U.S. patent application number 16/864373 was filed with the patent office on 2020-08-13 for drug coated balloon catheters for nonvascular strictures.
The applicant listed for this patent is Urotronic, Inc.. Invention is credited to Lixiao Wang.
Application Number | 20200254148 16/864373 |
Document ID | 20200254148 / US20200254148 |
Family ID | 1000004810818 |
Filed Date | 2020-08-13 |
Patent Application | download [pdf] |
United States Patent
Application |
20200254148 |
Kind Code |
A1 |
Wang; Lixiao |
August 13, 2020 |
DRUG COATED BALLOON CATHETERS FOR NONVASCULAR STRICTURES
Abstract
Embodiments of the present invention provide a method for
treatment of nonvascular body lumen strictures such as benign
prostatic hyperplasia (BPH), urethral strictures, ureteral
strictures, prostate cancer, esophageal strictures, sinus
strictures, biliary tract strictures, asthma and chronic
obstructive pulmonary disease (COPD). The method involves
delivering, preferably via drug coated balloon catheters, of
anti-inflammatory and anti-proliferative drugs (rapamycin or
paclitaxel and their analogues) and one or more additives.
Inventors: |
Wang; Lixiao; (Henderson,
NV) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Urotronic, Inc. |
Plymouth |
MN |
US |
|
|
Family ID: |
1000004810818 |
Appl. No.: |
16/864373 |
Filed: |
May 1, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16267434 |
Feb 5, 2019 |
10675386 |
|
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16864373 |
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14438327 |
Apr 24, 2015 |
10668188 |
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PCT/US13/64842 |
Oct 14, 2013 |
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16267434 |
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61795790 |
Oct 26, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61L 2300/41 20130101;
A61L 29/08 20130101; A61L 29/085 20130101; A61L 2300/802 20130101;
A61L 29/16 20130101; A61L 2300/606 20130101; A61L 2420/06 20130101;
A61L 2300/416 20130101; A61L 2300/45 20130101; A61L 2300/602
20130101 |
International
Class: |
A61L 29/16 20060101
A61L029/16; A61L 29/08 20060101 A61L029/08 |
Claims
1. A method for treating a stricture in a nonvascular body lumen,
the method comprising: inserting a balloon catheter to a target
site in the stricture of a nonvascular body lumen, the balloon
catheter comprising a balloon comprising a coating layer overlying
external surfaces of the balloon, wherein the coating layer
comprises a water-soluble first additive that comprises more than
one hydroxyl group, wherein the water-soluble first additive has a
molecular weight of 50 to 750, a water-soluble second additive that
is different than the first water-soluble additive and that
comprises more than one hydroxyl group, wherein the water-soluble
second additive has a molecular weight of 750 to 1,000, and an
initial drug load of a hydrophobic therapeutic agent; inflating the
balloon at least until the coating layer contacts walls of the
nonvascular body lumen at the target site; deflating the balloon
after the inflation period; and withdrawing the balloon catheter
from the nonvascular body lumen.
2. The method of claim 1, wherein the hydrophobic therapeutic agent
is chosen from paclitaxel, paclitaxel analogues, rapamycin,
rapamycin analogues, and combinations thereof
3. The method of claim 1, wherein the hydrophobic therapeutic agent
is chosen from rapamycin, rapamycin analogues, or a combination
thereof.
4. The method of claim 1, wherein the nonvascular body lumen is an
esophagus, airway, sinus, trachea, colon, biliary tract, urinary
tract, urethra, ureter, or a combination thereof.
5. The method of claim 1, wherein the nonvascular body lumen is a
urethra, a ureter, or a combination thereof.
6. The method of claim 1, wherein the method further treats benign
prostatic hyperplasia, and the method comprises inserting the
balloon catheter to the target site in the stricture of a
nonvascular body lumen that is the urethra, wherein the target site
in the stricture of the nonvascular body lumen is within a
prostate.
7. The method of claim 1, wherein the initial drug load is from 1
to 20 micrograms of the hydrophobic therapeutic agent per square
millimeter of the balloon.
8. The method of claim 1, wherein the initial drug load is from 1
to 6 micrograms of the hydrophobic therapeutic agent per square
millimeter of the balloon.
9. The method of claim 1, wherein the initial drug load is of from
2 to 6 micrograms of the hydrophobic therapeutic agent per square
millimeter of the balloon
10. The method of claim 1, wherein a weight ratio in the coating
layer of the combination of the water-soluble first additive and
the water-soluble second additive to the initial drug load is 0.2:1
to 0.8:1
11. The method of claim 1, wherein the balloon comprises a uniform
circular cross-section perpendicular to a longitudinal direction of
the balloon.
12. The method of claim 1, wherein the coating layer is a uniform
coating layer.
13. The method of claim 1, wherein during inflation the coating
layer makes uniform direct pressure contact with the stricture to
release the therapeutic agent rapidly with the uniform direct
pressure contact.
14. The method of claim 1, wherein the balloon comprises a
polyester, a polyamide, a nylon 12, a nylon 11, a polyamide 12, a
block copolymer of a polyether and a polyamide, a polyether block
amide, a polyurethane, a block copolymer of a polyether and a
polyester, or a combination thereof,
15. The method of claim 1, wherein the combination of the
water-soluble first and second additives promote rapid release of
the hydrophobic therapeutic agent from the balloon at the target
site during an inflation period;
16. The method of claim 1, wherein the inflation period is from 0.1
minutes to 10 minutes.
17. The method of claim 1, wherein after the withdrawing, the
balloon comprises residual drug amount of less than 45% of the
initial drug load.
18. The method of claim 1, wherein the coating layer is free of
iodine covalent-bonded contrast agents, dyes, oils, and lipids.
19. The method of claim 1, wherein the hydrophobic therapeutic
agent is free of enclosure in micelles and liposomes and is free of
encapsulation in polymer particles.
20. A method for treating benign prostatic hyperplasia, the method
comprising: inserting a balloon catheter to a target site, wherein
the target site is a stricture in a urethra, wherein the target
site in the stricture of the nonvascular body lumen is within a
prostate, the balloon catheter comprising a balloon comprising a
coating layer overlying a material of the balloon, wherein the
coating layer comprises a water-soluble first additive that
comprises more than one hydroxyl group, wherein the water-soluble
first additive has a molecular weight of 50 to 750, a water-soluble
second additive that is different than the first water-soluble
additive and that comprises more than one hydroxyl group, wherein
the water-soluble second additive has a molecular weight of 750 to
1,000, an initial drug load of a hydrophobic therapeutic agent;
inflating the balloon at least until the coating layer contacts
walls of the nonvascular body lumen at the target site to release
the hydrophobic therapeutic agent from the balloon at the target
site during an inflation period; deflating the balloon after the
inflation period; and withdrawing the balloon catheter from the
nonvascular body lumen.
Description
PRIORITY
[0001] This application is a continuation of U.S. application Ser.
No. 16/267,434, filed Feb. 5, 2019, which is a continuation of U.S.
application Ser. No. 14/438,327, filed Apr. 24, 2015, which is a
U.S. National Stage Filing under 35 U.S.C. 371 from International
Application No. PCT/US2013/064842, filed Oct. 14, 2013, which
claims the benefit of priority from U.S. Provisional Application
No. 61/795,790, filed Oct. 26, 2012, all of which are incorporated
by reference herein in their entirety.
FIELD OF THE INVENTION
[0002] Embodiments of the present invention relate to drug coated
medical devices, such as drug coated balloon catheters, and methods
for treatment of nonvascular strictures of body lumens. The
nonvascular strictures include benign prostatic hyperplasia (BPH),
urethral strictures, ureteral strictures, prostate cancer,
esophageal strictures, sinus strictures, biliary tract strictures,
asthma and chronic obstructive pulmonary disease (COPD). The
methods involve delivering of anti-inflammatory and
anti-proliferate drugs (rapamycin or paclitaxel and their
analogues) to the diseases.
BACKGROUND OF THE INVENTION
[0003] Benign prostatic hyperplasia is a non-cancerous enlargement
of the prostate gland, affecting more than 50% percent of men over
the age of 60. The prostate early in life is the size and shape of
a walnut and weight about 20 grams. Prostate enlargement appears to
be a normal process. With age, the prostate gradually increases in
size to twice or more its normal size. As the prostate grows, it
presses against and narrows the urethra, causing a urinary
obstruction that makes it difficult to urinate.
[0004] Male urethral stricture disease occurred at a rate as high
as 0.6% in some populations. Urethral stricture diseases appeared
to be more common in the elderly population. The patients with the
strictures experience moderate complications, such as bother from
lower urinary tract voiding symptoms, recurrent urinary tract
infection and the need for repeat urethral procedures such as
dilation or urethrotomy.
