U.S. patent application number 14/993190 was filed with the patent office on 2016-05-05 for composition containing rotigotine and use thereof and transdermal patch containing the composition.
The applicant listed for this patent is Jiangsu Kangbeide Pharmaceuticals Co. Ltd.. Invention is credited to Guohua Chi, Hongguang Du, Hongjun Lian, Xiquan Liu, Yucheng Lu, Xiaoyan Shi, Li Song, Li Wang, Shuming Wang, Enhong Zhang, Xuying Zhong, Huiyong Zue.
Application Number | 20160120822 14/993190 |
Document ID | / |
Family ID | 39248511 |
Filed Date | 2016-05-05 |
United States Patent
Application |
20160120822 |
Kind Code |
A1 |
Wang; Shuming ; et
al. |
May 5, 2016 |
COMPOSITION CONTAINING ROTIGOTINE AND USE THEREOF AND TRANSDERMAL
PATCH CONTAINING THE COMPOSITION
Abstract
A Rotigotine-containing composition having a matrix mixture
system formed from a polyvinylpyrrolidone and a combination of an
acrylic pressure-sensitive adhesive with a silicone
pressure-sensitive adhesive. The polyvinylpyrrolidone may be
present in an amount of about 1-10% by weight in the matrix mixture
system. The acrylic pressure-sensitive adhesive may be present in
an amount of about 1-25% by weight in the matrix mixture system.
The silicone pressure-sensitive adhesive may be present in an
amount of about 65-98% by weight in the matrix mixture system. The
composition further includes 1-40% of Rotigotine on the basis of
the total weight of the composition. The composition provides
improved properties in the solubility, release and initial
penetration level of Rotigotine. Also disclosed is a transdermal
patch that includes the Rotigotine-containing composition, as well
as methods of manufacturing and using the Rotigotine-containing
composition.
Inventors: |
Wang; Shuming; (Beijing,
CN) ; Zue; Huiyong; (Beijing, CN) ; Wang;
Li; (Beijing, CN) ; Zhang; Enhong; (Beijing,
CN) ; Lian; Hongjun; (Beijing, CN) ; Shi;
Xiaoyan; (Beijing, CN) ; Chi; Guohua;
(Beijing, CN) ; Lu; Yucheng; (Beijing, CN)
; Liu; Xiquan; (Beijing, CN) ; Song; Li;
(Beijing, CN) ; Zhong; Xuying; (Beijing, CN)
; Du; Hongguang; (Beijing, CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Jiangsu Kangbeide Pharmaceuticals Co. Ltd. |
Nanjing |
|
CN |
|
|
Family ID: |
39248511 |
Appl. No.: |
14/993190 |
Filed: |
January 12, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12667915 |
Jun 14, 2010 |
9265752 |
|
|
PCT/CN2008/001267 |
Jul 3, 2008 |
|
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|
14993190 |
|
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Current U.S.
Class: |
424/449 ;
514/438 |
Current CPC
Class: |
A61K 9/7061 20130101;
A61K 31/381 20130101; A61K 9/7069 20130101; A61K 9/7023 20130101;
A61K 9/7053 20130101; A61P 25/16 20180101; A61P 25/18 20180101;
A61P 25/14 20180101; A61P 25/24 20180101 |
International
Class: |
A61K 9/70 20060101
A61K009/70; A61K 31/381 20060101 A61K031/381 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 6, 2007 |
CN |
200710118491.X |
Claims
1. A rotigotine-containing transdermal patch comprising a matrix
layer composition, wherein the matrix layer composition comprises,
on the basis of the total weight of the matrix layer composition,
60-99% by weight of a matrix mixture system and 1-40% by weight of
rotigotine, wherein the matrix mixture system is formed from a
combination of an acrylic pressure-sensitive adhesive with a
silicone pressure-sensitive adhesive, and polyvinylpyrrolidone,
wherein (1) the acrylic pressure-sensitive adhesive is present in
an amount of 5-19% by weight in the matrix mixture system, (2) the
silicone pressure-sensitive adhesive is present in an amount of
79-94% by weight in the matrix mixture system, and (3) the
polyvinylpyrrolidone is present in an amount of 1-10% by weight in
the matrix mixture system; and wherein the rotigotine is in the
form of free base or a pharmaceutically acceptable salt.
2. The rotigotine-containing transdermal patch of claim 1, wherein
the matrix layer composition further comprises at least one
auxiliary selected from the group consisting of permeation
enhancers and antioxidants.
3. The rotigotine-containing transdermal patch of claim 2, wherein
the permeation enhancer is selected from the group consisting of
surfactants, organic solvents including alcohols, polyols, esters,
dimethyl sulfoxide, fatty acids, fatty alcohols, fatty acid esters,
azones, pyrrolidone derivatives selected from the group consisting
of N-methylpyrrolidone, 1,5-dimethylpyrrolidone and
5-carboxylpyrrolidone, salicylic acid and terpenes.
4. The rotigotine-containing transdermal patch of claim 2, wherein
the antioxidant is selected from the group consisting of vitamin E,
ascorbyl palmitate, sodium metasulfite and mixtures thereof.
5. The rotigotine-containing transdermal patch of claim 1, wherein
the acrylic pressure-sensitive adhesive is selected from the group
consisting of an acrylic pressure-sensitive polymer and a
combination of an acrylic pressure sensitive polymer with an
acrylic resin.
