Title of Invention	POLYMERIC ADHESIVE MATRIX WITH SALIFIED CARBOXYLIC GROUPS FOR TRANSDERMAL USE
Abstract	Polymeric matrices for the controlled release of medicaments for the topical transdermal use comprising copolymers of acrylic and/or methacrylic acid or esters thereof having a Tg lower than 0°C, whose free carboxy groups are salified with compatible organic or inorganic bases. The matrices of the invention allow to prepare therapeutical systems for the controlled-release of active principles through the transdermal route, thus solving stability, solubility and/or bioavailability problems of the active ingredient within the matrix.

Title of Invention

POLYMERIC ADHESIVE MATRIX WITH SALIFIED CARBOXYLIC GROUPS FOR TRANSDERMAL USE

Abstract

Polymeric matrices for the controlled release of medicaments for the topical transdermal use comprising copolymers of acrylic and/or methacrylic acid or esters thereof having a Tg lower than 0°C, whose free carboxy groups are salified with compatible organic or inorganic bases. The matrices of the invention allow to prepare therapeutical systems for the controlled-release of active principles through the transdermal route, thus solving stability, solubility and/or bioavailability problems of the active ingredient within the matrix.

Full Text	The present invention relates to a polymeric matrix for the conlrolled-release of medicaments for the topical transdermal use, which matrix improves the solubility and the stability of the active ingredient. Technological background Controlled-releasc therapeutical systems (based on a matrix) for the transdermal administration arc prepared by incorporation of an active ingredient (active principle) in a polymeric matrix, which acts both as adhesive and 'container" for the medicament. For this reason, a polymeric matrix must satisfy a series of specific requirements: • ability to dissolve (he active principle at the desired concentrations; • absence of chemical interactions with the active principle, so as to avoid degradation or alteration; • ability to allow the diffusion of the active principle towards the corneous layer; • absence of irritation or erythema at the application site; • ability to ensure adhesion of the system to the skin during the whole treatment period. The matrices arc made from solutions of adhesive polymers also referred to as "pressure sensitive adhesives". The most commonly used polymers are of acrylic type and are commercially available in the form of powders, granules, aqueous or solvent solutions. In general, the polymers used for pharmaceutical formulations belong to two classes, those with a glass transition temperature (Tg) higher than room temperature (or use temperature) and those with a Tg lower than room temperature. The former need plasticizers to be used in the formulation of transdermal patches, while the latter can be used as such, since they already have a soft consistency. For this reason, polymers with a Tg preferred, even if, due to their properties, they are commercialised dissolved in organic solvents. Many of these polymers are copolymers of acrylic or methacrylic acid and/or esters thereof, therefore the polymer chains contain acidic functions which can interact with the active principle causing oxidation and/or degradation of the active principle. U.S. 6,689,379 discloses transdermal therapeutic systems comprising a pressure-sensitive adhesive polymer having acrylic or methacrylic acid units in form of alkali or alkaline earth salts. FR 2719770 discloses transdermal formulations of ibuprofen comprising a mixture of acrylate copolymers and diethylphtalates. Other transdermal systems are disclosed in US 2003/0129220, US 2001/0038861, EP 0394956, WO 03/086370, US 2004/010054. It has now been found that matrix-based therapeutical systems for the controlled release of medicaments can be prepared by suitably salifying the free carboxy groups of the polymer chains of macromolecules mixtures having a lower Tg. 15 Disclosure of the invention The invention relates to a polymeric matrix for the controlled release of medicaments for the topical transdermal use, which matrix comprises copolymers of acrylic or methacrylic acid and/or esters thereof having a Tg lower than 0°C and wherein the free carboxy groups are salified with 20 compatible organic or inorganic bases. The copolymers that can be used according to the invention consist of two or more monomers in various percentages. Examples of said monomers comprise: • acrylic acid 25 • butyl acrylate • 2-ethylhexyl acrylate • glycidyl methacrylate • 2-hydroxyethyl acrylate • methyl acrylate • vinyl acetate • t-octylacrylamide Examples of copolymers according to the invention comprise poly(2- ethyl-hexyl acrylate-co-acrylic acid), poly(2-hydroxy-ethyl acrylate-co- acrylic acid -co-methyl-acrylates), poly(2-ethyl-hexyl acrylate-co-acrylic acid- co-methylacrylate), poly(2-ethyl-hexyl acrylate-co-acrylic acid-co- butilacrylate-co-vinyl