ethylene oxide to ethylenediamine
(BASF Wyandotte Corporation, Parsippany, N.J.)); a charged
phospholipid such as dimyristoyl phophatidyl glycerol,
dioctylsulfosuccinate (DOSS); Tetronic 1508.RTM. (T-1508) (BASF
Wyandotte Corporation), dialkylesters of sodium sulfosuccinic acid
(e.g., Aerosol OT.RTM., which is a dioctyl ester of sodium
sulfosuccinic acid (American Cyanamid)); Duponol P.RTM., which is a
sodium lauryl sulfate (DuPont); Tritons X-200.RTM., which is an
alkyl aryl polyether sulfonate (Rohm and Haas); Crodestas
F-110.RTM., which is a mixture of sucrose stearate and sucrose
distearate (Croda Inc.); p-isononylphenoxypoly-(glycidol), also
known as Olin-10G.RTM. or Surfactant 10-G.RTM. (Olin Chemicals,
Stamford, Conn.); Crodestas SL-40.RTM. (Croda, Inc.); and SA9OHCO,
which is
C.sub.18H.sub.37CH.sub.2(CON(CH.sub.3)CH.sub.2(CHOH).sub.4(CH.sub.2OH).su-
b.2 (Eastman Kodak Co.); decanoyl-N-methylglucamide; n-decyl
.beta.-D-glucopyranoside; n-decyl .beta.-D-maltopyranoside;
n-dodecyl .beta.-D-glucopyranoside; n-dodecyl .beta.-D-maltoside;
heptanoyl-N-methylglucamide; n-heptyl-.beta.-D-glucopyranoside;
n-heptyl .beta.-D-thioglucoside; n-hexyl .beta.-D-glucopyranoside;
nonanoyl-N-methylglucamide; n-nonyl .beta.-D-glucopyranoside;
octanoyl-N-methylglucamide; n-octyl-.beta.-D-glucopyranoside; octyl
.beta.-D-thioglucopyranoside; and the like. Tyloxapol is a
particularly preferred additive for the pulmonary or intranasal
delivery of steroids, even more so for nebulization therapies.
[0187] Some of the additives are characterized by rapid
extracellular distribution followed by renal excretion by
glomerular filtration. It has been reported (Topic in Current
Chemistry, Vol. 222, P 150) that these additives are extravasated
to a massive extent on the first pass and extraction of the
nonionic additives averaged 33% in normally perfused myocardial
area and 50% in stenotic area. In another model, approximately 80%
of the myocardial content of I-iothalamate was found in the
extravascular space 1 minute after intravenous injection in
rats.
[0188] Some of the X-ray contrast agents can be used as the
additives in embodiments of the invention. Iodinated contrast
agents are widely used in X-ray diagnostic procedure such as
angiography, urography and computed tomography. X-ray contrast
agents have been moved historically from inorganic iodide, to
organic mono-iodine compounds (Uroselectan A), bis-iodine
(Uroselectan B) and tris-iodine substances (diatrizoate), from
lipophilic to hydrophilic agents from ionic (diatrizoate) to
non-ionic drugs (iopromide) and from monomers (iopromide) to
dimmers (iotrolan).
[0189] All presented available X-ray contrast agents for
intravascular injection are based upon the triiodobenzene ring
substituted with two or three additional hydrophilic groups. In the
case of biliary contrast agents (compounds that are taken up by the
liver and excreted mainly by the biliary tract), two hydrophilic
groups are introduced. For angiographic/urographic agents
(compounds that stay within the extravascular distribution volume
and that are excreted by the kidneys), three hydrophilic groups are
introduced. The monomers are exclusively derived from
aminoisophathalic acid. They only differ by their side-chains,
which determine their physiochemical characteristics such as
solubility, hydrophilicity, viscosity and osmolality. The aqueous
solubility of X-ray contrast agents is generally extremely high
being in the order of 1000 mg/ml. Most preparations of X-ray
contrast agents are over-saturated solutions.
[0190] The relative amount of drug and additive can vary widely and
the optimal amount of the additive can depend upon, for example,
the particular drug and additives selected, the critical micelle
concentration of the additive if it forms micelles, the
hydrophilic-lipophilic-balance (HLB) of the additive, the melting
point of the additive, the water solubility of the additive and/or
drug, the surface tension of water solutions of the additive,
etc.
[0191] In embodiments of the present invention, the optimal ratio
of drug to additive is about 1% to about 99% drug, more preferably
about 30% to about 90% drug.
[0192] Adherent Layer
[0193] The adherent layer, which is an optional layer underlying
the drug coating layer, improves the adherence of the drug coating
layer to the exterior surface of the medical device, such as a
balloon catheter or stent, and protects coating integrity. If drug
and additive differ in their adherence to the medical device, the
adherent layer may prevent differential loss (during transit) or
elution (at the target site) of drug layer components in order to
maintain consistent drug-to-additive ratio delivery at the target
site of therapeutic intervention. Furthermore, the adherent layer
may function to facilitate release of coating layer components
which otherwise might adhere too strongly to the device for elution
during brief contact with tissues at the target site. For example,
in the case where a particular drug binds the medical device
tightly, more hydrophilic components are incorporated into the
adherent layer in order to decrease affinity of the drug to the
device surface.
[0194] The adherent layer comprises a polymer or an additive or
mixtures of both. The polymers that are useful for forming the
adherent layer are ones that are biocompatible and avoid irritation
of body tissue. Some examples of polymers that are useful for
forming the adherent layer are polymers that are biostable, such as
polyurethanes, silicones, and polyesters. Other polymers that are
useful for forming the adherent layer include polymers that can be
dissolved and polymerized on the medical device.