6. The rotigotine-containing transdermal patch of claim 5, wherein
the acrylic pressure-sensitive polymer is copolymerized from a soft
monomer, a hard monomer and a functional monomer, wherein the soft
monomer is selected from the group consisting of ethyl acrylate,
2-ethylhexyl acrylate, isooctyl acrylate, and butyl acrylate, the
hard monomer is selected from the group consisting of vinyl
acetate, methyl acrylate, styrene, acrylonitrile, methyl
methacrylate, ethyl methacrylate, and n-butyl methacrylate, and the
functional monomer is selected from the group consisting of
(meth)acrylic acid, (meth)acrylamide, .beta.-hydroxyethyl
(meth)acrylate, .beta.-hydroxypropyl (meth)acrylate, glycidyl
(meth)acrylate and N-hydoxylmethylacrylamide.
7. The rotigotine-containing transdermal patch of claim 6, wherein
the acrylic pressure-sensitive polymer is copolymerized from the
monomers: butyl acrylate, isooctyl acrylate, vinyl acetate,
acrylamide and .alpha.-methacrylic acid.
8. The rotigotine-containing transdermal patch of claim 2, wherein
the matrix layer composition comprises, on the basis of the total
weight of the matrix layer composition, 75-90% by weight of the
matrix mixture system, 5-15% by weight of rotigotine and 5-11% by
weight of the permeation enhancer.
9. The rotigotine-containing transdermal patch of claim 8, wherein
the matrix layer composition comprises, on the basis of the total
weight of the matrix layer composition, 79-84% by weight of a
matrix mixture system, 8-11% by weight of rotigotine and 8-10% by
weight of the permeation enhancer, wherein the acrylic
pressure-sensitive adhesive is present in an amount of 6-12.5% by
weight in the matrix mixture system, the silicone
pressure-sensitive adhesive is present in an amount of 86.5-93% by
weight in the matrix mixture system, and the polyvinylpyrrolidone
is present in an amount of 1-1.5% by weight in the matrix mixture
system.
10. The rotigotine-containing transdermal patch of claim 8, wherein
the permeation enhancer is selected from the group consisting of
isopropyl myristate, lauryl acid and N-methylpyrrolidone.
11. The rotigotine-containing transdermal patch of claim 1, wherein
the polyvinylpyrrolidone is present in an amount of 1-2% by weight
in the matrix mixture system.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
patent application Ser. No. 12/667,915, filed Jun. 14, 2010, which
is incorporated by reference herein in its entirety. U.S.
application Ser. No. 12/667,915 entered the U.S. national stage
from International Application No. PCT/CN2008/01267 filed Jul. 3,
2008. This application also claims the benefit of Chinese
Application No. 200710118491.X, filed Jul. 6, 2007, and
incorporated by reference herein in its entirety.
TECHNICAL FIELD
[0002] The present invention relates to a composition containing
Rotigotine and the use thereof in the manufacture of a
Rotigotine-containing transdermal patch, wherein said composition
is based on a matrix mixture system formed from a combination of an
acrylic pressure-sensitive adhesive with a silicone
pressure-sensitive adhesive, and polyvinylpyrrolidone which are
present in a particular weight ratio. The present invention further
relates to an improved transdermal patch containing Rotigotine
comprising said composition. Said patch has improved properties in
the solubility, release and initial penetration level of
Rotigotine.
[0003] Background Art
[0004] Rotigotine is a Non-Dihydroergotoxine
D.sub.3/D.sub.2/D.sub.1 dopamine receptor agonist, and long-term
research shows that it has therapeutic effects on a variety of
central nervous system diseases and mental disorders. As currently
known, Rotigotine has superior effects in regard to the treatment
or mitigation of Parkinson's disease, Restless Legs Syndrome,
schizophrenia, depression and the like, and to the preventive
treatment of Parkinson's disease (WO2005/063237). In particular,
the therapeutic and mitigative effects of Rotigotine on Parkinson's
disease are supported by substantive animal model studies and
clinical tests (Neurology, Vol.65 Suppl1: S3-S5/movement disorders
Vol. 9 No.2 P147-154; ARCH NEUROL, Vol.60, December 2003: 1721-28).
Rotigotine was first formulated into oral formulations, but was
then found to exhibit an overly high clearance and a relatively
short duration of action after oral intake. Thus, it could hardly
achieve a therapeutically effective plasma concentration or be
practically used owing to the need for frequent drug administration
(Neurology, Vol.65 Suppl1: S3-S5). Consequently, people tried to
formulate Rotigotine into transdermal patches.
[0005] WO99/49852 describes a transdermal drug delivery system
comprising Rotigotine on the basis of an acrylate or silicone. The
adhesive used in this system is an acrylate or silicone, which
independently of the other, forms a system involving a single
adhesive together with the active drug. The system comprising an
acrylate as adhesive has a low drug release rate; the system
comprising a silicone as adhesive has a small drug load and a
relatively low initial drug release rate.
[0006] WO2002/089778 describes the use of a silicone-based
transdermal therapeutic system in the manufacture of an
anti-Parkinson's disease medicament. This transdermal therapeutic
system comprises Rotigotine as active ingredient. However, said
system has a low drug release rate, and particularly requires too
long a period of time to achieve an effective dosage. Consequently,
there exist the following two problems: 1. the transdermal patch
has to be changed frequently, for example once per 24 hours or
shorter, to achieve an effective plasma concentration, and this is
contrary to the advantage of convenient use of the patch by a
patient; 2. the transdermal patch has a relatively low initial
penetration level such that it takes too long a period of time for
the drug to take effect after the application of the patch, usually
resulting in the delay of the control of a patient's state of
illness.