acetate). These copolymers are commercially available with the following trade names: Duro-tak® (National and Starch), MG-0607® (Dow Corning), Gelva® (UCB chemicals), Luvimer® (BASF). These acrylic or methacrylic copolymers have a percentage of free carboxy groups of 0.1-15%, preferably 1-10%. Since they are not hot-extrudable, they are commercialised dissolved in organic solvents. The bases with which the carboxy groups are salified can be either inorganic, for example alkali, alkaline-earth or transition metals hydroxides, carbonates or bicarbonates, or organic, for example ammonia, ammonium methyl acrylates copolymers, ethylenediamine, lysine. The matrices of the invention further comprise from 0.1 to 20% by weight of water, preferably 1 to 5%. The invention allows to formulate any active ingredient having therapeutical, dermatological or cosmetic activity when administered through topical and/or transdermal route. Examples of medicaments which can be advantageously formulated according to the invention comprise: non steroidal antiinflammatory agents, corticosteroids, local anaesthetics, alpha-adrenergic agonists, analgesics, antimigraine drugs, anti-allergies, antihistaminics, antimicrobials, antiemetics, anticholinergics, bronchodilators, antivirals, myorelaxants, cholinergic agents, central nervous system stimulators, cardioactive agents, beta-adrenergic agonists, hormones, anxiolytics, antidepressants, antipsychotics, opioid antagonists, coronary dilators. Particularly preferred are non steroidal antiinflammatories such as Diclofenac, Fenoprofen, Flurbiprofen, Ibuprofen, Ibuproxam, Indoprofen, Ketoprofen, Ketorolac, Naproxen, Oxametacine, Oxyphenbutazone, Piroxicam, Suprofen, Celecoxib and other COX-2 selective inhibitors and the like. The matrices of the invention are particularly suitable as adhesive layers in transdermal patches. A further object of the invention is a process for the preparation of transdermal matrices which comprises the treatment of a copolymer having a Tg lower than 0°C and free carboxy groups suspended in an organic solvent with an aqueous solution of organic or inorganic bases in stoichiometric amounts in respect of the carboxylic groups, followed by addition of the active ingredient and any other excipients. By indicating Tg lower than 0°C, it is meant that the chosen polymeric solutions should be liquid at room temperature so that they could be easily handled being in liquid form. As polymeric blends are usually not strictly defined even by their manufacturer, Tg can vary for the real composition and the amount of solids. The organic solvents may be selected from ethyl acetate, IsopropanoL, methanol, toluene, hexane, heptane, which are the most representative solvents used in the manufacture of adhesive blends. Active ingredients are the ones, as indicated hereinbefore, in particular anti- inflammatories and antihypertensives. The matrices of the invention allow to improve the solubility, the stability and the diffusion of the active principle from the matrix. Detailed disclosure of the invention 20 The polymeric matrix in the final formulation can be present in an amount ranging from 20 to 95%, preferably from 50 to 90%, based on the dry weight of the final composition. The acidic groups are neutralized with stoichiometric amounts of inorganic (alkali and transition metal hydroxides, e.g. sodium hydroxide, 25 potassium hydroxide) or organic (e.g. ammonia, ammonium methyl acrylate copolymers, ethylenediamine, lysine) bases in the presence of a suitable amount of demineralised water to promote ion-exchange between the acidic groups of the polymeric structure and the basic counter-ion in a solvent system. Water is used in an amount that forms the solvatation sphere of the free ions without destabilizing the solvent system, so as to prevent precipitation of the polymer. The polymeric matrix, at first solvent-based, is transformed according to the invention into a solvent/water-based mixture. The amount of water ranges from 0.1 to 20%, preferably from 1 to 5% based on the wet weight of the adhesive mixture. In this way the acidic functions are neutralised and interactions with the active principle are avoided. The active principle dissolves completely at high concentrations in this system through synergistic interaction of the polymeric matrix, the solvent and the ion exchanges promoted by water protons. The amount of active principle incorporated in the system varies according to the nature of the active principle and the desired therapeutical effect. Usually, the amount of active principle ranges from 0.1 to 50%, preferably from 0.1 to 30% based on the dry weight of the final composition. After drying, the polymeric matrix that contains the active principle forms a controlled-release therapeutical system for the topical use. This matrix promotes the diffusion of the active principle, as the salification of the acidic groups in the polymeric chains makes the matrix