[0195] Some examples of polymers that are useful in the adherent
layer of embodiments of the present invention include polyolefins,
polyisobutylene, ethylene-1-olefin copolymers, acrylic polymers and
copolymers, polyvinyl chloride, polyvinyl methyl ether,
polyvinylidene fluoride and polyvinylidene chloride,
polyacrylonitrile, polyvinyl ketones, polystyrene, polyvinyl
acetate, ethylene-methyl methacrylate copolymers,
acrylonitrile-styrene copolymers, ABS resins, Nylon 12 and its
block copolymers, polycaprolactone, polyoxymethylenes, polyethers,
epoxy resins, polyurethanes, rayon-triacetate, cellulose, cellulose
acetate, cellulose butyrate, cellophane, cellulose nitrate,
cellulose propionate, cellulose ethers, carboxymethyl cellulose,
chitins, polylactic acid, polyglycolic acid, polylactic
acid-polyethylene oxide copolymers, polyethylene glycol,
polypropylene glycol, polyvinyl alcohol, and mixtures and block
copolymers thereof.
[0196] Since medical devices such as balloon catheters and stents
undergo mechanical manipulation, i.e., expansion and contraction,
examples of polymers that are useful in the adherent layer include
elastomeric polymers, such as silicones (e.g., polysiloxanes and
substituted polysiloxanes), polyurethanes, thermoplastic
elastomers, ethylene vinyl acetate copolymers, polyolefin
elastomers, and EPDM rubbers. Due to the elastic nature of these
polymers, when these polymers are used, the coating better adheres
to the surface of the medical device when the device is subjected
to forces or stress.
[0197] The adherent layer may also comprise one or more of the
additives previously described, or other components, in order to
maintain the integrity and adherence of the coating layer to the
device and to facilitate both adherence of drug and additive
components during transit and rapid elution during deployment at
the site of therapeutic intervention.
[0198] Top Layer
[0199] In order to further protect the integrity of the drug layer,
an optional top layer may be applied to prevent loss of drug during
transit through tortuous anatomy to the target site or during the
initial expansion of the device before the coating makes direct
contact with target tissue. The top layer may release slowly in the
body lumen while protecting the drug layer. The top layer will
erode more slowly if it is comprised of more hydrophobic, high
molecular weight additives. Surfactants are examples of more
hydrophobic structures with long fatty chains, such as Tween 20 and
polyglyceryl oleate. High molecular weight additives include
polyethylene oxide, polyethylene glycol, and polyvinyl pyrrolidone.
Hydrophobic drug itself can act as a top layer component. For
example, paclitaxel or rapamycin are hydrophobic. They can be used
in the top layer. On the other hand, the top layer cannot erode too
slowly or it might actually slow the release of drug during
deployment at the target site. Other additives useful in the top
coat include additives that strongly interact with drug or with the
coating layer, such as p-isononylphenoxypolyglycidol, PEG laurate,
Tween 20, Tween 40, Tween 60, PEG oleate, PEG stearate, PEG
glyceryl laurate, PEG glyceryl oleate, PEG glyceryl stearate,
polyglyceryl laurate, plyglyceryl oleate, polyglyceryl myristate,
polyglyceryl palmitate, polyglyceryl-6 laurate, plyglyceryl-6
oleate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate,
polyglyceryl-10 laurate, plyglyceryl-10 oleate, polyglyceryl-10
myristate, polyglyceryl-10 palmitate PEG sorbitan monolaurate, PEG
sorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan
stearate, PEG oleyl ether, PEG laurayl ether, octoxynol, monoxynol,
tyloxapol, sucrose monopalmitate, sucrose monolaurate,
decanoyl-N-methylglucamide, n-decyl-.beta.-D-glucopyranoside,
n-decyl-.beta.-D-maltopyranoside,
n-dodecyl-.beta.-D-glucopyranoside, n-dodecyl-.beta.-D-maltoside,
heptanoyl-N-methylglucamide, n-heptyl-.beta.-D-glucopyranoside,
n-heptyl-.beta.-D-thioglucoside, n-hexyl-.beta.-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-.beta.-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside,
octyl-.beta.-D-thioglucopyranoside; cystine, tyrosine, tryptophan,
leucine, isoleucine, phenylalanine, asparagine, aspartic acid,
glutamic acid, and methionine; acetic anhydride, benzoic anhydride,
ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone
carboxylate, ethylenediaminetetraacetic dianhydride, maleic and
anhydride, succinic anhydride, diglycolic anhydride, glutaric
anhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;
cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal
5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin
phosphate, thiamine, folic acid, menadiol diphosphate, menadione
sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6,
vitamin K6, and vitamin U; albumin, immunoglobulins, caseins,
hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin,
fibronectins, vitronectins, firbinogens, lipases, benzalkonium
chloride, benzethonium chloride, docecyl trimethyl ammonium
bromide, sodium docecylsulfates, dialkyl methylbenzyl ammonium
chloride, and dialkylesters of sodium sulfonsuccinic acid,
L-ascorbic acid and its salt, D-glucoascorbic acid and its salt,
tromethamine, triethanolamine, diethanolamine, meglumine,
glucamine, amine alcohols, glucoheptonic acid, glucomic acid,
hydroxyl ketone, hydroxyl lactone, gluconolactone,
glucoheptonolactone, glucooctanoic lactone, gulonic acid lactone,
mannoic lactone, ribonic acid lactone, lactobionic acid,
glucosamine, glutamic acid, benzyl alcohol, benzoic acid,
hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt,
gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic
acid, vanillin, methyl paraben, propyl paraben, sorbitol, xylitol,
cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,
ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,
catechin gallate, tiletamine, ketamine, propofol, lactic acids,
acetic acid, salts of any organic acid and organic amine,
polyglycidol, glycerol, multiglycerols, galactitol, di(ethylene
glycol), tri(ethylene glycol), tetra(ethylene glycol),
penta(ethylene glycol), poly(ethylene glycol) oligomers,
di(propylene glycol), tri(propylene glycol), tetra(propylene
glycol, and penta(propylene glycol), poly(propylene glycol)
oligomers, a block copolymer of polyethylene glycol and
polypropylene glycol, and derivatives and combinations thereof. In
asthma and COPD, many of the clinical signs and symptoms are due to
airway obstruction resulting from smooth muscle constriction. The
magnitude of the obstructive response observed for a given degree
of smooth muscle activation reflects the contractile capacity of
the airway smooth muscle and the resistance to airway deformation.