[0007] The inventors have thoroughly investigated the inherent
disadvantages of the existing Rotigotine transdermal delivery
systems. After a lot of tests, the inventors have found out that a
matrix mixture system formed from a combination of an acrylic
pressure-sensitive adhesive with a silicone pressure-sensitive
adhesive, and polyvinylpyrrolidone which are present in a
particular weight ratio is capable of sufficiently dissolving and
releasing an effective amount of Rotigotine and of increasing the
initial penetration level of Rotigotine. Thus, the Rotigotine
releasing properties of the transdermal delivery system are
improved. The present invention is hence finished.
Contents of the Invention
[0008] The present invention provides a composition containing
Rotigotine, which comprises, on the basis of the weight of the
composition, 60-99%, preferably 70-95%, more preferably 75-90%,
particularly preferably 79-84% by weight, of a matrix mixture
system and 1-40% by weight of Rotigotine, wherein the said matrix
mixture system is formed from a combination of an acrylic
pressure-sensitive adhesive with a silicone pressure-sensitive
adhesive, and polyvinylpyrrolidone which are present in a
particular weight ratio, wherein: [0009] (1) the acrylic
pressure-sensitive adhesive is present in an amount of about 1-25%
by weight in the matrix mixture system, [0010] (2) the silicone
pressure-sensitive adhesive is present in an amount of about 65-98%
by weight in the matrix mixture system, and [0011] (3) the
polyvinylpyrrolidone is present in an amount of about 1-10% by
weight in the matrix mixture system.
[0012] In another aspect, the present invention provides the use of
said composition containing Rotigotine in the manufacture of a
transdermal patch.
[0013] Further still in another aspect, the present invention
provides a transdermal patch containing Rotigotine, with a
characteristic that the drug-containing matrix layer of the patch
is based on a matrix mixture system formed from a combination of an
acrylic pressure-sensitive adhesive with a silicone
pressure-sensitive adhesive, and polyvinylpyrrolidone which are
present in a particular weight ratio, wherein: [0014] (1) the
acrylic pressure-sensitive adhesive is present in an amount of
about 1-25% by weight in the matrix mixture system, [0015] (2) the
silicone pressure-sensitive adhesive is present in an amount of
about 65-98% by weight in the matrix mixture system, and [0016] (3)
the polyvinylpyrrolidone is present in an amount of about 1-10% by
weight in the matrix mixture system, and the drug-containing matrix
layer comprises 1-40% of Rotigotine on the basis of the total
weight of the drug-containing matrix layer.
[0017] In one embodiment, the Rotigotine-containing transdermal
patch of the present invention has a multi-layer complex structure
comprising a backing layer, a drug-containing matrix layer
comprising the active ingredient Rotigotine and a covering layer on
the drug-containing matrix layer, with a characteristic that the
drug-containing matrix layer is based on a matrix mixture system
formed from a combination of an acrylic pressure-sensitive adhesive
with a silicone pressure-sensitive adhesive, and
polyvinylpyrrolidone which are present in a particular weight
ratio, wherein: [0018] (1) the acrylic pressure-sensitive adhesive
is present in an amount of about 1-25% by weight in the matrix
mixture system, [0019] (2) the silicone pressure-sensitive adhesive
is present in an amount of about 65-98% by weight in the matrix
mixture system, and [0020] (3) the polyvinylpyrrolidone is present
in an amount of about 1-10% by weight in the matrix mixture system,
and the drug-containing matrix layer comprises 1-40% of Rotigotine
on the basis of the total weight of the drug-containing matrix
layer.
[0021] In the Rotigotine-containing composition of the present
invention, the acrylic pressure-sensitive adhesive is present in an
amount of preferably about 3-22%, more preferably about 4-20%,
particularly preferably about 5-19%, especially preferably about
6-12.5%, by weight in the matrix mixture system.
[0022] In the Rotigotine-containing composition of the present
invention, the silicone pressure-sensitive adhesive is present in
an amount of preferably about 70-96%, more preferably about 75-95%,
particularly preferably about 79-94%, especially preferably about
86.5-93%, by weight in the matrix mixture system.
[0023] In the Rotigotine-containing composition of the present
invention, the polyvinylpyrrolidone is present in an amount of
preferably about 1-8%, more preferably about 1-5%, particularly
preferably about 1-2%, especially preferably about 1-1.5%, by
weight in the matrix mixture system.
[0024] In the Rotigotine-containing composition of the present
invention, Rotigotine is present in an amount of preferably about
3-20%, more preferably about 5-15%, particularly preferably about
8-11%, on the basis of the total weight of the composition.
[0025] The Rotigotine-containing composition of the present
invention may further optionally comprise auxiliaries commonly used
in transdermal drug delivery systems, such as permeation enhancers
and antioxidants.
[0026] The Rotigotine-containing composition of the present
invention preferably comprises a permeation enhancer, which may be
present in an amount of about 0-15%, preferably about 2-13%, more
preferably about 5-11%, particularly preferably 8-10% on the basis
of the total weight of the composition.
[0027] The Rotigotine-containing composition of the present
invention may comprise an antioxidant, which may be present in an
amount of about 0-0.1% on the basis of the total weight of the
composition.