[0005] Ureteral strictures of upper urinary tract are either
congenital or acquired. Congenital ureteral strictures are most
commonly located at the ureteropelvic junction. Most of ureteral
strictures are acquired and usually are iatrogenic. The most common
etiology of the ureteral strictures is injury during endoscopic,
open, or laparoscopic surgical procedures.
[0006] Esophageal strictures are a problem commonly encountered in
gastroenterological medicine and can be caused by malignant or
benign lesions. Dysphagia is the symptom experienced by all
patients. Most of these patients require palliative treatment to
relieve the dysphagia.
[0007] 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. 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.
[0008] 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.
[0009] 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.
[0010] One of the most common treatments of the strictures
described above is balloon catheter dilation. The balloon dilation
usually results in symptomatic relief, however, the effect may not
persist and recurrent strictures do occur. Repeated the balloon
dilations or surgical procedures are often used to treat the
recurrent strictures.
[0011] The causes of coronary heart disease and the strictures are
neointimal proliferation of smooth muscle in arterial vessels and
in walls of body lumen. One aspect of the invention is to deliver
paclitaxel or rapamycin and their analogues to the wall of body
lumen to treat the narrowing and strictures. Drug coated stents and
drug coated balloon catheters with these drugs have been approved
for inhibiting the growth of the smooth muscle cells in vascular
arterial vessels.
[0012] The present invention provides new methods for treatments of
nonvascular diseases of benign prostatic hyperplasia (BPH)
strictures, urethral strictures, ureteral strictures, prostate
cancer, esophageal strictures, biliary tract strictures, asthma and
chronic obstructive pulmonary disease (COPD) to have a long term
persist effect. The new methods will prevent renarrowing and
recurrent strictures in years. The methods involve delivering of
anti-inflammatory and anti-proliferate drugs (rapamycin or
paclitaxel and their analogues) and an additive to a target tissue.
Embodiments of the present invention provide a medical device
coating formulation comprising a drug for treatment of the
nonvascular strictures, and an additive that enhances absorption of
the drug into tissue of body lumens.
SUMMARY OF THE INVENTION
[0013] Embodiments of the present invention are directed to the
treatment of nonvascular strictures of the body lumens by
delivering of an effective amount of anti-inflammatory and
anti-proliferate drugs (rapamycin or paclitaxel and their
analogues) to a target tissue. The nonvascular strictures include
benign prostatic hyperplasia (BPH), urethral strictures, ureteral
strictures, prostate cancer, esophageal strictures, sinus
strictures, biliary tract strictures, asthma and chronic
obstructive pulmonary disease (COPD). The treatment is intended for
a variety of animals, such as premature neonates to adult
humans.
[0014] The present inventor has found that coating the exterior
surface of a medical device, and particularly of a balloon catheter
or a stent, for example, with a layer comprising a therapeutic
agent and an additive that has both a hydrophilic part and a drug
affinity part is useful in solving the problems associated with the
coatings discussed above. 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. Surprisingly, the
present inventor has found that the at least one additive according
to embodiments of the present invention, which comprises a
hydrophilic part and a drug affinity part, in combination with a
therapeutic agent, forms an effective drug delivery coating on a
medical device without the use of oils and lipids, thereby avoiding
the lipolysis dependence and other disadvantages of conventional
oil-based coating formulations. Moreover, the additives according
to embodiments of the present invention facilitate rapid drug
elution and superior permeation of drug into tissues at a disease
site. Thus, coatings according to embodiments of the present
invention provide an enhanced rate and/or extent of absorption of
the hydrophobic therapeutic agent in diseased tissues of the
vasculature or other body lumen. In embodiments of the present
invention, the coated device delivers therapeutic agent to
nonvascular tissues during a very brief deployment time of less
than 10 minutes, less than 2 minutes, and reduces renarrowing and
reoccurring of the strictures of a nonvascular body lumen.
[0015] In one embodiment, the present invention relates to a
medical device for delivering a therapeutic agent to a nonvascular
tissue, the device comprising a layer overlying an exterior surface
of the medical device. The device includes one of a balloon
catheter, a perfusion balloon catheter, an infusion catheter such
as distal perforated drug infusion tube, a perforated balloon,
spaced double balloon, porous balloon, and weeping balloon, a
cutting balloon catheter, a scoring balloon catheter. Further, the
nonvascular tissue includes tissue of one of esophagus, airways,
sinus, trachea, colon, biliary tract, urinary tract, prostate,
urethral, ureteral, and other nonvascular lumens.
[0016] In one embodiment of the medical devices, the additive
enhances absorption of the drug into nonvascular tissue of the body
lumens. The nonvascular body lumens include esophagus, airways,
sinus, trachea, colon, biliary tract, urinary tract, prostate,
urethral, ureteral, and other nonvascular lumens. In another
embodiment of the medical devices, 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.
[0017] In one embodiment of the medical devices, 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.
[0018] In another embodiment, the additive is chosen from
p-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween 40,
Tween 60, Tween 80, 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;
cycothiamine, 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.
[0019] 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.
[0020] 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; cycothiamine, 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.
[0021] 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; cycothiamine, 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).
[0022] 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.
[0023] In another embodiment, the medical device further comprises
a dimethylsulfoxide solvent layer, wherein the dimethylsulfoxide
solvent layer is overlying the surface of the layer.
[0024] In one embodiment of the medical device, the device is
capable of releasing the therapeutic agent and the additive and
delivering therapeutic agent to the tissue in about 0.1 to 10
minutes. In one embodiment, the concentration of the therapeutic
agent in the layer is from 1 to 20 .mu.g/mm.sup.2. In one
embodiment, the concentration of the therapeutic agent in the layer
is from 2 to 10 .mu.g/mm.sup.2. In one embodiment, the therapeutic
agent is not water-soluble.
[0025] In one embodiment, the additive enhances release of the
therapeutic agent off the balloon. In another embodiment, the
additive enhances penetration and absorption of the therapeutic
agent in tissue. In another embodiment, the additive has a water
and ethanol solubility of at least 1 mg/ml and the therapeutic
agent is not water-soluble.
[0026] In another embodiment of the medical device, the layer
overlying the exterior surface of the medical device comprises a
therapeutic agent and at least two additives, wherein each of the
additives 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, and wherein each
additive is soluble in polar organic solvent and is soluble in
water. In one aspect of this embodiment, the polar organic solvent
is chosen from methanol, ethanol, isopropanol, acetone,
dimethylformide, tetrahydrofuran, methylethyl ketone,
dimethylsulfoxide, acetonitrile, ethyl acetate, and chloroform and
mixtures of these polar organic solvents with water. In another
aspect of this embodiment, the device further comprises a top layer
overlying the surface of the layer overlying the exterior surface
of the medical device to reduce loss of drug during transit through
a body to the target tissue.
[0027] In another embodiment of the medical device, the layer
overlying the exterior surface of the medical device comprises a
therapeutic agent and an additive, 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, wherein the additive reduces crystal size and number
of particles of the therapeutic agent, and wherein the additive is
water-soluble and the therapeutic agent is not water-soluble.
[0028] In another embodiment of the medical device, the layer
overlying the exterior surface of the medical device comprises a
therapeutic agent and an additive, 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, wherein the additive has a fatty chain of an acid,
ester, ether, or alcohol, wherein the fatty chain can directly
insert into lipid membrane structures of the tissue, and wherein
the therapeutic agent is not water-soluble.
[0029] In another embodiment of the medical device, the layer
overlying the exterior surface of the medical device comprises a
therapeutic agent and an additive, wherein the additive comprises a
hydrophilic part and a hydrophobic part, wherein the additive can
penetrate into and rearrange lipid membrane structures of the
tissue, and wherein the therapeutic agent is not water-soluble and
is not enclosed in micelles or encapsulated in polymer
particles.
[0030] In another embodiment of the medical device, the layer
overlying the exterior surface of the medical device comprises a
therapeutic agent and an additive, wherein the additive comprises a
hydrophilic part and a drug affinity part, wherein the additive has
a fatty chain of an acid, ester, ether, or alcohol, wherein the
fatty chain directly inserts into lipid membrane structures of
tissue, wherein the additive has one or more functional groups
which have affinity to the drug by hydrogen bonding and/or van der
Waals interactions (the functional groups include hydroxyl, ester,
amide, carboxylic acid, primary, second, and tertiary amine,
carbonyl, anhydrides, oxides, and amino alcohols), wherein the
therapeutic agent is not water-soluble and is not enclosed in
micelles or encapsulated in polymer particles, and wherein the
layer does not include a polymer, and the layer does not include an
iodine covalent bonded contrast agent.