The airway smooth muscle plays a central role in asthma. The
luminal folding or buckling as a consequence of airway smooth
muscle constriction has been observed in asthma. Such bucking has
also been observed in arteries, blood vessels in the myocardium,
and the gastrointestinal tract (J. Appl. Physiol. 83(6): 1814-1821,
1977). Studies also show that airway smooth muscle cell, in
addition to its contractile function, can participate in and
coordinate the inflammatory response. The inflammatory smooth
muscle produces excess thick and sticky mucus, which causes asthma
attack by blocking airways. The smooth muscle hyperplasia has been
linked to airway hyper responsiveness that is a critical phenotypic
characteristic of asthma.
[0200] The causes of the coronary heart diseases and asthma may be
the neointimal proliferation of smooth muscle in arterial vessels
and in walls of airways. The one aspect of the invention is to
deliver paclitaxel or rapamycin and their analogues to the wall of
airways to treat the asthma. The drug coated stents with the two
drugs have been approved for inhibiting the growth of the smooth
muscle cells in vascular arterial vessels. Drug coated balloon has
been approved to achieve similar results as the drug coated stent.
Therefore, the drug coated stent and drug coated balloon used for
vascular diseases can be adapted in the obstructive airway for the
treatment of asthma. The method comprises inserting the
therapeutic-agent-delivery balloon catheter into the airway in the
lung, inflating the balloon catheter, releasing drug to an airway
wall of an airway such that a diameter of the airway is increased,
deflating the balloon, withdrawing the balloon catheter from the
airway. The drug may be released to the airway wall prior to,
during, or after an asthma attack. The drug may be released in an
amount sufficient to temporarily or permanently increase the
diameter of the airway. The method may be performed while the
airway is open, closed, or partially closed.
[0201] The pulmonary balloon catheters and stents are similar to
vascular balloon catheters and stents. The diameters of the
pulmonary balloon catheters and stents are 8, 10, 12, 14, 16, 18,
20, 22 mm with lengths of 20, 30, 40, 50, 60, 70, 80 mm. It is
designed to pass over a 0.035 in guide wire through its guide wire
lumen. The balloon can also be passed through a minimum 5.0 mm
working channel bronchoscope. The diameters of the sinus balloon
catheters are 2.0, 3.0, 3.0, 4.0 mm and 10 mm with lengths of 10,
12, 15, 18, 20, and 30 mm.
[0202] The paclitaxel or rapamycin and their analogues can be used
for treatments of respiratory disorders such as asthma, chronic
obstructive pulmonary disease and chronic sinusitis. A method of
treating respiratory disorders comprises administrating an
anti-proliferate and anti-inflammatory effective amount of
rapamycin, or paclitaxel or their analogues to said mammal orally,
parenterally, intravascularly, intranasally, intrabronchially,
transdermally, rectally, or via an impregnated vascular stent or
balloon catheters.
[0203] The paclitaxel or rapamycin and their analogues can be used
in combinations with inhaled corticosteroids, inhaled atrovent,
inhaled leukotriene inhibitors, and inhaled epinephrine, long
acting & selective beta agonists for treatments of asthma and
COPD. A method of treating asthma and COPD in the lung comprises
administrating an anti-proliferate and anti-inflammatory effective
amount of rapamycin, or paclitaxel or their analogues in
combinations with inhaled corticosteroids, inhaled atrovent,
inhaled leukotriene inhibitors, inhaled epinephrine, long acting
& selective beta agonists to said mammal orally, parenterally,
intravascularly, intranasally, intrabronchially, transdermally,
rectally, or via an impregnated vascular stent or balloon
catheters.
[0204] Embodiments of the present invention also pertain to a
method for treating the disease state, especially nasal and sinus
dysplasia in mammals caused by mammalian nasal and sinus cells
involved in the inflammatory response and compositions useful in
the method. The method for treating the disease state in mammals
caused by mammalian nasal and sinus cells involved in the
inflammatory response comprises: contacting the mammalian nasal and
sinus cells participating in the inflammatory response with the
anti-proliferate and anti-inflammatory drugs.
[0205] Embodiments of the present invention also pertain to
compositions for reducing and treating the disease state in mammals
caused by undesired inflammatory response of nasal and sinus cells
comprising an anti-proliferate and anti-inflammatory drug a
carrier, and an additive composition, wherein the drugs are
paclitaxel, rapamycin and their analogues.