structure more hydrophilic. The formulation can contain one or more excipients having different functions, for example skin-emollients, percutaneous permeation enhancers, preservatives and the like. The amount of each excipient varies within broad ranges, for example from 0.01 to 30%, and according to their action. Preservatives are usually comprised in the final formulation in amounts of 0.01-2%, whereas emollients are comprised in the final formulation in amounts of 5-20%. The invention is illustrated in greater detail in the following examples. Example 1 1 kg of Durotak® 87-2852 (poly(2-ethyl hexyl acrylate-co-acrylic acid- co-methyl acrylate)), having a solid content of 33.5% w/w, is added under mechanical stirring with 62 g of a 32% w/w potassium hydroxide aqueous solution; the mixture becomes more viscous and is left under moderate stirring for 30 min. Thereafter, 90 g of Diclofenac are added, and stirring is continued until complete dissolution. For the preparation of the matrix layer, the mixture is spread on a film of silicon polyester and the solvents are evaporated off in a static drier, heating at 60°C for 20 min. The spread matrix has a dry weight of about 50 g/m2. After coupling to a polyethylene film, the patch is formed with a suitable punch. Example 2 1 kg of Durotak® 87-2051 (poly(2-ethyl-hexyl acrylate-co-acrylic acid- co-butyl acrylate-co-vinyl acetate)), having a solid content of 51% w/w, is added under mechanical stirring with 64 g of a 32% w/w potassium hydroxide aqueous solution; the mixture becomes more viscous and is left under moderate stirring for 30 min. Thereafter, 90 g of Ketoprofen are added, and stirring is continued until complete dissolution. For the preparation of the matrix layer, the mixture is spread on a film of silicon polyester and the solvents are evaporated off in a static drier, heating at 60°C for 20 min. The spread matrix has a dry weight of about 60 g/m2. After coupling to a polyethylene film, the patch is formed with a suitable punch. Example 3 .1 kg of Durotak® 87-2852, having a content solid of 33.5% w/w, is added under mechanical stirring with 300 g of a 30%w/w Eudragit E100 water/solvent-based solution; the mixture becomes more viscous and is left under moderate stirring for 30 min. Thereafter, 100 g of Diclofenac are added, and stirring is continued until complete dissolution. For the preparation of the matrix layer, the mixture is spread on a film of silicon polyester and the solvents are evaporated off in a static drier, heating at 60°C for 20 min. The spread matrix has a dry weight of about 60 g/m2. After coupling to a polyethylene film, the patch is formed with a suitable punch. WE CLAIM: 1. A polymeric matrix for the controlled release of medicaments for the topical transdermal use comprising copolymers of acrylic or methacrylic acid and/or esters thereof having a Tg lower than 0°C, wherein the free carboxy groups are salified with stoichiometric amounts of ammonia, ammonium methyl-acrylate copolymers, ethylenediamine, lysine. 2. A matrix as claimed in claim 1, wherein the copolymers are selected from poly(2-ethyl- hexyl acrylate-co-acrylic acid), poly(2-hydroxy ethylacrylate-co- acrylic acid-co-methyl ac- rylates), poly(2-ethyl-hexyl acrylate-co-acrylic acid-co-methyl acrylates), poly(2-ethyl-hexyl ac- rylate-co-acrylic acid-co-butyl acrylate-co-vinyl acetate). 3. A matrix as claimed in claim 1 or 2, wherein the acrylic or methacrylic copolymers have a percentage of free carboxy groups ranging from 0.1 to 15%. 4. A matrix as claimed in claim 3, wherein the acrylic or methacrylic copolymers have a per- centage of free carboxy groups ranging from 1 to 10%. 5. A matrix as claimed in any one of claims 1 to 4, containing 0.1 to 20% by weight of water. 6. A matrix as claimed in claim 5, containing 1 to 5% by weight of water. 7. A matrix as claimed in any one of claims 1 to 6, as adhesive layer in a transdermal patch. 8. A process for the preparation of the matrices as claimed in any of claims 1 to 7, which process comprises the treatment of a copolymer having a Tg lower than 0°C and free carboxylic groups suspended in an organic solvent, such as herein described, with an aqueous solution of ammonia, ammonium methyl-acrylate copolymers, ethylenediamine, lysine in stoichiometric amounts in respect of the carboxylic groups, followed by addition of the active ingredient and any other excipients, such as herein described. Polymeric matrices for the controlled release of medicaments for the topical transdermal use comprising copolymers of acrylic and/or methacrylic acid or esters thereof having a Tg lower than 0°C, whose free carboxy groups are salified with compatible organic or inorganic bases. The matrices of the invention allow to prepare therapeutical systems for the controlled-release of active principles through the transdermal route, thus solving stability, solubility and/or bioavailability problems of the active ingredient within the matrix.