[0031] In yet another embodiment, the present invention relates to
a medical device coating for delivering a drug to a tissue that is
prepared from a mixture. In one aspect of this embodiment, the
coating is prepared from a mixture comprising an organic phase
containing drug particles dispersed therein and an aqueous phase
containing a water-soluble additive. In one aspect of this
embodiment, the water-soluble additive is chosen from polyethylene
glycol, polyvinyl alcohol, polyvinylpyrrolidinone, polypeptides,
water-soluble surfactants, water-soluble vitamins, and proteins. In
another aspect of this embodiment, the preparation of the mixture
includes homogenization under high shear conditions and optionally
under pressure.
[0032] In another embodiment, the present invention relates to a
balloon catheter for delivering a therapeutic agent to a body
lumen, the catheter comprising a coating layer overlying an
exterior surface of a balloon. In one embodiment of the balloon
catheter, the coating layer comprises a therapeutic agent and an
additive, 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,
wherein the additive is water-soluble, and wherein the additive is
at least one of a surfactant and a chemical compound, and wherein
the chemical compound has a molecular weight of from 50 to 750.
[0033] In another embodiment of the balloon catheter, the coating
layer comprises a therapeutic agent and an additive, 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, wherein the
additive is at least one of a surfactant and a chemical compound,
and wherein the chemical compound has more than four hydroxyl
groups. In one aspect of this embodiment, the chemical compound
having more than four hydroxyl groups has a melting point of
120.degree. C. or less, and the chemical compound is an alcohol or
an ester.
[0034] In one embodiment of the balloon catheter, the coating layer
overlying an exterior surface of the exterior surface of the
medical device consists essentially of the therapeutic agent and
the additive. In another embodiment, the layer overlying the
exterior surface of the medical device does not include an iodine
covalent bonded contrast agent.
[0035] 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 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, and 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.
[0036] In one embodiment of the balloon catheters, 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.
[0037] In another embodiment of the balloon catheters, 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.
[0038] In another embodiment of the balloon catheters, 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 balloon catheters, the additive is PEG-24
cholesterol ether. In another embodiment of the balloon catheters,
the additive is chosen from sterol polyethylene glycol
derivatives.
[0039] In one embodiment, the present invention relates to a method
for treating a nonvascular stricture of body lumen comprising
inserting a balloon catheter comprising a coating layer into an
body stricture, wherein the stricture is one of benign prostatic
hyperplasia (BPH), urethral strictures, ureteral strictures,
prostate cancer, esophageal strictures, sinus strictures, biliary
tract strictures, asthma and chronic obstructive pulmonary disease
(COPD), wherein the coating layer comprises a drug and an additive,
inflating the balloon catheter and releasing the drug to a wall of
the stricture, deflating the balloon; and withdrawing the balloon
catheter, wherein the residual drug is about 1 to 45% of the total
loading drug on the balloon catheter. In one aspect of this
embodiment, the additive enhances absorption of the drug into
tissue of the nonvascular body lumen. 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-glucopyranoside,
n-heptyl-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.
[0040] 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-hydroxycholecalciferol, vitamin D2, vitamin D3,
alpha-carotene, beta-carotene, gamma-carotene, vitamin A,
fursultiamine, methylolriboflavin, octotiamine, prosultiamine,
riboflavine, vintiamol, dihydrovitam in K1, menadiol diacetate,
menadiol dibutyrate, menadiol disulfate, menadiol, vitamin K1,
vitamin K1 oxide, vitamins K2, and vitamin K-S(II), and folic
acid.
[0041] In another embodiment of the method, the additive is chosen
from acetiamine, benfotiamine, pantothenic acid, cetotiamine,
cycothiamine, 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.
[0042] 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.
[0043] 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.
[0044] 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;
cycothiamine, 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.
[0045] In one embodiment, the additive is chosen from
p-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween 40,
Tween 60, Tween 80, 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-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;
cycothiamine, 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.
[0046] 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.
[0047] 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.
[0048] In one embodiment, the water insoluble drug is chosen from
paclitaxel and analogues thereof and rapamycin and analogues
thereof.
[0049] In one embodiment, some drugs that are considered
particularly suitable for the airway, sinus and other nasal lumens
are corticosteroids such as, budesonide, flunisolide,
triamcinolone, beclomethasone, fluticasone, mometasone, mometasone
furoate, dexamethasone, hydrocortisone, methylprednisolone,
prednisone, cotisone, betamethasone, triamcinolone acetonide, or
the like.
[0050] In one embodiment, the present invention relates to a method
for treating a nonvascular body lumen comprising inserting a
balloon catheter comprising a coating layer into an body lumen,
wherein the body lumen is one of esophagus, airways, sinus,
trachea, colon, biliary tract, urinary tract, prostate, urethral,
ureteral, and other nonvascular lumens, wherein the coating layer
comprises a drug and an additive, inflating the balloon catheter
and releasing the drug to a wall of the body lumen, deflating the
balloon; and withdrawing the balloon catheter. In another
embodiment, the present invention relates to a method for treating
a nonvascular stricture of body lumen comprising inserting a
balloon catheter comprising a coating layer into a nonvascular
strictures of body lumen, wherein the nonvascular strictures of
body lumen is one of benign prostatic hyperplasia (BPH), urethral
strictures, ureteral strictures, prostate cancer, esophageal
strictures, sinus strictures, biliary strictures, asthma and
chronic obstructive pulmonary disease (COPD), wherein the coating
layer comprises a drug and an additive, inflating the balloon
catheter and releasing the drug to a wall of the body lumen,
deflating the balloon; and withdrawing the balloon catheter. In one
aspect of this embodiment, the additive enhances absorption of the
drug into tissue of the nonvascular body lumens. 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. In yet another aspect
of this embodiment, the drug can be released to the wall of the
esophagus. In yet another aspect of this embodiment, the drug can
be released to the wall of the sinus. In yet another aspect of this
embodiment, the drug can be released to the wall of the biliary
tract. In yet another aspect of this embodiment, the drug can be
released to the wall of the urinary tract, prostate, urethral, and
ureteral lumens.
[0051] 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.
[0052] 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.
[0053] 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;
cycothiamine, 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.
[0054] 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.
BRIEF DESCRIPTION OF THE DRAWINGS
[0055] FIG. 1 is a perspective view of an exemplary embodiment of a
balloon catheter according to the present invention.
[0056] FIGS. 2A-2C are cross-sectional views of different
embodiments of the distal portion of the balloon catheter of FIG.
1, taken along line A-A, showing exemplary coating layers.
DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS
[0057] Embodiments of the present invention relate to medical
devices, including particularly balloon catheters and stents,
having a rapid drug-releasing coating and methods for preparing
such coated devices. The therapeutic agent according to embodiments
of the present invention does not require a delayed or long term
release and instead preferably the therapeutic agent and the
additive are released in a very short time period to provide a
therapeutic effect upon contact with tissue. An object of
embodiments of the present invention is to facilitate rapid and
efficient uptake of drug by target tissue during transitory device
deployment at a target site.
[0058] As shown in FIG. 1, in one embodiment, the medical device is
a balloon catheter. The balloon catheter may be any suitable
catheter for the desired use, including conventional balloon
catheters known to one of ordinary skill in the art. For example,
balloon catheter 10 may include an expandable, inflatable balloon
12 at a distal end of the catheter 10, a handle assembly 16 at a
proximal end of the catheter 10, and an elongate flexible member 14
extending between the proximal and distal ends. Handle assembly 16
may connect to and/or receive one or more suitable medical devices,
such as a source of inflation media (e.g., air, saline, or contrast
media). Flexible member 14 may be a tube made of suitable
biocompatible material and having one or more lumens therein. At
least one of the lumens is configured to receive inflation media
and pass such media to balloon 12 for its expansion. The balloon
catheter may be a rapid exchange or over-the-wire catheter and made
of any suitable biocompatible material. The material of balloon 12
is made of one of polyesters, polyamides, nylon 12, nylon 11,
polyamide 12, block copolymers of polyether and polyamide, Pebax,
polyurethanes, and block copolymers of polyether and polyester.
[0059] In one embodiment, the present invention provides a medical
device for delivering a therapeutic agent to a nonvascular tissue.
The device includes a layer applied to an exterior surface of the
medical device, such as a balloon catheter or stent, for example.
The layer includes a therapeutic agent and an additive. For
example, as shown in the embodiment depicted in FIG. 2A, the
balloon 12 is coated with a layer 20 that includes a therapeutic
agent and an additive. In some embodiments, the layer consists
essentially of a therapeutic agent and an additive, i.e., the layer
includes only the therapeutic agent and the additive, without any
other materially significant components. In some embodiments, the
device may optionally include an adherent layer. For example, as
shown in the embodiment depicted in FIG. 2B, the balloon 12 is
coated with an adherent layer 22. A layer 24 that includes a
therapeutic agent and an additive is overlying the adherent layer.