[0206] In a preferred embodiment, the therapeutic compositions are
administered by nasal inhalation. In another preferred embodiment,
the therapeutic compositions are administered by nose drops. The
therapeutic compositions may be first nebulized by any suitable
means. The therapeutic compositions may be in liquid or solid form
with liquid droplets or particle size being small enough to
facilitate access to nasal and sinus tissue by inhalation or nose
drops.
[0207] In one embodiment, the ratio by weight of the additive to
the therapeutic agent in the layer is from about 0.05 to 100, for
example, from about 0.1 to 5, from 0.5 to 2, and further for
example, from about 0.8 to 1.2.
[0208] Although various embodiments are specifically illustrated
and described herein, it will be appreciated that modifications and
variations of the present invention are covered by the above
teachings and are within the purview of the appended claims without
departing from the spirit and intended scope of the invention.
EXAMPLES
[0209] The following examples include embodiments of formulations
and medical device coating layers within the scope of the present
invention. The examples presented here are all vascular
applications. The pathological structure of blood vessels and
airway and sinus lumen are very similar. All of the layer structure
and cell types are very similar as well. The drug formulation,
device and drug absorption can be applied in the treatment of
asthma, chronic obstructive pulmonary disease, and chronic
sinusitis. While the following examples are considered to embody
the present invention, the examples should not be interpreted as
limitations upon the present invention.
Example 1
Preparation of Coating Solutions
[0210] Formulation 1--50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6
ml acetone (or ethanol), 25-100 mg ascorbyl palmitate, 25-100 mg
L-ascorbic acid and 0.5 ml ethanol were mixed.
[0211] Formulation 2--50-150 mg (0.05-0.16 mmole) rapamycin, 2-6 ml
acetone (or ethanol), 50-200 mg polyglyceryl-10 oleate and 0.5 ml
ethanol were mixed.
[0212] Formulation 3--50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6
ml acetone (or ethanol), 50-200 mg octoxynol-9 and 0.5 ml ethanol
were mixed.
[0213] Formulation 4--50-150 mg (0.05-0.16 mmole) rapamycin, 2-6 ml
acetone (or ethanol), 50-200 mg p-isononylphenoxypolyglycidol and
0.5 ml ethanol were mixed.
[0214] Formulation 5--50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6
ml acetone (or ethanol), 50-200 mg Tyloxapol and 0.5 ml ethanol was
mixed.
[0215] Formulation 6--50-150 mg (0.05-0.16 mmole) rapamycin in 2-6
ml acetone (or ethanol), 50-150 mg L-ascorbic acid in 1 ml water or
ethanol, both, then were mixed.
[0216] Formulation 7--50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6
ml acetone (or ethanol), 50-150 mg niacinamide in 1 ml water or
ethanol, and both were mixed.
[0217] Formulation 8--50-150 mg (0.05-0.16 mmole) rapamycin, 2-6 ml
acetone (or ethanol), 50-200 mg nicotinic acid in 1 ml water or
ethanol and both were mixed.
[0218] Formulation 9--50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6
ml ethanol (or acetone), 150 mg thiamine hydrochloride in 1 ml
water, and 0.5 ml both were mixed.
[0219] Formulation 10--50-150 mg (0.05-0.16 mmole) rapamycin, 2-6
ml acetone or ethanol, 150 mg 2-pyrrolidone-5-carboxylic acid in 1
ml water or ethanol, and both were mixed.
[0220] Formulation 11--50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6
ml acetone (or ethanol), 75 mg p-isononylphenoxypolyglycidol, 75 mg
niacinamide in 1 ml water or ethanol, and 0.5 ml ethanol were
mixed.
[0221] Formulation 12--50-150 mg (0.05-0.16 mmole) rapamycin, 2-6
ml acetone (or ethanol), 75 mg Octoxynol-9, 75 mg thiamine
hydrochloride in 1 ml water or ethanol, and 0.5 ml ethanol were
mixed.
[0222] Formulation 13--50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6
ml acetone (or ethanol), 75 mg p-isononylphenoxypolyglycidol, 75 mg
2-pyrrolidone-5-carboxylic acid in 1 ml water or ethanol, and 0.5
ml ethanol were mixed.
[0223] Formulation 14--50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6
ml acetone (or ethanol), 75 mg p-isononylphenoxypolyglycidol, 75 mg
nicotinic acid in 1 ml water or ethanol, and 0.5 ml ethanol were
mixed.
[0224] Formulation 15 50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6
ml acetone (or ethanol), 75 mg p-isononylphenoxypolyglycidol, 75 mg
L-ascorbic acid in 1 ml water or ethanol, and 0.5 ml ethanol were
mixed.
[0225] Formulation 16 50-150 mg (0.06-0.18 mmole) paclitaxel was
dissolved in 5-10 ml methylene chloride. The solution was added to
30 ml of human serum albumin solution (5% w/v). The solution was
then homogenized for 5 minutes at low speed to form an emulsion.
The emulsion was then sonicated at 40 kHz at 50-90% power at 0 to 5
degrees C. for 1 to 5 min.
[0226] Formulation 17--50-150 mg (0.05-0.16 mmole) rapamycin was
dissolved in 5-10 ml methylene chloride and 10-30 mg
p-isononylphenoxypolyglycidol. The solution was added to 30 ml of
human serum albumin solution (5% w/v). The solution was then
homogenized for 5 minutes at low speed to form an emulsion. The
emulsion was then sonicated at 40 kHz at 50-90% power at 0 to
5.degree. C. for 1 to 5 min.