Full Text

The present invention relates to a polymeric matrix for the
conlrolled-release of medicaments for the topical transdermal use, which
matrix improves the solubility and the stability of the active ingredient.
Technological background
Controlled-releasc therapeutical systems (based on a matrix) for the
transdermal administration arc prepared by incorporation of an active
ingredient (active principle) in a polymeric matrix, which acts both as
adhesive and 'container" for the medicament.
For this reason, a polymeric matrix must satisfy a series of specific
requirements:
• ability to dissolve (he active principle at the desired concentrations;
• absence of chemical interactions with the active principle, so as to
avoid degradation or alteration;
• ability to allow the diffusion of the active principle towards the
corneous layer;
• absence of irritation or erythema at the application site;
• ability to ensure adhesion of the system to the skin during the whole
treatment period.
The matrices arc made from solutions of adhesive polymers also
referred to as "pressure sensitive adhesives".
The most commonly used polymers are of acrylic type and are
commercially available in the form of powders, granules, aqueous or solvent
solutions.
In general, the polymers used for pharmaceutical formulations belong to
two classes, those with a glass transition temperature (Tg) higher than room
temperature (or use temperature) and those with a Tg lower than room
temperature. The former need plasticizers to be used in the formulation of
transdermal patches, while the latter can be used as such, since they already
have a soft consistency. For this reason, polymers with a Tg preferred, even if, due to their properties, they are commercialised dissolved
in organic solvents.
Many of these polymers are copolymers of acrylic or methacrylic acid
and/or esters thereof, therefore the polymer chains contain acidic functions
which can interact with the active principle causing oxidation and/or
degradation of the active principle.
U.S. 6,689,379 discloses transdermal therapeutic systems comprising a pressure-sensitive
adhesive polymer having acrylic or methacrylic acid units in form of alkali or alkaline earth salts.
FR 2719770 discloses transdermal formulations of ibuprofen comprising a mixture of
acrylate copolymers and diethylphtalates.
Other transdermal systems are disclosed in US 2003/0129220, US 2001/0038861, EP
0394956, WO 03/086370, US 2004/010054.
It has now been found that matrix-based therapeutical systems for the
controlled release of medicaments can be prepared by suitably salifying the
free carboxy groups of the polymer chains of macromolecules mixtures having
a lower Tg.
15 Disclosure of the invention
The invention relates to a polymeric matrix for the controlled release of
medicaments for the topical transdermal use, which matrix comprises
copolymers of acrylic or methacrylic acid and/or esters thereof having a Tg
lower than 0°C and wherein the free carboxy groups are salified with
20 compatible organic or inorganic bases.
The copolymers that can be used according to the invention consist of
two or more monomers in various percentages.
Examples of said monomers comprise:
• acrylic acid
25 • butyl acrylate
• 2-ethylhexyl acrylate
• glycidyl methacrylate
• 2-hydroxyethyl acrylate
• methyl acrylate
• vinyl acetate
• t-octylacrylamide
Examples of copolymers according to the invention comprise poly(2-
ethyl-hexyl acrylate-co-acrylic acid), poly(2-hydroxy-ethyl acrylate-co-
acrylic acid -co-methyl-acrylates), poly(2-ethyl-hexyl acrylate-co-acrylic acid-
co-methylacrylate), poly(2-ethyl-hexyl acrylate-co-acrylic acid-co-
butilacrylate-co-vinyl acetate).
These copolymers are commercially available with the following trade
names: Duro-tak® (National and Starch), MG-0607® (Dow Corning),
Gelva® (UCB chemicals), Luvimer® (BASF).
These acrylic or methacrylic copolymers have a percentage of free
carboxy groups of 0.1-15%, preferably 1-10%. Since they are not
hot-extrudable, they are commercialised dissolved in organic solvents.
The bases with which the carboxy groups are salified can be either
inorganic, for example alkali, alkaline-earth or transition metals hydroxides,
carbonates or bicarbonates, or organic, for example ammonia, ammonium
methyl acrylates copolymers, ethylenediamine, lysine.