The adherent layer, which is a separate layer underlying the drug
coating layer, improves the adherence of the drug coating layer to
the exterior surface of the medical device and protects coating
integrity. For example, if drug and additive differ in their
adherence to the medical device, the adherent layer may prevent
differential loss of components and maintain drug-to-additive ratio
in the coating during transit to a target site for therapeutic
intervention. Furthermore, the adherent layer may function to
facilitate rapid release of coating layer components off the device
surface upon contact with tissues at the target site. In other
embodiments, the device may include a top layer. The top layer may
reduce loss of the drug layer before it is brought into contact
with target tissues, for example during transit of the balloon 12
to the site of therapeutic intervention or during the first moments
of inflation of balloon 12 before coating layer 20 is pressed into
direct contact with target tissue.
[0060] Embodiments of the present invention are directed to the
treatment of nonvascular strictures of the body lumens by
delivering of an effective amount of anti-inflammatory and
anti-proliferate drugs (rapamycin or paclitaxel and their
analogues). The nonvascular strictures include benign prostatic
hyperplasia (BPH), urethral strictures, ureteral strictures,
prostate cancer, esophageal strictures, sinus strictures, biliary
tract strictures, asthma and chronic obstructive pulmonary disease
(COPD). According to embodiments, the method involves delivering of
anti-inflammatory and anti-proliferate drugs (rapamycin or
paclitaxel and their analogues) via coated medical devices, such as
balloon catheters and stents. The anti-inflammatory and
anti-proliferate drugs can be coated with the medical device alone
or with one or more additives.
[0061] In one embodiment, the present invention relates to a method
for treating a nonvascular stricture of body lumen comprising
inserting a balloon catheter comprising a coating layer into the
stricture, wherein the stricture is one of benign prostatic
hyperplasia (BPH), urethral strictures, ureteral strictures,
prostate cancer, esophageal strictures, sinus strictures, biliary
tract strictures, asthma and chronic obstructive pulmonary disease
(COPD), wherein the coating layer comprises a drug and an additive,
inflating the balloon catheter and releasing the drug to a wall of
the stricture, deflating the balloon; and withdrawing the balloon
catheter, wherein the residual drug is about 1 to 45% of the total
loading drug on the balloon catheter, wherein the drug in the wall
of body lumen is about 0.1 to 25% of the total loading drug on the
balloon catheter. In one aspect of this embodiment, the additive
enhances absorption of the drug into tissue of the nonvascular
stricture of body lumen.
[0062] In one embodiment, the present invention relates to a method
for treating a nonvascular body lumen comprising inserting a
balloon catheter comprising a coating layer into an body lumen,
wherein the body lumen is one of esophagus, airways, sinus,
trachea, colon, biliary tract, urinary tract, prostate, urethral,
ureteral, and other nonvascular lumens, wherein the coating layer
comprises a drug and an additive, inflating the balloon catheter
and releasing the drug to a wall of the body lumen, deflating the
balloon; and withdrawing the balloon catheter, wherein the residual
drug is about 1 to 45% of the total loading drug on the balloon
catheter, wherein the drug in the wall of body lumen is about 0.1
to 25% of the total loading drug on the balloon catheter. In one
aspect of this embodiment, the additive enhances absorption of the
drug into tissue of the nonvascular body lumens. 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.
[0063] Additive
[0064] The additive of 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 lipophilic drug, such as rapamycin or paclitaxel. The
hydrophilic portion accelerates diffusion and increases permeation
of the drug into tissue. It may facilitate rapid movement of drug
off the 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 lumen through polar head groups to
the lipid bilayer of cell membranes of target tissues. The
additives of embodiments of the present invention have two parts
that function together to facilitate rapid release of drug off the
device surface and uptake by target tissue during deployment (by
accelerating drug contact with tissues for which drug has high
affinity) while preventing the premature release of drug from the
device surface prior to device deployment at the target site.
[0065] In embodiments of the present invention, the therapeutic
agent is rapidly released after the medical device is brought into
contact with tissue and is readily absorbed. For example, certain
embodiments of devices of the present invention include drug coated
balloon catheters that deliver a lipophilic anti-proliferative
pharmaceutical (such as paclitaxel or rapamycin) to nonvascular
tissue through brief, direct pressure contact at high drug
concentration during balloon angioplasty. The lipophilic drug is
preferentially retained in target tissue at the delivery site,
where it inhibits hyperplasia and restenosis yet allows
endothelialization. In these embodiments, coating formulations of
the present invention not only facilitate rapid release of drug
from the balloon surface and transfer of drug into target tissues
during deployment, but also prevent drug from diffusing away from
the device during transit through tortuous arterial anatomy prior
to reaching the target site and from exploding off the device
during the initial phase of balloon inflation, before the drug
coating is pressed into direct contact with the surface of the
vessel wall.
[0066] The additive according to certain embodiments 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 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 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. One or more 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 has
components to both bind drug and facilitate its rapid movement off
the medical device during deployment and into target tissues.
[0067] 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 chosen
from 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.
[0068] 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.
[0069] 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 during brief
deployment at the site of intervention. 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.
[0070] 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.
[0071] Surfactants
[0072] 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 lipid bilayers of cell membranes to form part of the lipid
structure, while other components of the surfactants loosen the
lipid structure and enhance drug penetration and absorption. The
contrast agent iopromide does not have these properties.
[0073] 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. In certain embodiments of the
present invention, a higher HLB value is preferred, since increased
hydrophilicity may facilitate release of hydrophobic drug from the
surface of the device. In one embodiment, the HLB of the surfactant
additive is higher than 10. In another embodiment, the additive HLB
is higher than 14. Alternatively, surfactants having lower HLB may
be preferred when used to prevent drug loss prior to device
deployment at the target site, for example in a top coat over a
drug layer that has a very hydrophilic additive.
[0074] 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.
[0075] PEG-Fatty Acids and PEG-Fatty Acid Mono and Diesters
[0076] 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.
[0077] 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.
[0078] 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.
[0079] Polyethylene Glycol Glycerol Fatty Acid Esters
[0080] 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.
[0081] Alcohol-Oil Transesterification Products
[0082] 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 castor
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-6 caprylic/capric glycerides
(Softigen 767). Preferred hydrophobic surfactants in this class
include PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castor
oil, PEG-9 hydrogenated castor oil, 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).
[0083] Polyglyceryl Fatty Acids
[0084] 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-O), 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.
[0085] Propylene Glycol Fatty Acid Esters
[0086] 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-06), propylene glycol dicaprylate/dicaprate (Captex.RTM. 200),
and propylene glycol dioctanoate (Captex.RTM. 800).
[0087] Sterol and Sterol Derivatives
[0088] 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).
[0089] Polyethylene Glycol Sorbitan Fatty Acid Esters
[0090] 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). PEG-20 sorbitan monooleate
(Tween-80). Laurate esters are preferred because they have a short
lipid chain compared with oleate esters, increasing drug
absorption.
[0091] Polyethylene Glycol Alkyl Ethers
[0092] 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).
[0093] Sugar and its Derivatives
[0094] 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-noyl-.beta.-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside, and
octyl-.beta.-D-thioglucopyranoside.
[0095] Polyethylene Glycol Alkyl Phenols
[0096] 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.
[0097] Polyoxyethylene-Polyoxypropylene (POE-POP) Block
Copolymers
[0098] 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.
[0099] 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.
[0100] Sorbitan Fatty Acid Esters
[0101] 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.
[0102] 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.
[0103] Ionic Surfactants
[0104] 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, dialkylester 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.
[0105] Some of the surfactants described herein are very stable
under heating. They survive an ethylene oxide sterilization
process. They do not react with drugs such as paclitaxel or
rapamycin under the sterilization process. The hydroxyl, ester,
amide groups are preferred because they are unlikely to react with
drug, while amine and acid groups often do react with paclitaxel or
rapamycin during sterilization. Furthermore, surfactant additives
improve the integrity and quality of the coating layer, so that
particles do not fall off during handling. When the surfactants
described herein are formulated with paclitaxel, experimentally it
protects drug from premature release during the device delivery
process while facilitating rapid release and elution of paclitaxel
during a very brief deployment time of 0.2 to 10 minutes at the
target site. Drug absorption by tissues at the target site is
unexpectedly high experimentally.
[0106] Chemical Compounds with One or More Hydroxyl, Amino,
Carbonyl, Carboxyl, Acid, Amide or Ester Moieties
[0107] 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, sorbitan, glycerol, polyalcohol, phosphates, sulfates,
organic acids, esters, salts, vitamins, combinations of amino
alcohols 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 750-1,000, or most preferably less than 750.