[0227] Formulation 18--50-100 mg (0.06-0.12 mmole) paclitaxel,
1-1.6 ml acetone, 1-1.6 ml ethanol, 0.4-1.0 ml water, and 50-200 mg
gluconolactone were mixed.
[0228] Formulation 19--35-70 mg (0.042-0.084 mmole) paclitaxel,
0.5-1.0 ml acetone, 0.5-1.0 ml ethanol, 35-70 mg Tween 20, and
35-70 mg N-octanoyl N-methylglucamine were mixed.
[0229] Formulation 20--35-70 mg (0.042-0.084 mmole) paclitaxel,
0.4-1.0 ml acetone, 0.4-1.0 ml ethanol, 0.2-0.4 ml water, 35-70 mg
Tween 20, and 35-70 mg sorbitol were mixed.
[0230] Formulation 21--40-80 mg (0.048-0.096 mmole) paclitaxel,
0.5-1.0 ml acetone, 0.5-1.0 ml ethanol, 40-80 mg meglumine, and
32-64 mg gensitic acid (equal molar ratio with meglumine) were
mixed.
[0231] Formulation 22--35-70 mg (0.042-0.084 mmole) paclitaxel,
0.4-0.8 ml acetone, 0.4-0.8 ml ethanol, 0.25-0.50 ml water, 35-70
mg lactobionic acid, and 10-20 mg diethanolamine (equal molar ratio
with lactobionic acid) were mixed.
[0232] Formulation 23--35-70 mg (0.042-0.084 mmole) paclitaxel,
0.5-1.0 ml acetone, 0.5-1.0 ml ethanol, and 70-140 mg N-octanoyl
N-methylglucamine were mixed.
[0233] Formulation 24--35-70 mg (0.042-0.084 mmole) paclitaxel,
0.4-0.8 ml acetone, 0.4-0.8 ml ethanol, 0.2-0.4 ml water, 35-70 mg
meglumine, and 18-36 mg lactic acid (equal molar ratio with
meglumine) were mixed.
[0234] Formulation 25--50-100 mg (0.06-0.12 mmole) paclitaxel,
0.8-1.6 ml acetone, 0.8-1.6 ml ethanol, 0.4-1.0 ml water, 50-100 mg
gensitic acid, and 30-60 mg diethanolamine (equal molar ratio with
gensitic acid) were mixed.
[0235] Formulation 26--Comparison solution-50 mg (0.06 mmole)
paclitaxel, 1 ml ethanol, 0.2 ml acetone, 0.042 ml Ultravist 370
were mixed.
[0236] Formulation 27--Comparison solution-40 mg (0.048 mmole)
paclitaxel, 0.5 ml ethanol, 0.5 ml acetone were mixed.
[0237] Formulation 28--35-70 mg (0.042-0.084 mmole) paclitaxel,
0.5-1.0 ml acetone, 0.5-1.0 ml ethanol, 35-70 mg Triton X-100, and
35-70 mg N-heptanoyl N-methylglucamine were mixed.
Example 2
[0238] 5 PTCA balloon catheters (3 mm in diameter and 20 mm in
length) were folded with three wings under vacuum. The folded
balloon under vacuum was sprayed or dipped in a formulation (1-17)
in example 1. The folded balloon was then dried, sprayed or dipped
again, dried again, and sprayed or dipped again until sufficient
amount of drug on the balloon (3 microgram per square mm) was
obtained. The coated folded balloon was then rewrapped and
sterilized for animal testing.
Example 3
[0239] 5 PTCA balloon catheters (3 mm in diameter and 20 mm in
length) were folded with three wings under vacuum. The folded
balloon under vacuum was sprayed or dipped in a formulation (1-5)
in example 1. The folded balloon was then dried, sprayed or dipped
again in a formulation (6-10), dried, and sprayed or dipped again
until sufficient amount of drug on the balloon (3 microgram per
square mm) is obtained. The coated folded balloon was then
rewrapped and sterilized for animal testing.
Example 4
[0240] PTCA balloon catheters crimped with bare metal coronary
stent (3 mm in diameter and 20 mm in length) were sprayed or dipped
in a formulation (1-5) in example 1. The stent delivery system was
then dried, sprayed or dipped again in a formulation (6-10), dried
and sprayed or dipped again until sufficient amount of drug on the
stent and balloon (3 microgram per square mm) was obtained. The
coated folded stent delivery system was then sterilized for animal
testing.
Example 5
[0241] Drug coated balloon catheters and uncoated balloon catheters
(as control) were inserted into coronary arteries in pigs. The
balloon was over dilated (1:1.2), and the inflated balloon was held
in the vessel for 60 seconds to release drug, then deflated and
withdraw from the pig. The animals were angiographed after 3 days,
31 days, 3 months, 6 months, 9 months and 12 months. The amount of
drug in the artery tissues of the sacrificed animal was measured
after 60 minutes, 3 days, 31 days, 3 months, 6 months, 9 months and
12 months.
Example 6
[0242] 5 coronary stents (3 mm in diameter and 18 mm in length)
were spray or dip coated with the formulation (1-17) in example 1.
The stents were then dried, sprayed or dipped again, and dried
again until a sufficient amount of drug on the stent (3 microgram
per square mm) is obtained. The coated stent was then crimped on
PTCA balloon catheters (3 mm in diameters and 20 mm in length). The
coated stents with balloon catheters were then sterilized for
animal testing.