The matrices of the invention further comprise from 0.1 to 20% by
weight of water, preferably 1 to 5%.
The invention allows to formulate any active ingredient having
therapeutical, dermatological or cosmetic activity when administered through
topical and/or transdermal route.
Examples of medicaments which can be advantageously formulated
according to the invention comprise: non steroidal antiinflammatory agents,
corticosteroids, local anaesthetics, alpha-adrenergic agonists, analgesics,
antimigraine drugs, anti-allergies, antihistaminics, antimicrobials, antiemetics,
anticholinergics, bronchodilators, antivirals, myorelaxants, cholinergic agents,
central nervous system stimulators, cardioactive agents, beta-adrenergic
agonists, hormones, anxiolytics, antidepressants, antipsychotics, opioid
antagonists, coronary dilators.
Particularly preferred are non steroidal antiinflammatories such as
Diclofenac, Fenoprofen, Flurbiprofen, Ibuprofen, Ibuproxam, Indoprofen,
Ketoprofen, Ketorolac, Naproxen, Oxametacine, Oxyphenbutazone,
Piroxicam, Suprofen, Celecoxib and other COX-2 selective inhibitors and the
like.
The matrices of the invention are particularly suitable as adhesive
layers in transdermal patches.
A further object of the invention is a process for the preparation of
transdermal matrices which comprises the treatment of a copolymer having a
Tg lower than 0°C and free carboxy groups suspended in an organic solvent
with an aqueous solution of organic or inorganic bases in stoichiometric
amounts in respect of the carboxylic groups, followed by addition of the active
ingredient and any other excipients.
By indicating Tg lower than 0°C, it is meant that the chosen polymeric solutions should
be liquid at room temperature so that they could be easily handled being in liquid form. As
polymeric blends are usually not strictly defined even by their manufacturer, Tg can vary for
the real composition and the amount of solids.
The organic solvents may be selected from ethyl acetate, IsopropanoL, methanol, toluene,
hexane, heptane, which are the most representative solvents used in the manufacture of
adhesive blends.
Active ingredients are the ones, as indicated hereinbefore, in particular anti-
inflammatories and antihypertensives.
The matrices of the invention allow to improve the solubility, the
stability and the diffusion of the active principle from the matrix.
Detailed disclosure of the invention
20 The polymeric matrix in the final formulation can be present in an
amount ranging from 20 to 95%, preferably from 50 to 90%, based on the dry
weight of the final composition.
The acidic groups are neutralized with stoichiometric amounts of
inorganic (alkali and transition metal hydroxides, e.g. sodium hydroxide,
25 potassium hydroxide) or organic (e.g. ammonia, ammonium methyl acrylate
copolymers, ethylenediamine, lysine) bases in the presence of a suitable amount
of demineralised water to promote ion-exchange between the acidic groups of the
polymeric structure and the basic counter-ion in a solvent system.
Water is used in an amount that forms the solvatation sphere of the free
ions without destabilizing the solvent system, so as to prevent precipitation of
the polymer. The polymeric matrix, at first solvent-based, is transformed
according to the invention into a solvent/water-based mixture. The amount of
water ranges from 0.1 to 20%, preferably from 1 to 5% based on the wet
weight of the adhesive mixture.
In this way the acidic functions are neutralised and interactions with the
active principle are avoided.
The active principle dissolves completely at high concentrations in this
system through synergistic interaction of the polymeric matrix, the solvent and
the ion exchanges promoted by water protons. The amount of active principle
incorporated in the system varies according to the nature of the active
principle and the desired therapeutical effect.
Usually, the amount of active principle ranges from 0.1 to 50%,
preferably from 0.1 to 30% based on the dry weight of the final composition.
After drying, the polymeric matrix that contains the active principle forms a
controlled-release therapeutical system for the topical use. This matrix
promotes the diffusion of the active principle, as the salification of the acidic
groups in the polymeric chains makes the matrix structure more hydrophilic.
The formulation can contain one or more excipients having different