In these embodiments, the molecular weight of the additive is
preferred to be less than that of the drug to be delivered.
Further, 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 the coating 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 lumens.
[0108] In certain embodiments, 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 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. 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.
[0109] 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 0.2-10 minutes of deployment, for example, with the
additive hydroxyl lactones such as ribonic acid lactone and
gluconolactone.
[0110] Fat-Soluble Vitamins and Salts Thereof
[0111] 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.
[0112] 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-hydroxycholecalciferol, 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.
[0113] Water-Soluble Vitamins and their Amphiphilic Derivatives
[0114] 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.
[0115] 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, palm itic, 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.
[0116] Amino Acids and their Salts
[0117] Alanine, arginine, asparagines, aspartic acid, cysteine,
cystine, glutamic acid, glutamine, glycine, histidine, proline,
isoleucine, leucine, lysine, methionine, phenylalanine, serine,
threonine, tryptophan, tyrosine, valine, and derivatives thereof
are other useful additives in embodiments of the invention.
[0118] 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.
[0119] Amino acid dimers, sugar-conjugates, and other derivatives
are also useful. 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.
[0120] Catecholamines, such as dopamine, levodopa, carbidopa, and
DOPA, are also useful as additives.
[0121] Oligopeptides, Peptides and Proteins
[0122] 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.
[0123] 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 use.
[0124] Other useful proteins include, without limitation, other
albumins, immunoglobulins, caseins, hemoglobins, lysozymes,
immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,
firbinogens, lipases, and the like.
[0125] Organic Acids and their Esters and Anhydrides
[0126] Examples are acetic acid and anhydride, benzoic acid and
anhydride, 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.
[0127] These esters and anhydrides are soluble in organic solvents
such as ethanol, acetone, methylethylketone, ethylacetate. 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.
[0128] Other Chemical Compounds with One or More Hydroxyl, Amine,
Carbonyl, Carboxyl, or Ester Moieties
[0129] The additives according to embodiments include amino
alcohols, alcohols, amines, acids, amides and hydroxyl acids in
both cyclo and linear aliphatic and aromatic groups. 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,
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, sorbitol, glucitol,
sugar phosphates, glucopyranose phosphate, sugar sulphates, 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.
[0130] Combinations of additives are also useful for purposes of
the present invention.
[0131] 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.
[0132] 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. They are often phase separated from the small
water-soluble molecules, which can lead to suboptimal coating
uniformity and integrity. 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, 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.
Surprisingly, 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.
[0133] 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.
[0134] 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.
[0135] 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,
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, sorbitol, glucitol,
sugar phosphates, glucopyranose phosphate, sugar sulphates, 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.
[0136] 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.
[0137] 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.
[0138] 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.
[0139] 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.
[0140] 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.
[0141] 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.
[0142] 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/or van der Waals interactions with drug.
They are also useful in the top layer in the coating. Compounds
containing one or more hydroxyl, carboxyl, or amine groups, for
example, are especially useful as additives since they facilitate
drug release from the device surface and easily displace water next
to the polar head groups and surface proteins of cell membranes and
may thereby remove this barrier to hydrophobic drug permeability.
They accelerate movement of a hydrophobic drug off the balloon to
the lipid layer of cell membranes and tissues for which it has very
high affinity. They may also carry or accelerate the movement of
drug off the balloon into more aqueous environments such as the
interstitial space, for example, of nonvascular tissues that have
been injured by balloon angioplasty or stent expansion. Additives
such as polyglyceryl fatty esters, ascorbic ester of fatty acids,
sugar esters, alcohols and ethers of fatty acids have fatty chains
that can integrate 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. They have structural parts that 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.
[0143] 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 for 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.
[0144] 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. 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 these water-insoluble
drugs in water and enhance their absorption into tissues. However,
they often have poor adhesion to the surface of medical devices.
They are therefore preferably used in combination with other
additives in the drug layer and top layer where they are useful to
enhance drug absorption. Vitamin D2 and D3 are especially useful
because they themselves have anti-restenotic effects and reduce
thrombosis, especially when used in combination with
paclitaxel.
[0145] In embodiments of the present invention, the additive is
soluble in aqueous solvents and is soluble in organic solvents.
Extremely hydrophobic compounds that lack sufficient hydrophilic
parts and are insoluble in aqueous solvent, such as the dye Sudan
Red, are not useful as additives in these embodiments. Sudan red is
also genotoxic.
[0146] In one embodiment, the concentration density of the at least
one therapeutic agent applied to the surface of the medical device
is from about 1 to 20 .mu.g/mm.sup.2, or more preferably from about
2 to 6 .mu.g/mm.sup.2. In one embodiment, the concentration of the
at least one additive applied to the surface of the medical device
is from about 1 to 20 .mu.g/mm.sup.2. The ratio of additives to
drug by weight in the coating layer in embodiments of the present
invention is about 20 to 0.05, preferably about 10 to 0.5, or more
preferably about 5 to 0.8.
[0147] The relative amount of the therapeutic agent and the
additive in the coating layer may vary depending on applicable
circumstances. The optimal amount of the additive can depend upon,
for example, the particular therapeutic agent and additive
selected, the critical micelle concentration of the surface
modifier if it forms micelles, the hydrophilic-lipophilic-balance
(HLB) of a surfactant or an additive's octonol-water partition
coefficient (P), the melting point of the additive, the water
solubility of the additive and/or therapeutic agent, the surface
tension of water solutions of the surface modifier, etc.
[0148] Other considerations will further inform the choice of
specific proportions of different additives. These considerations
include the degree of bioacceptability of the additives and the
desired dosage of hydrophobic therapeutic agent to be provided.
[0149] Therapeutic Agent
[0150] The drugs or biologically active materials, which can be
used in embodiments of the present invention, can be any
therapeutic agent or substance. The drugs can be of various
physical states, e.g., molecular distribution, crystal forms or
cluster forms. Examples of drugs that are especially useful in
embodiments of the present invention are lipophilic substantially
water insoluble drugs, such as paclitaxel, rapamycin, daunorubicin,
doxorubicin, lapachone, vitamin D2 and D3 and analogues and
derivatives thereof. These drugs are especially suitable for use in
a coating on a balloon catheter used to treat tissue of the
vasculature.
[0151] Other drugs that may be useful in embodiments of the present
invention include, without limitation, glucocorticoids (e.g.,
dexamethasone, betamethasone), hirudin, angiopeptin, aspirin,
growth factors, antisense agents, anti-cancer agents,
anti-proliferative agents, oligonucleotides, and, more generally,
anti-platelet agents, anti-coagulant agents, anti-mitotic agents,
antioxidants, anti-metabolite agents, anti-chemotactic, and
anti-inflammatory agents.
[0152] Some drugs that are considered particularly suitable for the
airway, sinus and other nasal lumens are corticosteroids such as,
budesonide, flunisolide, triamcinolone, beclomethasone,
fluticasone, mometasone, mometasone furoate, dexamethasone,
hydrocortisone, methylprednisolone, prednisone, cotisone,
betamethasone, triamcinolone acetonide, or the like. Some other
suitable drugs are bronchodilators such as terbutaline, albuterol,
ipratropium, pirbuterol, epinephrine, salmeterol, levalbuterol,
formoterol, or the like.
[0153] Also useful in embodiments of the present invention are
polynucleotides, antisense, RNAi, or siRNA, for example, that
inhibit inflammation and/or smooth muscle cell or fibroblast
proliferation.
[0154] Anti-platelet agents can include drugs such as aspirin and
dipyridamole. Aspirin is classified as an analgesic, antipyretic,
anti-inflammatory and anti-platelet drug. Dipyridamole is a drug
similar to aspirin in that it has anti-platelet characteristics.
Dipyridamole is also classified as a coronary vasodilator.
Anti-coagulant agents for use in embodiments of the present
invention can include drugs such as heparin, protamine, hirudin and
tick anticoagulant protein. Anti-oxidant agents can include
probucol. Anti-proliferative agents can include drugs such as
amlodipine and doxazosin. Anti-mitotic agents and anti-metabolite
agents that can be used in embodiments of the present invention
include drugs such as methotrexate, azathioprine, vincristine,
vinblastine, 5-fluorouracil, adriamycin, and mutamycin. Antibiotic
agents for use in embodiments of the present invention include
penicillin, cefoxitin, oxacillin, tobramycin, and gentamicin.
Suitable antioxidants for use in embodiments of the present
invention include probucol. Additionally, genes or nucleic acids,
or portions thereof can be used as the therapeutic agent in
embodiments of the present invention. Furthermore,
collagen-synthesis inhibitors, such as tranilast, can be used as a
therapeutic agent in embodiments of the present invention.