Example 7
[0243] The drug coated stent and uncoated stent (as control) were
inserted into coronary arteries in pigs, then the balloon is over
dilated (1:1.2). The stent was implanted and drug released, and the
balloon is deflated and withdraws from the pig. The animals were
then angiographed after 5, 30, 60 minutes, 3 days, 31 days, 3
months, 6 months, 9 months and 12 months. The amount of drug in the
artery tissues of the sacrificed animal was measured 60 minutes, 1
day, 3 days, 31 days, 3 months, 6 months, 9 months and 12
months.
Example 8
[0244] 5 PTCA balloon catheters were sprayed or dipped in the
formulation (1-17) in example 1, dried, and sprayed or dipped and
dried again until sufficient amount of drug on balloon i was
obtained (3 microgram per square mm) was obtained. A bare metal
coronary stent (3 mm in diameter and 20 mm in length) was crimped
on each coated balloon. The coated balloons with crimped bare metal
stents was then wrapped and sterilized for animal test.
Example 9
[0245] 5 PTCA balloon catheters were sprayed or dipped in a
formulation (1-5) in example 1, dried, and sprayed or dipped again
in a formulation (6-10). Balloons were then dried and sprayed or
dipped again until sufficient amount of drug on the balloon (3
microgram per square mm) was obtained. A bare metal coronary stent
(3 mm in diameter and 20 mm in length) was crimped on each coated
balloon. The coated balloons with crimped bare metal stents were
then wrapped and sterilized for animal test.
Example 10
[0246] The drug coated balloon-expandable bare metal stent of
Example 8 and 9 and plain balloon-expandable bare metal stent (as
control) were inserted into coronary arteries in pigs, and the
balloon is over dilated (1:1.2). Stent was implanted, and the
balloon is held inflated for 60 seconds to release drug, and the
balloon was deflated and withdraw from the pig. The animals were
then angiographed after 5, 30, 60 minutes, 3 days, 31 days, 3
months, 6 months, 9 months and 12 months. The amount of drug in the
artery tissues of the sacrificed animal was measured after 60
minutes, 1 day, 3 days, 31 days, 3 months, 6 months, 9 months and
12 months.
Example 11
[0247] 150 mg (0.18 mmole) paclitaxel, 5 ml acetone (or ethyl
acetate or methyl ethyl ketone), 150 mg acetic anhydride or maleic
anhydride or diglycolic anhydride and 0.5 ml ethanol were mixed,
then stirred until a solution was obtained. 5 PTCA balloon
catheters are sprayed or dipped in the solution, dried, and sprayed
or dipped again until sufficient amount of drug on the balloon (3
microgram per square mm) was obtained. The coated balloon was then
treated under high pH (range pH 8-11.5) conditions to hydrolyze the
anhydride. This was confirmed by IR method. The hydrophilicity of
the coating was increased. The coated balloons were then sterilized
for animal test.
Example 12
[0248] The drug coated balloon catheters and uncoated balloon
catheters (as control) were inserted via a bronchoscope into the
pulmonary airway in pigs. The balloon was dilated, and the inflated
balloon was held expanded in the lumen for 60 seconds to release
drug. The balloon was deflated and withdrawn from the pig. The
animals were then examined bronchoscopically and tissues samples
were taken for pathology and quantification of drug uptake after 3
days, 31 days, 3 months, 6 months, 9 months and 12 months.
Example 13
[0249] The uncoated stent delivery catheters were inserted into the
vascular lumen in pigs. The balloon was dilated, the stent was
deployed and the deflated balloon was then withdrawn. The
pharmaceutical formulation 1-15 of example 1 (10-100 ml) is
injected (about 5-15 mg drug per pig) at the site of stent
implantation. The drug is then absorbed by injuried tissue. The
animals are then examined and tissues samples are taken for
pathology.
Example 14
[0250] The diseased tissue (breast cancer or atheroma or stenosis)
was removed surgically from a human body. The pharmaceutical
formulation 1-15 of example 1 (10-100 ml) was then injected into or
onto the surgical cavities created by the surgical intervention
(about 5-20 mg drug). The local drug delivery includes injection by
long needle, guide catheters, introducer sheath, drug infusion tube
and other drug delivery catheters. The drug was then absorbed by
tissue at the target site.
Example 15
[0251] 6 PTCA balloon catheters (3.5 and 3.0 mm in diameter and 20
mm in length) were inflated at 1-3 atm. The inflated balloon was
loaded with a formulation 18-27 in example 1. The sufficient amount
of drug on the balloon (3 microgram per square mm) was obtained.
The inflated balloon was folded, and then dried. The coated folded
balloon was then rewrapped and sterilized for animal testing.
[0252] The coated PTCA balloon catheter was inserted into target
site in the blood vessels (LAD, LCX and RCA) in the 25-45 ib pig
was inflated to 12 atm. The stretch ratio (the ratio of balloon
diameter to vessel diameter) was about 1.15-1.20. The drug was
delivered into the target tissue in 30-60 seconds. The balloon
catheter was then deflated and was withdrawn from the animal body.