[0028] In a preferred embodiment of the composition according to
the present invention, the composition comprises, on the basis of
the total weight of the composition, about 70-95%, preferably about
75-90%, of the matrix mixture system, wherein the acrylic
pressure-sensitive adhesive is present in an amount of about 3-22%,
preferably about 4-20%, by weight in the matrix mixture system, the
silicone pressure-sensitive adhesive is present in an amount of
about 70-96%, preferably about 75-95%, by weight in the matrix
mixture system, and the polyvinylpyrrolidone is present in an
amount of about 1-8%, preferably about 1-5%, by weight in the
matrix mixture system; and comprises, on the basis of the total
weight of the composition, about 3-20%, preferably about 5-15% by
weight of Rotigotine and about 0-15%, preferably about 2-13% by
weight of a permeation enhancer.
[0029] In a more preferred embodiment of the composition according
to the present invention, the composition comprises, on the basis
of the total weight of the composition, about 75-90%, particularly
about 79-84%, of the matrix mixture system, wherein the acrylic
pressure-sensitive adhesive is present in an amount of about 5-19%,
particularly about 6-12.5%, by weight in the matrix mixture system,
the silicone pressure-sensitive adhesive is present in an amount of
about 79-94%, particularly about 86.5-93%, by weight in the matrix
mixture system, and the polyvinylpyrrolidone is present in an
amount of about 1-2%, particularly about 1-1.5%, by weight in the
matrix mixture system; and comprises, on the basis of the total
weight of the composition, about 5-15%, particularly about 8-11% of
Rotigotine; and about 5-11%, particularly about 8-10% of a
permeation enhancer.
[0030] The term "an acrylic pressure-sensitive adhesive" according
to the present invention refers to an acrylic pressure-sensitive
polymer and combinations thereof with a Eudragit-type acrylic
resin.
[0031] The term "an acrylic pressure-sensitive polymer" as used
herein, refers to a type of polymers known in the art. Such a type
of polymers is formed by copolymerization of acrylic acids and
derivatives thereof, and has a saturated hydrocarbon backbone and
an ester side chain. A sticky acrylic pressure-sensitive polymer is
obtainable by modifying the co-monomers and side chain groups. The
monomers commonly used include soft monomers such as ethyl
acrylate, 2-ethylhexyl acrylate or isooctyl acrylate, butyl
acrylate and the like, for improving the adhesion of the
pressure-sensitive polymers, hard monomers such as vinyl acetate,
methyl acrylate, styrene, acrylonitrile, C.sub.1-10 alkyl
methacrylate, e.g., methyl methacrylate, ethyl methacrylate and
n-butyl methacrylate and the like, for improving the cohesion of
the pressure-sensitive polymers, and functional monomers such as
(meth)acrylic acid, (meth)acrylamide, .beta.-hydroxyethyl
(meth)acrylate, .beta.-hydroxypropyl (meth)acrylate, glycidyl
(meth)acrylate, N-hydoxylmethylacrylamide, divinylbenzene, maleic
acid, maleic anhydride and the like (YANG Yukun, Pressure-Sensitive
Adhesives, Science Press, June 1994, p.149-150), for forming
chemical cross-links. The acrylic pressure-sensitive polymers used
in the present invention are those particularly preferably
copolymerized from butyl acrylate, isooctyl acrylate, vinyl
acetate, acrylamide and .alpha.-methacrylic acid monomers. In
particular, for example, the copolymer (A) of Example 2 in Table 1
on page 21 of CN1640500A (Beijing Kangbeide Pharmaceuticals Co.,
Ltd), which is incorporated herein in its entirety by reference,
i.e. PAS-10-K, is copolymerized from 33.1% of butyl acrylate, 40.9%
of isooctyl acrylate, 21.0% of vinyl acetate, 3.8% of acrylamide
and 1.2% of .alpha.-methacrylic acid.
[0032] The term "a Eudragit-type acrylic resin", as used herein
refers to, but not limited to, Eudragit.RTM. L100, Eudragit.RTM.
S100, Eudragit.RTM. RL100, Eudragit.RTM. RS100, Eudragit.RTM. E100,
Eudragit.RTM. L100-55, Eudragit.RTM. E PO, Eudragit.RTM. RL PO,
Eudragit.RTM. RS PO and the like produced by Rohm Co. Ltd.
(Germany), and Eudragit Nos. I, II, III and IV produced by Jiangsu
Lianyun'gang Iodine Factory.
[0033] In the present invention, the acrylic pressure-sensitive
adhesive is preferably a mixture of an acrylic pressure-sensitive
polymer with a Eudragit-type acrylic resin, more preferably the
acrylic-based adhesive composition disclosed in CN1640500A (Beijing
Kangbeide Pharmaceuticals Co., Ltd), which consists of an acrylic
pressure-sensitive polymer and Eudragit.RTM. E100 (see the adhesive
composition used in CN1640500A, page 24, Table 4, Example 4), i.e.
an adhesive composition consisting of PAS-10-K and different
percents of Eudragit.RTM. E100, and particularly preferably an
adhesive composition with a PAS-10-K to Eudragit.RTM. E100 ratio of
9:1.
[0034] The silicone pressure-sensitive adhesives according to the
present invention are a type of pressure-sensitive adhesives
prepared by dissolving low-viscosity dimethyl silicone polymers
(12,000 to 15,000 cp) and silicone resins together in a suitable
organic solvent. The ratio of resin to polymer and the silanol
group content are important parameters for the determination of the
properties of the silicone pressure-sensitive adhesives (Sobieski,
et al., "Silicone Pressure Sensitive Adhesives," Handbook of
Pressure Sensitive Technology, 2nd ed., 508-517, Van Nostrand
Reinhold, New York (1989)). In the present invention, the silicone
pressure-sensitive adhesives are preferably commercially available,
including the BIO-PSA.RTM. 4600 series, BIO-PSA.RTM. 4500 series,
BIO-PSA.RTM. 4400 series, BIO-PSA.RTM. 4300 series, BIO-PSA.RTM.