[0155] Photosensitizing agents for photodynamic or radiation
therapy, including various porphyrin compounds such as porfimer,
for example, are also useful as drugs in embodiments of the present
invention.
[0156] Drugs for use in embodiments of the present invention also
include everolimus, somatostatin, tacrolimus, roxithromycin,
dunaimycin, ascomycin, bafilomycin, erythromycin, midecamycin,
josamycin, concanamycin, clarithromycin, troleandomycin, folimycin,
cerivastatin, simvastatin, lovastatin, fluvastatin, rosuvastatin,
atorvastatin, pravastatin, pitavastatin, vinblastine, vincristine,
vindesine, vinorelbine, etoposide, teniposide, nimustine,
carmustine, lomustine, cyclophosphamide, 4-hydroxycyclophosphamide,
estramustine, melphalan, ifosfamide, trofosfamide, chlorambucil,
bendamustine, dacarbazine, busulfan, procarbazine, treosulfan,
temozolomide, thiotepa, daunorubicin, doxorubicin, aclarubicin,
epirubicin, mitoxantrone, idarubicin, bleomycin, mitomycin,
dactinomycin, methotrexate, fludarabine,
fludarabine-5'-dihydrogenphosphate, cladribine, mercaptopurine,
thioguanine, cytarabine, fluorouracil, gemcitabine, capecitabine,
docetaxel, carboplatin, cisplatin, oxaliplatin, amsacrine,
irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin,
aldesleukin, tretinoin, asparaginase, pegaspargase, anastrozole,
exemestane, letrozole, formestane, aminoglutethimide, adriamycin,
azithromycin, spiramycin, cepharantin, smc proliferation
inhibitor-2w, epothilone A and B, mitoxantrone, azathioprine,
mycophenolatmofetil, c-myc-antisense, b-myc-antisense, betulinic
acid, camptothecin, lapachol, beta.-lapachone, podophyllotoxin,
betulin, podophyllic acid 2-ethylhydrazide, molgramostim
(rhuGM-CSF), peginterferon a-2b, lenograstim (r-HuG-CSF),
filgrastim, macrogol, dacarbazine, basiliximab, daclizumab,
selectin (cytokine antagonist), CETP inhibitor, cadherines,
cytokinin inhibitors, COX-2 inhibitor, NFkB, angiopeptin,
ciprofloxacin, camptothecin, fluoroblastin, monoclonal antibodies,
which inhibit the muscle cell proliferation, bFGF antagonists,
probucol, prostaglandins, 1,11-dimethoxycanthin-6-one,
1-hydroxy-11-methoxycanthin-6-one, scopoletin, colchicine, NO
donors such as pentaerythritol tetranitrate and syndnoeimines, S-n
itrosoderivatives, tamoxifen, staurosporine, beta.-estradiol,
a-estradiol, estriol, estrone, ethinylestradiol, fosfestrol,
medroxyprogesterone, estradiol cypionates, estradiol benzoates,
tranilast, kamebakaurin and other terpenoids, which are applied in
the therapy of cancer, verapamil, tyrosine kinase inhibitors
(tyrphostines), cyclosporine A, 6-a-hydroxy-paclitaxel, baccatin,
taxotere and other macrocyclic oligomers of carbon suboxide (MCS)
and derivatives thereof, mofebutazone, acemetacin, diclofenac,
lonazolac, dapsone, o-carbamoylphenoxyacetic acid, lidocaine,
ketoprofen, mefenamic acid, piroxicam, meloxicam, chloroquine
phosphate, penicillamine, hydroxychloroquine, auranofin, sodium
aurothiomalate, oxaceprol, celecoxib, .beta.-sitosterin,
ademetionine, myrtecaine, polidocanol, non ivamide, levomenthol,
benzocaine, aescin, ellipticine, D-24851 (Calbiochem), colcem id,
cytochalasin A-E, indanocine, nocodazole, S 100 protein,
bacitracin, vitronectin receptor antagonists, azelastine, guanidyl
cyclase stimulator tissue inhibitor of metal proteinase-1 and -2,
free nucleic acids, nucleic acids incorporated into virus
transmitters, DNA and RNA fragments, plasminogen activator
inhibitor-1, plasminogen activator inhibitor-2, antisense
oligonucleotides, VEGF inhibitors, IGF-1, active agents from the
group of antibiotics such as cefadroxil, cefazolin, cefaclor,
cefotaxim, tobramycin, gentamycin, penicillins such as
dicloxacillin, oxacillin, sulfonamides, metronidazol,
antithrombotics such as argatroban, aspirin, abciximab, synthetic
antithrombin, bivalirudin, coumadin, enoxaparin, desulphated and
N-reacetylated heparin, tissue plasminogen activator, GpIIb/IIIa
platelet membrane receptor, factor Xa inhibitor antibody, heparin,
hirudin, r-hirudin, PPACK, protamin, prourokinase, streptokinase,
warfarin, urokinase, vasodilators such as dipyramidole, trapidil,
nitroprussides, PDGF antagonists such as triazolopyrimidine and
seramin, ACE inhibitors such as captopril, cilazapril, lisinopril,
enalapril, losartan, thiol protease inhibitors, prostacyclin,
vapiprost, interferon a, .beta and y, histamine antagonists,
serotonin blockers, apoptosis inhibitors, apoptosis regulators such
as p65 NF-kB or Bcl-xL antisense oligonucleotides, halofuginone,
nifedipine, tranilast, molsidomine, tea polyphenols, epicatechin
gallate, epigallocatechin gallate, Boswellic acids and derivatives
thereof, leflunomide, anakinra, etanercept, sulfasalazine,
etoposide, dicloxacillin, tetracycline, triamcinolone, mutamycin,
procainamide, retinoic acid, quinidine, disopyramide, flecamide,
propafenone, sotalol, amidorone, natural and synthetically obtained
steroids such as bryophyllin A, inotodiol, maquiroside A,
ghalakinoside, mansonine, strebloside, hydrocortisone,
betamethasone, dexamethasone, non-steroidal substances (NSAIDS)
such as fenoprofen, ibuprofen, indomethacin, naproxen,
phenylbutazone and other antiviral agents such as acyclovir,
ganciclovir and zidovudine, antimycotics such as clotrimazole,
flucytosine, griseofulvin, ketoconazole, miconazole, nystatin,
terbinafine, antiprozoal agents such as chloroquine, mefloquine,
quinine, moreover natural terpenoids such as hippocaesculin,
barringtogenol-C21-angelate, 14-dehydroagrostistachin, agroskerin,
agrostistachin, 17-hydroxyagrostistachin, ovatodiolids,
4,7-oxycycloanisomelic acid, baccharinoids B1, B2, B3 and B7,
tubeimoside, bruceanol A, B and C, bruceantinoside C, yadanziosides
N and P, isodeoxyelephantopin, tomenphantopin A and B, coronarin A,
B, C and D, ursolic acid, hyptatic acid A, zeorin,
iso-iridogermanal, maytenfoliol, effusantin A, excisanin A and B,
longikaurin B, sculponeatin C, kamebaunin, leukamenin A and B,
13,18-dehydro-6-a-senecioyloxychaparrin, taxamairin A and B,
regenilol, triptolide, moreover cymarin, apocymarin, aristolochic
acid, anopterin, hydroxyanopterin, anemonin, protoanemonin,
berberine, cheliburin chloride, cictoxin, sinococuline,
bombrestatin A and B, cudraisoflavonei A, curcum in,
dihydronitidine, nitidine chloride,
12-beta-hydroxypregnadien-3,20-dione, bilobol, ginkgol, ginkgolic
acid, helenalin, indicine, indicine-N-oxide, lasiocarpine,
inotodiol, glycoside 1a, podophyllotoxin, justicidin A and B,
larreatin, malloterin, mallotochromanol,
isobutyrylmallotochromanol, maquiroside A, marchantin A,
maytansine, lycoridicin, margetine, pancratistatin, liriodenine,
bisparthenolidine, oxoushinsunine, aristolactam-All,
bisparthenolidine, periplocoside A, ghalakinoside, ursolic acid,
deoxypsorosperm in, psychorubin, ricin A, sanguinarine, manwu wheat
acid, methylsorbifolin, sphatheliachromen, stizophyllin, mansonine,
strebloside, akagerine, dihydrousambarensine, hydroxyusambarine,
strychnopentamine, strychnophylline, usambarine, usambarensine,
berberine, liriodenine, oxoushinsunine, daphnoretin, lariciresinol,
methoxylariciresinol, syringaresinol, umbelliferon, afromoson,
acetylvismione B, desacetylvismione A, and vismione A and B.