The target blood vessel was harvested at 0.25-24 hours after
inflation. The drug content in the target tissue and the residual
drug remained on the balloon were analyzed by tissue extraction and
HPLC. In some of the animal tests the stent was crimped on the drug
coated balloon catheters prior to deployment. In chronic animal
tests, angiography was performed before and after all interventions
and at 28-35 days after the procedure. Luminal diameters were
measured and late lumen loss was calculated. Late lumen loss is the
difference between the minimal lumen diameter measured after the
intervention and minimal lumen diameter after a period of follow-up
time. Restenosis may be quantified by the diameter stenosis, which
is the difference between the mean lumen diameters at follow-up and
immediately after the procedure divided by the mean lumen diameter
immediately after the procedure.
[0253] The animal test results for the Formulation 18-28 are
reported here. All data is the average of five or six experimental
data points.
[0254] The drug content of the formulation 18 on the 3.5 mm balloon
catheters was 3.26 .mu.g/mm.sup.2. After the 15-30 minute
procedure, the residual drug on the balloon was 15.92 .mu.g or 2.3%
of the total drug loading. The drug content in the tissue harvested
15-30 minutes after the procedure was 64.79 .mu.g or 9.2% of the
total drug content originally loaded on the balloon. If the 18 mm
stent was depolyed by the coated balloon, the residual drug on the
balloon was 31.96 .mu.g or 4.5% of the total drug load, and the
drug content in tissue harvested 15-30 minutes after the procedure
was 96.49 .mu.g, or 13.7% of drug load. The stretch ratio was 1.3
in the procedure. The late lumen loss after 28-35 days was 0.10 (sd
0.2) mm. The diameter stenosis was 3.3%.
[0255] The drug content of the formulation 19 on the 3.5 mm balloon
catheters was 3.08 .mu.g/mm.sup.2. After the 15-30 minute
procedure, the residual drug on the balloon was 80.58 .mu.g or
11.4% of the total drug load. The drug content in tissue harvested
15-30 minutes after the procedure was 42.23 .mu.g or 6.0% of the
total drug load. After 28-35 days late lumen loss was 0.30 (sd
0.23) mm. The diameter stenosis was 5.4%.
[0256] The drug content of formulation 20 on the 3.5 mm balloon
catheters was 3.61 .mu.g/mm.sup.2. After the 15-30 minute
procedure, the residual drug on the balloon was 174.24 .mu.g or
24.7% of the total drug load. The drug content in tissue harvested
15-30 minutes after the procedure was 83.83 .mu.g or 11.9% of the
total drug load. When deployed with a pre-crimped 18 mm stent, the
residual drug on the balloon was 114.53 .mu.g or 16.1% of the total
drug load, and the drug content in the tissue harvested 15-30
minutes post procedure was 147.95 .mu.g or 18.1% of the total drug
load. The stretch ratio was 1.3 in the procedure. Late lumen loss
after 28-35 days was 0.10 (sd 0.1) mm. The diameter stenosis was
3.4%.
[0257] The drug content of formulation 21 on the 3.5 mm balloon
catheters was 4.71 .mu.g/mm.sup.2. After the 15-30 minute
procedure, the residual drug on the balloon was 44.39 .mu.g or 6.3%
of the total drug load. The drug content in tissue harvested 15-30
minutes after the procedure was 77.87 .mu.g or 11.0% of the total
drug load. After 28-35 days minimal lumen diameter was 0.23 (sd
0.44) mm. The diameter stenosis was 7.3%.
[0258] The drug content of formulation 22 on the 3.5 mm balloon
catheters was 3.85 .mu.g/mm.sup.2. After the 15-30 minute
procedure, the residual drug on the balloon was 24.59 .mu.g or 3.5%
of the total drug load. The drug content in tissue harvested 15-30
minutes after the procedure was 37.97 .mu.g or 5.4% of the total
drug load. After 28-35 days late lumen loss was 0.33 (sd 0.14) mm.
The diameter stenosis was 6.7%.
[0259] The drug content of formulation 23 on the 3.5 mm balloon
catheters was 3.75 .mu.g/mm.sup.2. After 60 minute procedure, the
residual drug on the balloon was 0.82 .mu.g or 0.1% of the total
drug load. The drug content in the tissue harvested 60 minutes
after the procedure was 45.23 .mu.g or 5.5% of the total drug load.
After 28-35 days late lumen loss was 0.49 (sd 0.26) mm. The
diameter stenosis was 11.3%.
[0260] The drug content of formulation 24 on the 3.5 mm balloon
catheters was 3.35 .mu.g/mm.sup.2. After the 60 minute procedure,
the residual drug on the balloon is 62.07 .mu.g and 7.5% of the
total drug loading. The drug content in the tissue harvested 60
minutes after the procedure was 40.55 .mu.g or 4.9% of the total
drug load. After 28-35 days late lumen loss was 0.47 (sd 0.33) mm.
The diameter stenosis was 9.9%.
[0261] The drug content of formulation 25 on the 3.5 mm balloon
catheters was 3.41 .mu.g/mm.sup.2. After the 60 minute procedure,
the residual drug on the balloon was 50.0 .mu.g or 6.0% of the
total drug load. The drug content in the tissue harvested 60
minutes post procedure was 26.72 .mu.g or 3.2% of the total drug
load. After 28-35 days late lumen loss was 0.36 (sd 0.41) mm. The
diameter stenosis was 9.3%.
[0262] The drug content of formulation 28 on the 3.5 mm balloon
catheters was 3.10 .mu.g/mm.sup.2. After the procedure, the
residual drug on the balloon was 1.9% of the total drug load. The
drug content in tissue harvested 2 hours after the procedure was
34.17 .mu.g or 5.0% of the total drug load. In tissue harvested
after the procedure, the drug content in tissue was 28.92 .mu.g or
4.2% of the total drug load.