4200 series and BIO-PSA.RTM. 4100 series silicone
pressure-sensitive adhesives sold by Dow Corning Corporation.
Anti-amine silicone pressure-sensitive adhesives of the
BIO-PSA.degree. 4300 series and BIO-PSA.RTM. 4200 series are more
preferred.
[0035] The polyvinylpyrrolidone used in the present invention is
useful as a crystallization inhibitor in transdermal drug delivery
formulations. Polyvinylpyrrolidones or "PVPs" are non-ionic
water-soluble macromolecular compounds formed by polymerization of
N-vinylpyrrolidone under certain conditions. The use of
polyvinylpyrrolidones in transdermal drug delivery formulations is
already mentioned in EP0524776. Suitable PVPs include the products
under the trademark Kollidon produced by BASF. In the present
invention, Kollidon 17PF, 25, 30 and 90 are preferably used, and
Kollidon 30 and Kollidon 90 are particularly preferred.
[0036] The inventors have found out, after conducting a lot of
tests, that a matrix mixture system comprising a combination of an
acrylic pressure-sensitive adhesive with a silicone
pressure-sensitive adhesive in a certain ratio improves the
solubility and skin permeability of the drug significantly, and the
addition of a small amount of polyvinylpyrrolidone further improves
the drug load and penetration level without affecting the
mechanical properties of the patch. Although an increased percent
by weight of the acrylic pressure-sensitive adhesive in the matrix
mixture system increases the solubility and initial dispersion rate
of the drug, it lowers the drug's sustained release ability in the
system, and finally results in a relatively high level of drug
residue after the application of the patch. A decreased percent by
weight of the acrylic pressure-sensitive adhesive in the matrix
mixture system fails to increase the initial dispersion rate of the
drug. Thus, the ratio of the acrylic pressure-sensitive adhesive to
the silicone pressure-sensitive adhesive is within a limited range.
The polyvinylpyrrolidone is a solubility enhancer and
crystallization inhibitor. Anyone with ordinary skill in the art
can determine its suitable amount by conducting conventional tests.
In the system, an excessively high polyvinylpyrrolidone content
will affect the mechanical properties of the patch, and a suitable
amount of polyvinylpyrrolidone can change the dispersion state of
the drug in the system.
[0037] In the transdermal patch containing Rotigotine of the
present invention, the acrylic pressure-sensitive adhesive is
present in an amount of about 1-25%, preferably about 3-22%, more
preferably about 4-20%, particularly preferably about 5-19%,
especially preferably about 6-12.5%, by weight in the matrix
mixture system.
[0038] In the transdermal patch containing Rotigotine of the
present invention, the silicone pressure-sensitive adhesive is
present in an amount of about 65-98%, preferably about 70-96%, more
preferably about 75-95%, particularly preferably about 79-94%,
especially preferably about 86.5-93%, by weight in the matrix
mixture system.
[0039] In the transdermal patch containing Rotigotine of the
present invention, the polyvinylpyrrolidone is present in an amount
of about 1-10%, preferably about 1-8%, more preferably about 1-5%,
particularly preferably about 1-2%, especially preferably about
1-1.5%, by weight in the matrix mixture system.
[0040] In the transdermal patch containing Rotigotine of the
present invention, the Rotigotine is present in an amount of about
1-40%, preferably about 3-20%, more preferably about 5-15%,
particularly preferably about 8-11%, on the basis of the total
weight of the drug-containing matrix layer.
[0041] In the transdermal patch containing Rotigotine of the
present invention, the matrix mixture system is present in an
amount of 60-99%, preferably 70-95%, more preferably 75-90%,
particularly preferably 79-84%, on the basis of the total weight of
the drug-containing matrix layer.
[0042] In the transdermal patch of the present invention, the
drug-containing matrix layer may optionally comprise auxiliaries
commonly used in transdermal drug delivery systems, such as
permeation enhancers, antioxidants and so on, so as to assist to
improve the properties of the patch.
[0043] The transdermal patch of the present invention preferably
comprises a permeation enhancer, which may be present in an amount
of about 0-15%, preferably about 2-13%, more preferably about
5-11%, particularly preferably 8-10% on the basis of the total
weight of the drug-containing matrix layer.
[0044] The transdermal patch of the present invention may comprise
an antioxidant, which may be present in an amount of about 0-0.1%
on the basis of the total weight of the drug-containing matrix
layer.
[0045] In a preferred embodiment of the transdermal patch according
to the present invention, the drug-containing matrix layer of the
transdermal patch comprises, on the basis of the total weight of
the drug-containing matrix layer, about 70-95%, preferably about
75-90%, of the matrix mixture system, wherein the acrylic
pressure-sensitive adhesive is present in an amount of about 3-22%,
preferably about 4-20%, by weight in the matrix mixture system, the
silicone pressure-sensitive adhesive is present in an amount of
about 70-96%, preferably about 75-95%, by weight in the matrix
mixture system, and the polyvinylpyrrolidone is present in an
amount of about 1-8%, preferably about 1-5%, by weight in the
matrix mixture system; and comprises, on the basis of the total
weight of the drug-containing matrix layer, about 3-20%, preferably
about 5-15% of Rotigotine; and about 0-15%, preferably about 2-13%
of a permeation enhancer.