[0157] A combination of drugs can also be used in embodiments of
the present invention. Some of the combinations have additive
effects because they have a different mechanism, such as paclitaxel
and rapamycin, paclitaxel and active vitamin D, paclitaxel and
lapachone, rapamycin and active vitamin D, rapamycin and lapachone.
Because of the additive effects, the dose of the drug can be
reduced as well. These combinations may reduce complications from
using a high dose of the drug.
[0158] Adherent Layer
[0159] 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 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 or
drug-to-drug ratio in the drug layer and therapeutic delivery at
the target site of 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.
[0160] As described above, 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.
[0161] 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.
[0162] Since the medical device undergoes 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.
[0163] 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.
[0164] Top Layer
[0165] 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, Tween 80, 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.
[0166] Solvents
[0167] Solvents for preparing of the coating layer may include, as
examples, any combination of one or more of the following: (a)
water, (b) alkanes such as hexane, octane, cyclohexane, and
heptane, (c) aromatic solvents such as benzene, toluene, and
xylene, (d) alcohols such as ethanol, propanol, and isopropanol,
diethylamide, ethylene glycol monoethyl ether, Trascutol, and
benzyl alcohol (e) ethers such as dioxane, dimethyl ether and
tetrahydrofuran, (f) esters/acetates such as ethyl acetate and
isobutyl acetate, (g) ketones such as acetone, acetonitrile,
diethyl ketone, and methyl ethyl ketone, and (h) mixture of water
and organic solvents such as water/ethanol, water/acetone,
water/methanol, water/tetrahydrofuran. A preferred solvent in the
top coating layer is methanol, ethanol, and acetone.
[0168] Organic solvents, such as short-chained alcohol, dioxane,
tetrahydrofuran, dimethylformamide, acetonitrile,
dimethylsulfoxide, etc., are particularly useful and preferred
solvents in embodiments of the present invention because these
organic solvents generally disrupt collodial aggregates and
co-solubilize all the components in the coating solution.
[0169] The therapeutic agent and additive or additives may be
dispersed in, solubilized, or otherwise mixed in the solvent. The
weight percent of drug and additives in the solvent may be in the
range of 0.1-80% by weight, preferably 2-20% by weight.
[0170] Another embodiment of the invention relates to a method for
preparing a medical device, particularly, for example, a balloon
catheter or a stent. First, a coating solution or suspension
comprising at least one solvent, at least one therapeutic agent,
and at least one additive is prepared. In at least one embodiment,
the coating solution or suspension includes only these three
components. The content of the therapeutic agent in the coating
solution can be from 0.5-50% by weight based on the total weight of
the solution. The content of the additive in the coating solution
can be from 1-45% by weight, 1 to 40% by weight, or from 1-15% by
weight based on the total weight of the solution. The amount of
solvent used depends on the coating process and viscosity. It will
affect the uniformity of the drug-additive coating but will be
evaporated.
[0171] In other embodiments, two or more solvents, two or more
therapeutic agents, and/or two or more additives may be used in the
coating solution.
[0172] In other embodiments, a therapeutic agent, an additive and a
polymeric material may be used in the coating solution, for example
in a stent coating. In the coating, the therapeutic agent is not
encapsulated in polymer particles.
[0173] Various techniques may be used for applying a coating
solution to a medical device such as casting, spinning, spraying,
dipping (immersing), ink jet printing, electrostatic techniques,
and combinations of these processes. Choosing an application
technique principally depends on the viscosity and surface tension
of the solution. In embodiments of the present invention, dipping
and spraying are preferred because it makes it easier to control
the uniformity of the thickness of the coating layer as well as the
concentration of the therapeutic agent applied to the medical
device. Regardless of whether the coating is applied by spraying or
by dipping or by another method or combination of methods, each
layer is usually deposited on the medical device in multiple
application steps in order to control the uniformity and the amount
of therapeutic substance and additive applied to the medical
device.
[0174] Each applied layer is from about 0.1 microns to 15 microns
in thickness. The total number of layers applied to the medical
device is in a range of from about 2 to 50. The total thickness of
the coating is from about 2 to 200 microns.
[0175] As discussed above, spraying and dipping are particularly
useful coating techniques for use in embodiments of the present
invention. In a spraying technique, a coating solution or
suspension of an embodiment of the present invention is prepared
and then transferred to an application device for applying the
coating solution or suspension to a balloon catheter.
[0176] With the balloon rotating in a substantially horizontal
plane, the spray nozzle is adjusted so that the distance from the
nozzle to the balloon is about 1-4 inches. First, the coating
solution is sprayed substantially horizontally with the brush being
directed along the balloon from the distal end of the balloon to
the proximal end and then from the proximal end to the distal end
in a sweeping motion at a speed such that one spray cycle occurred
in about three balloon rotations. The balloon is repeatedly sprayed
with the coating solution, followed by drying, until an effective
amount of the drug is deposited on the balloon.
[0177] In one embodiment of the present invention, the balloon is
inflated or partially inflated, the coating solution is applied to
the inflated balloon, for example by spraying, and then the balloon
is deflated and folded before drying. Drying may be performed under
vacuum.
[0178] It should be understood that this description of an
application device, fixture, and spraying technique is exemplary
only. Any other suitable spraying or other technique may be used
for coating the medical device, particularly for coating the
balloon of a balloon catheter or stent delivery system or
stent.
[0179] After the medical device is sprayed with the coating
solution, the coated balloon is subjected to a drying in which the
solvent in the coating solution is evaporated. This produces a
coating matrix on the balloon containing the therapeutic agent. One
example of a drying technique is placing a coated balloon into an
oven at approximately 20.degree. C. or higher for approximately 24
hours. Any other suitable method of drying the coating solution may
be used. The time and temperature may vary with particular
additives and therapeutic agents.
[0180] Optional Post Treatment
[0181] After depositing the drug-additive containing layer on the
device of certain embodiments of the present invention, dimethyl
sulfoxide (DMSO) or other solvent may be applied, by dip or spray
or other method, to the finished surface of the coating. DMSO
readily dissolves drugs and easily penetrates membranes and may
enhance tissue absorption.
[0182] It is contemplated that the medical devices of embodiments
of the present invention have applicability for treating blockages
and occlusions of any body lumens, including, among others, the
gastrointestinal tract, including the esophagus, stomach, small
intestine, and colon, the pulmonary airways, including the trachea,
bronchi, bronchioles, the sinus, the biliary tract, the urinary
tract, urethral, ureteral, and prostate and other lumens. They are
especially suited for treating tissue of the urological tract with,
for example, a balloon catheter or a stent.
[0183] Yet another embodiment of the present invention relates to a
method of treating a prostate. The method includes inserting a
medical device comprising a coating into a prostate. The coating
layer comprises a therapeutic agent and an additive. In this
embodiment, the medical device can be configured as having at least
an expandable portion. Some examples of such devices include
balloon catheters, perfusion balloon catheters, an infusion
catheter such as distal perforated drug infusion catheters, a
perforated balloon, spaced double balloon, porous balloon, and
weeping balloon, cutting balloon catheters, scoring balloon
catheters, self-expanded and balloon expanded-stents, guide
catheters, guide wires, embolic protection devices, and various
imaging devices.
[0184] As mentioned above, one example of a medical device that is
particularly useful in the present invention is a coated balloon
catheter. A balloon catheter typically has a long, narrow, hollow
tube tabbed with a miniature, deflated balloon. In embodiments of
the present invention, the balloon is coated with a drug solution.
Then, the balloon is maneuvered through the body lumen strictures
to the site of a blockage, occlusion, or other tissue requiring a
therapeutic agent. Once in the proper position, the balloon is
inflated and contacts the walls of the body lumen strictures and/or
a blockage or occlusion. It is an object of embodiments of the
present invention to rapidly deliver drug to and facilitate
absorption by target tissue. It is advantageous to efficiently
deliver drug to tissue in as brief a period of time as possible
while the device is deployed at the target site. The therapeutic
agent is released into such tissue, for example the lumen walls, in
about 0.1 to 30 minutes, for example, or preferably about 0.1 to 10
minutes, or more preferably about 0.2 to 2 minutes, or most
preferably, about 0.1 to 1 minutes, of balloon inflation time
pressing the drug coating into contact with diseased nonvascular
tissue.
[0185] Given that a therapeutically effective amount of the drug
can be delivered by embodiments of the present invention into, for
example, the prostate, in some cases the need for a stent may be
eliminated, obviating the complications of fracture and dripping
associated therewith.