functions, for example skin-emollients, percutaneous permeation enhancers,
preservatives and the like. The amount of each excipient varies within broad
ranges, for example from 0.01 to 30%, and according to their action.
Preservatives are usually comprised in the final formulation in amounts of
0.01-2%, whereas emollients are comprised in the final formulation in
amounts of 5-20%.
The invention is illustrated in greater detail in the following examples.
Example 1
1 kg of Durotak® 87-2852 (poly(2-ethyl hexyl acrylate-co-acrylic acid-
co-methyl acrylate)), having a solid content of 33.5% w/w, is added under
mechanical stirring with 62 g of a 32% w/w potassium hydroxide aqueous
solution; the mixture becomes more viscous and is left under moderate stirring
for 30 min.
Thereafter, 90 g of Diclofenac are added, and stirring is continued until
complete dissolution.
For the preparation of the matrix layer, the mixture is spread on a film
of silicon polyester and the solvents are evaporated off in a static drier,
heating at 60°C for 20 min. The spread matrix has a dry weight of about
50 g/m2. After coupling to a polyethylene film, the patch is formed with a
suitable punch.
Example 2
1 kg of Durotak® 87-2051 (poly(2-ethyl-hexyl acrylate-co-acrylic acid-
co-butyl acrylate-co-vinyl acetate)), having a solid content of 51% w/w, is
added under mechanical stirring with 64 g of a 32% w/w potassium hydroxide
aqueous solution; the mixture becomes more viscous and is left under
moderate stirring for 30 min.
Thereafter, 90 g of Ketoprofen are added, and stirring is continued until
complete dissolution.
For the preparation of the matrix layer, the mixture is spread on a film of
silicon polyester and the solvents are evaporated off in a static drier, heating at
60°C for 20 min. The spread matrix has a dry weight of about 60 g/m2. After
coupling to a polyethylene film, the patch is formed with a suitable punch.
Example 3
.1 kg of Durotak® 87-2852, having a content solid of 33.5% w/w, is
added under mechanical stirring with 300 g of a 30%w/w Eudragit E100
water/solvent-based solution; the mixture becomes more viscous and is left
under moderate stirring for 30 min.
Thereafter, 100 g of Diclofenac are added, and stirring is continued
until complete dissolution.
For the preparation of the matrix layer, the mixture is spread on a film
of silicon polyester and the solvents are evaporated off in a static drier,
heating at 60°C for 20 min. The spread matrix has a dry weight of about 60
g/m2. After coupling to a polyethylene film, the patch is formed with a
suitable punch.
WE CLAIM:
1. A polymeric matrix for the controlled release of medicaments for the topical transdermal
use comprising copolymers of acrylic or methacrylic acid and/or esters thereof having a Tg lower
than 0°C, wherein the free carboxy groups are salified with stoichiometric amounts of ammonia,
ammonium methyl-acrylate copolymers, ethylenediamine, lysine.
2. A matrix as claimed in claim 1, wherein the copolymers are selected from poly(2-ethyl-
hexyl acrylate-co-acrylic acid), poly(2-hydroxy ethylacrylate-co- acrylic acid-co-methyl ac-
rylates), poly(2-ethyl-hexyl acrylate-co-acrylic acid-co-methyl acrylates), poly(2-ethyl-hexyl ac-
rylate-co-acrylic acid-co-butyl acrylate-co-vinyl acetate).
3. A matrix as claimed in claim 1 or 2, wherein the acrylic or methacrylic copolymers have a
percentage of free carboxy groups ranging from 0.1 to 15%.
4. A matrix as claimed in claim 3, wherein the acrylic or methacrylic copolymers have a per-
centage of free carboxy groups ranging from 1 to 10%.
5. A matrix as claimed in any one of claims 1 to 4, containing 0.1 to 20% by weight of water.
6. A matrix as claimed in claim 5, containing 1 to 5% by weight of water.
7. A matrix as claimed in any one of claims 1 to 6, as adhesive layer in a transdermal patch.
8. A process for the preparation of the matrices as claimed in any of claims 1 to 7, which process
comprises the treatment of a copolymer having a Tg lower than 0°C and free carboxylic groups
suspended in an organic solvent, such as herein described, with an aqueous solution of ammonia,
ammonium methyl-acrylate copolymers, ethylenediamine, lysine in stoichiometric amounts in respect
of the carboxylic groups, followed by addition of the active ingredient and any other excipients, such as
herein described.