[0046] In a more preferred embodiment of the transdermal patch
according to the present invention, the drug-containing matrix
layer of the transdermal patch comprises, on the basis of the total
weight of the drug-containing matrix layer, about 75-90%,
particularly about 79-84%, of the matrix mixture system, wherein
the acrylic pressure-sensitive adhesive is present in an amount of
about 5-19%, particularly about 6-12.5%, by weight in the matrix
mixture system, the silicone pressure-sensitive adhesive is present
in an amount of about 79-94%, particularly about 86.5-93%, by
weight in the matrix mixture system, and the polyvinylpyrrolidone
is present in an amount of about 1-2%, particularly about 1-1.5%,
by weight in the matrix mixture system; and comprises, on the basis
of the total weight of the drug-containing matrix layer, about
5-15%, particularly about 8-11% of Rotigotine; and about 5-11%,
particularly about 8-10% of a permeation enhancer.
[0047] Permeation enhancers useful in the present invention may be
selected from the group consisting of (1) surfactants, such as
tweens, spans, sodium lauryl sulfate, sodium dodecylsulfate and the
like, (2) organic solvents including alcohols, polyols, esters,
dimethyl sulfoxide and analogues thereof, specific examples may be
mentioned, such as ethyl acetate, propylene glycol diacetate,
glycol, glycerine, dimethyl sulfoxide, decylmethyl sulfoxide etc.,
(3) fatty acids, fatty alcohols and fatty acid esters, such as
oleic acid, lactic acid, myristic acid, lauryl acid, isopropyl
myristate and the like, (4) azones and pyrrolidone derivatives,
such as N-methylpyrrolidone, 1,5-dimethylpyrrolidone,
5-carboxylpyrrolidone and the like, (5) keratinous emollients and
softeners, such as salicylic acid and urea, and (6) terpenes, such
as menthol, camphor and the like. Isopropyl myristate, lauryl acid
and N-methylpyrrolidone are preferred.
[0048] A variety of antioxidants are suitable for use in the
present invention. For example, suitable antioxidants may be
selected from inorganic and organic antioxidants and determined by
conventional stability tests in the art. Said antioxidants may be
selected from, for example, the group consisting of vitamin E,
ascorbyl palmitate, sodium metasulfite or mixtures thereof. Vitamin
E and ascorbyl palmitate are preferred.
[0049] The active ingredient, Rotigotine used in the present
invention may be a free base of Rotigotine or a pharmaceutically
acceptable salt of Rotigotine, such as a hydrochloride, sulfate,
nitrate or succinate of Rotigotine, but a free base of Rotigotine
is preferred.
[0050] In the transdermal patch of the present invention, the
backing layer is made from a backing material well known by those
with skill in the art; such a backing material may be aluminum
foil, polyethylene glycol terephthalate, polyethylene or non-woven
fabric. In the transdermal patch of the present invention, the
covering layer applied on the drug-containing matrix layer is made
from a protective material well known by those with skill in the
art; such a protective material may be a polyester, polyvinyl
chloride or polyethylene glycol terephthalate film, or the
above-mentioned film is treated conventionally with a release
coating, including the application of a silicone resin or fluorine
resin on the surface of the film in direct contact with the
drug-containing matrix layer. The covering layer of the transdermal
patch of the present invention is preferably the polyester film
surface coated with a fluorine resin.
[0051] The transdermal patch of the present invention may be
processed into various shapes and sizes in regard to practical
needs, and its surface area is preferably 1.0-150 cm.sup.2 with
preferred specifications of 4.5 mg Rotigotine/10 cm.sup.2, 9 mg
Rotigotine/20 cm.sup.2, 13.5 mg Rotigotine/30 cm.sup.2, and 18 mg
Rotigotine/40 cm.sup.2.
[0052] The drug-containing matrix layer of the
Rotigotine-containing transdermal patch of the present invention
has a thickness of 20-80 .mu.m, preferably 40-60 .mu.m.
[0053] The drug-containing matrix layer of the
Rotigotine-containing transdermal patch of the present invention
may be in the form of a mono-layer or multi-layer complex
well-known in the art. Such transdermal patch structure may
comprise a backing layer, a high-content active drug Rotigotine
layer and/or an intermediate-content active drug Rotigotine layer,
a low-content active drug Rotigotine layer, and a covering
layer.
[0054] The Rotigotine-containing composition of the present
invention can be prepared by techniques known in the art. For
example, in accordance with the formula, polyvinylpyrrolidone is
weighed into a suitable container, a suitable amount of the
solution of an antioxidant (if present) in ethanol is added, and
the polyvinylpyrrolidone is dissolved by stirring. Into the same
container, Rotigotine, a silicone pressure-sensitive adhesive, an
acrylic pressure-sensitive adhesive (wherein the acrylic
pressure-sensitive polymer is prepared according to the process for
preparing a (meth)acrylate copolymer comprising (meth)acrylamide or
an N,N-substituted monomer thereof as described in the Example on
pages 20-21 of CN1640500A) and an optional permeation enhancer are
added according to the formula, a suitable amount of a solvent,
such as ethyl acetate, is added, and the components are
sufficiently dissolved by stirring. At last, the
polyvinylpyrrolidone is completely dissolved by adding a suitable
amount of ethanol and performing ultrasonic treatment for 30
minutes, and a Rotigotine-containing composition is thus
prepared.