[0186] Should placement of a stent still be desired, a particularly
preferred use for embodiments of the present invention is to crimp
a stent, such as a bare metal stent (BMS), for example, over the
drug coated balloon described in embodiments herein. When the
balloon is inflated to deploy the stent at the site of diseased
nonvasculature, an effective amount of drug is delivered into the
arterial wall to prevent or decrease the severity of restenosis or
other complications. Alternatively, the stent and balloon may be
coated together, or the stent may be coated and then crimped on a
balloon.
[0187] Further, the balloon catheter may be used to treat
nonvascular tissue/disease alone or in combination with other
methods for treating the non vasculature, for example, photodynamic
therapy or atherectomy. Atherectomy is a procedure to remove plaque
from arteries. Specifically, atherectomy removes plaque from
peripheral and coronary arteries. The medical device used for
peripheral or coronary atherectomy may be a laser catheter or a
rotablator or a direct atherectomy device on the end of a catheter.
The catheter is inserted into the body and advanced through a
nonvascular lumen to the area of narrowing. After the atherectomy
has removed some of the plaque, balloon angioplasty using the
coated balloon of embodiments of the present invention may be
performed. In addition, stenting may be performed thereafter, or
simultaneous with expansion of the coated balloon as described
above. Photodynamic therapy is a procedure where light or
irradiated energy is used to kill target cells in a patient. A
light-activated photosensitizing drug may be delivered to specific
areas of tissue by embodiments of the present invention. A targeted
light or radiation source selectively activates the drug to produce
a cytotoxic response and mediate a therapeutic anti-proliferative
effect.
[0188] In some of the embodiments of drug-containing coatings and
layers according to the present invention, the coating or layer
does not include polymers, oils, or lipids. And, furthermore, the
therapeutic agent is not encapsulated in polymer particles,
micelles, or liposomes. As described above, such formulations have
significant disadvantages and can inhibit the intended efficient,
rapid release and tissue penetration of the agent, especially in
the environment of diseased tissue of the nonvasculature.
[0189] 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.
[0190] Other than the operating examples, or where otherwise
indicated, all numbers expressing quantities of components in a
layer, reaction conditions, and so forth used in the specification
and claims are to be understood as being modified in all instances
by the term "about." Accordingly, unless otherwise indicated to the
contrary, the numerical parameters set forth in this specification
and attached claims are approximations that may vary depending upon
the desired properties sought to be obtained by the present
disclosure.
[0191] Preparation
[0192] The medical device and the coating layers of embodiments of
the present invention can be made according to various methods. For
example, the coating solution can be prepared by dispersing,
dissolving, diffusing, or otherwise mixing all the ingredients,
such as a therapeutic agent, an additive, and a solvent,
simultaneously together. Also, the coating solution can be prepared
by sequentially adding each component based on solubility or any
other parameters. For example, the coating solution can be prepared
by first adding the therapeutic agent to the solvent and then
adding the additive. Alternatively, the additive can be added to
the solvent first and then the therapeutic agent can be later
added. If the solvent used does not sufficiently dissolve the drug,
it is preferable to first add the additive to the solvent, then the
drug, since the additive will increase drug solubility in the
solvent.
EXAMPLES
[0193] The following examples include embodiments of medical
devices and coating layers within the scope of the present
invention. 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
[0194] Preparation of Coating Solutions
[0195] 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.
[0196] 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 wemixed.
[0197] 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.
[0198] 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.
[0199] 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
were mixed.
[0200] 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.
[0201] 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, were mixed.
[0202] 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, were mixed.
[0203] 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 were mixed.
[0204] 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, were mixed.
[0205] 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.
[0206] 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.
[0207] 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.
[0208] 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.
[0209] 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.
[0210] 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.degree. C. for 1 to 5 min.
[0211] 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.
[0212] 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.
[0213] 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.
[0214] 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.
[0215] 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.
[0216] 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.
[0217] 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.
[0218] 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.
[0219] 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.
[0220] Formulation 26--Comparison solution-50 mg (0.06 mmole)
paclitaxel, 1 ml ethanol, 0.2 ml acetone, 0.042 ml Ultravist 370
were mixed.
[0221] Formulation 27--Comparison solution-40 mg (0.048 mmole)
paclitaxel, 0.5 ml ethanol, 0.5 ml acetone were mixed.
[0222] 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
[0223] 5 PTA balloon catheters (4-8 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 (1-28)
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
[0224] 5 PTA balloon catheters (4-8 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 (1-28)
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) was obtained. The coated folded balloon was then
rewrapped and sterilized for animal testing.
Example 4
[0225] 5 PTA balloon catheters crimped with bare metal stent (4-8
mm in diameter and 20 mm in length) were sprayed or dipped in a
formulation (1-28) in example 1. The stent delivery system was then
dried, sprayed or dipped again in a formulation (20-28), dried and
sprayed or dipped again until sufficient amount of drug on the
stent and balloon (3 microgram per square mm) is obtained. The
coated folded stent delivery system was then sterilized for animal
testing.
Example 5
[0226] Drug coated balloon catheters and uncoated balloon catheters
(as control) were inserted into prostate 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 and additive, 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
[0227] 5 stents (3 mm in diameter and 18 mm in length) were spray
or dip coated with the formulation (1-28) 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 PTA balloon
catheters (3-8 mm in diameters and 20 mm in length). The coated
stents with balloon catheters were then sterilized for animal
testing.
Example 7
[0228] The drug coated stent and uncoated stent (as control) were
inserted into urological tract in dogs, then the balloon was over
dilated (1:1.2). The stent was implanted and drug and additive
released, and the balloon was deflated and withdrawn 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
[0229] 5 PTA 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 is obtained
(3 microgram per square mm) was obtained. A bare metal coronary
stent (3-6 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 9
[0230] 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
[0231] The drug coated balloon-expandable bare metal stent of
Examples 8 and 9 and plain balloon-expandable bare metal stent (as
control) were inserted into urethral in dogs, and the balloon is
over dilated (1:1.2). Stent is implanted, and the balloon was held
inflated for 60 seconds to release drug and additive, and the
balloon was deflated and withdrawn 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 is measured after 60
minutes, 1 day, 3 days, 31 days, 3 months, 6 months, 9 months and
12 months.
Example 11
[0232] 150 mg (0.18 mmole) paclitaxel, 5 ml acetone (or
ethylacetate 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 were 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) is obtained. The coated balloon
was then treated under high pH (range pH 8-11.5) conditions to
hydrolyze the anhydride. This can be confirmed by IR method. The
hydrophilicity of the coating was now increased. The coated
balloons were then sterilized for animal test.
Example 12
[0233] 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 and additive. 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
[0234] The uncoated stent delivery catheters were inserted into the
esophageal lumen in pigs. The balloon was dilated, the stent was
deployed and the deflated balloon was the withdrawn. The
pharmaceutical formulation 1-15 of example 1 (10-100 ml) was
injected (about 5-15 mg drug per pig) at the site of stent
implantation. The drug was then absorbed by injured tissue. The
animals were then examined and tissues samples were taken for
pathology.
Example 14
[0235] The diseased tissue (breast cancer or prostate or atheroma
or stenosis) was removed surgically from a human body. The
pharmaceutical formulation 1-28 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 included
injection by long needle, guide catheters, introducer shealth, drug
infusion tube and other drug delivery catheters. The drug was then
absorbed by tissue at the target site.
Example 15
[0236] 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 18-28 in example 1. A 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.
[0237] The coated PTA balloon catheter was inserted into a target
site in the prostate or urethral of a 25-45 pound dogs. The balloon
was inflated to about 12 atm. The overstretch ratio (the ratio of
balloon diameter to vessel diameter) was about 1.15-1.20. The drug
delivered into the target tissue during 30-60 seconds of inflation.
The balloon catheter was then deflated and was withdrawn from
animal body. The target prostate was harvested 0.25-24 hours after
the procedure. The drug content in the target tissue and the
residual drug remaining on the balloon were analyzed by tissue
extraction and HPLC.
[0238] In chronic animal tests, angiography or endoscope 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 a period of follow-up time
and the minimal lumen diameter measured immediately after the
intervention. 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. The animal
test results for Formulations 18-28 are reported below. All data is
an average of five or six experimental data points.
[0239] The drug content of the formulation 20 on the 3.5-6.5 mm
balloon catheters was about 2/mm.sup.2. After the procedure, the
residual drug on the balloon was 2-45% of the total drug loaded on
the balloon. The drug content in tissue harvested 15-30 minutes
after the procedure was 3-15% of the total drug content originally
loaded on the balloon.
[0240] The drug content of formulation 20 on the 3.5 mm balloon
catheters was 2 .mu.g/mm.sup.2. After the procedure, the residual
drug on the balloon was 5-45% of the total drug load. The drug
content in tissue harvested 15-30 minutes after the procedure was
3-15% of the total drug load. The stretch ratio was 1.3 in the
procedure.
* * * * *