[0263] The drug content of control formulation (uncoated balloon)
on the 3.5 mm balloon catheters was 0.0 .mu.g/mm.sup.2. After the
procedure, residual drug on the balloon was 0% of the total drug
load. The drug content in tissue harvested 15 minutes after the
procedure was 0 .mu.g. In tissue harvested 24 hours after the
procedure, the drug content in tissue was 0 .mu.g. after 28-35 days
late lumen loss was 0.67 (sd 0.27) mm. The diameter stenosis is
20.8%. In the second repeat experiment, the stretch ratio was 1.3.
The late lumen loss was 1.1 (sd 0.1). The diameter stenosis was
37.5%.
[0264] The drug content of formulation 26 on the 3.5 mm balloon
catheters was 3.21 .mu.g/mm.sup.2. After the 15-30 minute
procedure, the residual drug on the balloon was 13.52 .mu.g or 1.9%
of the total drug loading. The drug content in the tissue was 28.32
.mu.g or 4.0% of the total drug load. When the balloon was deployed
with a pre-crimped 18 mm stent, the residual drug on the balloon
was 26.45 .mu.g or 3.7% of the total drug load. The drug content in
tissue was 113.79 .mu.g or 16.1% of the total drug load. After
28-35 days, late lumen loss was 0.27 (sd 0.15) mm. The diameter
stenosis was 7.1%.
[0265] The drug content of formulation 27 without additive on the
3.5 mm balloon catheters was 4.22 .mu.g/mm.sup.2. After the 15-30
minute procedure, the residual drug on the balloon was 321.97 .mu.g
or 45.6% of the total drug load. The drug content in the tissue was
12.83 .mu.g or 1.8% of the total drug load.
[0266] The drug absorption of the formulation 18-25 in the
invention is higher than those of formulation 26 and formulation
27. Late lumen loss after 28-35 days follow up was improved.
Example 16
[0267] 6 PTCA balloon catheters (3.5 and 3.0 mm in diameter and 20
mm in length) were inflated at 1-3 atm. The inflated balloon was
loaded with a formulation 18-25 in example 1. The sufficient amount
of drug on the balloon (3 .mu.g/mm.sup.2) was obtained. The
inflated balloon was dried. The drug coated balloon was then loaded
with a top coating formulation. The top coating formulation in
acetone or ethanol was chosen from gentisic acid, methyl paraben,
acetic acid, Tween 80, Tween 20, vanillin and aspirin. The coated
folded balloon was dried, then rewrapped and sterilized for animal
testing.
[0268] A floating experiment was designed to test how much drug is
lost during balloon catheter insertion and transit to the target
site prior to inflation. A control balloon catheter was coated with
formulation 18. Top-coated catheters also were prepared having a
top coating of propyl paraben. For top-coated catheters, the
balloon catheter was coated with formulation 18, then dried, 25-50
mg propyl paraben (about 50% of paclitaxel by weight) in acetone
was coated over the formulation 18 coating. Each of the control and
top-coated balloon catheters was inserted in pig arteries. The
floating time in pig arterial vasculature was 1 minute. The drug,
additive and top coating were released. The catheter was then
withdrawn. The residual drug on the balloon catheters was analyzed
by HPLC. The residual drug content of the control balloon catheters
was 53% of the total drug loading. The residual drug content of the
top-coated balloon catheter was 88%. The top coat reduced drug loss
in the vasculature during conditions that simulate transit of the
device to a site of therapeutic intervention. The same animal tests
were performed as in Example 15 with formulation 18 first coated on
the balloon, and propyl paraben as a top coating layer overlying
the first coating layer. The drug content on the 3.5 mm balloon
catheter was 3.39 .mu.g/mm.sup.2. After the procedure, residual
drug on the balloon was 64.5 .mu.g, or 8.6% of the total drug load.
The drug content in the tissue was 28.42 .mu.g, or 4% of the total
drug load.
Example 17
[0269] 6 PTCA balloon components (3.5 and 3.0 mm in diameter and 20
mm in length) were loaded with formulation 18 provided in Example
1. A sufficient amount of drug (3 .mu.g/mm.sup.2) was obtained on
the balloon surface. The balloon was dried.
[0270] A formulation for a top coating layer was then prepared. The
formulation of the top coating layer was paclitaxel, and one
additive chosen from Tween 20, Tween 80, polypropylene glycol-425
(PPG-425), and polypropyl glycol-1000 (PPG-1000), in acetone. The
balloon surface of the control catheters was only loaded with
formulation 18. 25-50 mg of the top coating formulation (about 50%
of paclitaxel by weight) in acetone was coated over the formulation
18 coating layer on the other balloon surfaces. The coated balloons
were dried for drug releasing testing in vitro.
[0271] The releasing experiment was designed to test how much drug
is lost during balloon inflation. Each of the coated balloons were
inflated to 12 atm. in 1% BSA solution at 37.degree. C. for 2
minutes. The drug, additive and top coating were released. The
residual drug on the balloon catheters was analyzed by HPLC. The
residual drug content of the control balloon catheter was 34% of
the total drug loading. The residual drug content of the balloon
catheter that included a top coating layer with Tween 20, Tween 80,
polypropylene glycol-425 (PPG-425) or polypropyl glycol-1000
(PPG-1000) was 47%, 56%, 71% and 81%, respectively. Thus, the top
coating layer reduced drug loss in the tests in vitro during
inflation of the balloon components.
* * * * *