[0055] The transdermal patch of the present invention may be
prepared by techniques known in the art. The techniques comprise
for example, the following steps:
[0056] 1. Adding into a suitable container, polyvinylpyrrolidone
according to the formula, a suitable amount of a solution of an
antioxidant (if present) in ethanol and stirring to dissolve the
polyvinylpyrrolidone;
[0057] 2. Adding into the same container, Rotigotine, a silicone
pressure-sensitive adhesive, an acrylic pressure-sensitive adhesive
(wherein the acrylic pressure-sensitive polymer is prepared
according to the process for preparing a (meth)acrylate copolymer
comprising (meth)acrylamide or an N,N-substituted monomer thereof
as described in the Example on pages 20-21 of CN1640500A) and an
optional permeation enhancer according to the formula, a suitable
amount of a solvent such as ethyl acetate to build up the volume to
a certain level, and stirring to sufficiently dissolve the
components;
[0058] 3. Adding a suitable amount of ethanol and performing
ultrasonic treatment for 30 minutes to completely dissolve the
polyvinylpyrrolidone, at which point the resultant mixture becomes
clear and transparent, hence obtaining the material for the
drug-containing matrix layer of the transdermal patch;
[0059] 4. Finally, applying the resulting material with a certain
thickness on a patulous backing material, primarily drying it by
air, then moving it to an oven where it is dried for 2 hours at
80.degree. C., removing the volatile solvent prior to taking it out
and cooling it, later applying it with a covering layer, and
finally die-cutting it to patches with certain surface areas and
shapes.
[0060] The transdermal patch of the present invention comprising a
drug-containing matrix layer in the form of a multi-layer complex
may be prepared according to a conventional process known in the
art. For example, first of all, matrices comprising the same
concentration or different concentrations of the active drug are
formulated. Then the matrices are respectively applied to a backing
support material and a specially made, protective liner by a
scraper method and dried to take shape. Subsequently, the matrix
layer applied on the protective liner is transferred onto the
matrix layer applied on the backing support material, the
protective liner is removed, the layers are transferred one by one
according to this method and laminated, then a covering layer is
applied onto the laminate, and finally patches comprising a
drug-containing matrix layer in the form of multi-layer complex are
die-cut into certain surface areas and shapes (see LIANG Bingwen,
Transdermal Drug Delivery Formulations, China
Medical-Pharmaceutical Science and Technology Publishing House,
September 1992, p.329-334).
[0061] The present invention provides a transdermal patch
containing Rotigotine which can sufficiently dissolve and release
an effective amount of drug, Rotigotine. This patch has an
increased Rotigotine initial penetration level. Judging from this
feature, it can be predicted that the transdermal patch containing
Rotigotine of the present invention needs a relatively short period
of time to take effect in clinical use.
DESCRIPTION OF THE DRAWING
[0062] FIG. 1 shows the curve of the in vitro transdermal release
amount (.mu.g/cm.sup.2) accumulated from 1 to 72 hours of
Rotigotine in the transdermal patches of Example 1 (the present
invention), NEUPRO.RTM. (Comparative Example 1) and Comparative
Examples 2-5.
EXAMPLES
[0063] The present invention is further illustrated by, but not
limited to, the following Examples.
[0064] Preparation of a Transdermal Patch
Example 1
[0065] Into a suitable container, 0.05 g of polyvinylpyrrolidone
(Kollidon 30 produced by BASF Germany) was added, 1 ml of a
solution of ascorbyl palmitate (produced by Beijing Chen Ao Hi-Tech
Co. Ltd.) in ethanol (3 mg/ml) as antioxidant was added, and the
polyvinylpyrrolidone was dissolved by stirring. Into the same
container, 0.45 g of a Rotigotine base (which was synthesized and
prepared according to the process described in "Synthesis and
radioreceptor binding activity of N-0437, a new, extremely potent
and selective D2 dopamine receptor agonist", Pharm Weekbl Sci,
Vol.7.1985:208-211), 6.25 g of a 30% solid content silicone
pressure-sensitive adhesive (BIO-PSA.RTM. 7-4302 Dow Corning
Corporation), 0.72 g of a 35% solid content acrylic
pressure-sensitive adhesive (which was prepared according to the
process for preparing a (meth)acrylate copolymer comprising
(meth)acrylamide or an N,N-substituted monomer thereof as described
in the Example on pages 20-21 of CN1640500A, wherein the monomer
used in Example 2 was used for the preparation of an acrylic
pressure-sensitive polymer, and the acrylic pressure-sensitive
polymer thus prepared was mixed with Eudragit.RTM. E100 (produced
by Rohm Germany) in a ratio of 9:1 (dry weight)) and 0.5 g of
isopropyl myristate (Jiangsu Kunshan Huaxin Daily Chemicals Co.,
Ltd) was added. A suitable amount of ethyl acetate (produced by
Beijing Organic Chemical Plant, chemically pure) was added to build
up the volume to a certain level, and the components were
sufficiently mixed by stirring. Subsequently, a suitable amount of
ethanol (produced by Beijing Yili Fine Chemical Co., Ltd.,
chemically pure) was added, and ultrasonic treatment was performed
for 30 minutes to completely dissolve the polyvinylpyrrolidone to
form a mucilage. At that time, the mucilage was clear and
transparent. The resulting mucilage was applied with a certain
thickness to a backing material of a patulous polyester film
(SCOTCHPAK.RTM. 1109) to prepare a drug-containing matrix layer,
and then dried at 85.degree. C. for 2 to 3 hours to obtain a
thickness of about 40 pm. A fluorine-containing layer-coated
polyester film (SCOTCHPAK.RTM. 1022) was then applied on the
resulting drug-containing matrix layer, and finally the resultant
layers were die-cut to produce patches having certain surface areas
and sizes, i.e. the transdermal patches of the present invention.
The patches contained 0.45 mg/cm.sup.2 of Rotigotine and the
amounts (parts by weight) of the other components as shown in Table
1.
Examples 2 to 3
[0066] Patches of Examples 2 and 3 were prepared according to the
process described in Example 1 wherein the components of the
drug-containing matrix layer and the amounts thereof (parts by
weight) were as shown in Table 1.
Examples 4 to 8
[0067] Patches of Examples 4-8 were prepared according to the
process described in Example 1, wherein the components of the
drug-containing matrix layer and the amounts thereof (parts by
weight) were as shown in Table 2.
Comparative Example 1
[0068] A commercially available Rotigotine patch NEUPRO.RTM. was
obtained from Schwarz Pharm AG. with a Rotigotine content of 0.45
mg/cm.sup.2
Comparative Examples 2 to 5
[0069] Patches prepared according to the process described in
Example 1: the formula of Comparative Example 2 contained no
silicone pressure-sensitive adhesives, the formula of Comparative
Example 3 contained no acrylic pressure-sensitive adhesive, the
formula of Comparative Example 4 contained no polyvinylpyrrolidone
(the process for the preparation of the patch of Comparative
Example 4 did not have the step of dissolving
polyvinylpyrrolidone), and the amounts of the acrylic and silicone
pressure-sensitive adhesives in the formula of Comparative Example
5 were beyond the ranges of the present invention. The specific
formulae of the drug-containing matrix layers of these patches are
as shown in Table 1.
Measurement of the Release amount of Rotigotine in the Transdermal
Patches
[0070] The above-mentioned patches were subjected to in vitro
transdermal tests according to the experimental methods introduced
by the Transdermal Drug Delivery Formulations (LIANG Bingwen, China
Medical--Pharmaceutical Science and Technology Publishing House,
September 1992, p.252).
[0071] Experimental Apparatus: FRANZ-type transdermal diffuser
(Model: TK-60B, Shanghai Kaikai Technology&Trade Co., Ltd.)
[0072] Experimental Carrier: freshly prepared whole-thickness skin
from the rib part and back of a guinea pig (prepared according to
the Transdermal Drug Delivery Formulations, LIANG Bingwen, China
Medical--Pharmaceutical Science and Technology Publishing House,
September 1992, p.252)
[0073] Number of Samples: 5 (five samples for each tested subject
of the patches of the Examples or Comparative Examples)
[0074] Patch Surface Area: 10 cm.sup.2
[0075] Diffusion Medium: a phosphate buffer of pH 6.2
[0076] Measuring Method: high-performance liquid chromatography (UV
detector, Waters, Model: 2487)
[0077] The 1-72 hours accumulative release amounts (.mu.g/cm.sup.2)
of Rotigotine in the patches of Example 1 and Comparative Examples
1-5 were measured, and the results are as shown in FIG. 1. The 0-12
hours accumulative release amounts (.mu.g/cm.sup.2) of Rotigotine
in the patches of Examples 1-3 and Comparative Examples 2-5 are as
shown in Table 1.
TABLE-US-00001 TABLE 1 Example Example Example Comparative
Comparative Comparative Comparative Drug-containing 1 2 3 Example 2
Example 3 Example 4 Example 5 matrix layer Parts by weight Acrylic
pressure- 5 10 15 80 -- 5 50 sensitive adhesive Silicone pressure-
75 70 65 -- 80 75 30 sensitive adhesive (BIO-PSA .RTM. 7-4302)
Polyvinylpyrrolidone 1 1 1 1 1 -- 1 (Kollidon 30) Rotigotine base 9
9 9 9 9 9 9 Isopropyl myristate 10 10 10 10 10 11 10 Ascorbyl
palmitate 0.0006 0.0006 0.0006 0.0006 0.0006 0.0006 0.0006 0-12
hours accumulative 226.7 221.4 210.3 86.3 181.4 117.7 144.7 release
amounts (.mu.g/cm.sup.2) of Rotigotine
[0078] Note: All the Examples and Comparative Examples (including
the test sample of NEUPRO.RTM. of Comparative Example 1) contain
the same amount of Rotigotine (0.45 mg/cm.sup.2) to ensure the
comparability of the experimental results.
TABLE-US-00002 TABLE 2 Drug-containing Example 4 Example 5 Example
6 Example 7 Example 8 Matrix layer Parts by weight Acrylic
pressure- 5 5 5 5 5 sensitive adhesive Silicone pressure- 93 84 70
65 65 sensitive adhesive (BIO-PSA .RTM. 7-4302)
Polyvinylpyrrolidone 1 1 2 2 2 (Kollidon 30) Rotigotine base 1 5 15
18 25 Isopropyl myristate 0 5 8 10 3 Ascorbyl palmitate 0.0006
0.0006 0.0006 0.0006 0.0006
[0079] It can be seen from FIG. 1 that Example 1 of the present
invention had a higher transdermal release amount than NEUPRO.RTM.
and the patches of the other Comparative Examples, and showed the
characteristic of zero-order release. More importantly, it can be
seen from FIG. 1 that the transdermal patches of the present
invention had a significantly increased drug penetration level
within the initial 12 hours of diffusion, which means that the
patches took effect faster. It can be seen from FIG. 1 and Table 1
that the transdermal patches of the present invention exhibited
unique advantages of Rotigotine transdermal rate over the patches
of Comparative Examples 2-5, and had the properties of a longer
duration and a uniform drug release.
* * * * *