Polymeric matrices for the controlled release of medicaments for the topical transdermal use comprising copolymers
of acrylic and/or methacrylic acid or esters thereof having a Tg lower than 0°C, whose free carboxy groups are salified with
compatible organic or inorganic bases. The matrices of the invention allow to prepare therapeutical systems for the controlled-release
of active principles through the transdermal route, thus solving stability, solubility and/or bioavailability problems of the active
ingredient within the matrix.

Documents:

00417-kolnp-2007-assignment.pdf

00417-kolnp-2007-claims-1.1.pdf

00417-kolnp-2007-correspondence-1.1.pdf

00417-kolnp-2007-international search authority report-1.1.pdf

0417-kolnp-2007-abstract.pdf

0417-kolnp-2007-claims.pdf

0417-kolnp-2007-correspondence others.pdf

0417-kolnp-2007-description (complete).pdf

0417-kolnp-2007-form1.pdf

0417-kolnp-2007-form3.pdf

0417-kolnp-2007-form5.pdf

0417-kolnp-2007-international publication.pdf

0417-kolnp-2007-international search authority report.pdf

0417-kolnp-2007-pct form.pdf

0417-kolnp-2007-priority document.pdf

417-KOLNP-2007-ABSTRACT 1.1.pdf

417-KOLNP-2007-AMANDED CLAIMS.pdf

417-KOLNP-2007-ASSIGNMENT.pdf

417-KOLNP-2007-CORRESPONDENCE.pdf

417-KOLNP-2007-DESCRIPTION (COMPLETE) 1.1.pdf

417-KOLNP-2007-EXAMINATION REPORT REPLY RECIEVED.pdf

417-KOLNP-2007-EXAMINATION REPORT.pdf

417-KOLNP-2007-FORM 1-1.1.pdf

417-kolnp-2007-form 18.pdf

417-KOLNP-2007-FORM 2.pdf

417-KOLNP-2007-FORM 3-1.1.pdf

417-KOLNP-2007-FORM 3.pdf

417-KOLNP-2007-FORM 5.pdf

417-KOLNP-2007-GPA.pdf

417-KOLNP-2007-GRANTED-ABSTRACT.pdf

417-KOLNP-2007-GRANTED-CLAIMS.pdf

417-KOLNP-2007-GRANTED-DESCRIPTION (COMPLETE).pdf

417-KOLNP-2007-GRANTED-FORM 1.pdf

417-KOLNP-2007-GRANTED-FORM 2.pdf

417-KOLNP-2007-GRANTED-SPECIFICATION.pdf

417-KOLNP-2007-OTHERS 1.1.pdf

417-KOLNP-2007-OTHERS.pdf

417-KOLNP-2007-PA.pdf

417-KOLNP-2007-PETITION UNDER RULE 137.pdf

417-KOLNP-2007-REPLY TO EXAMINATION REPORT 1.1.pdf

417-KOLNP-2007.pdf

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Patent Number

250276

Indian Patent Application Number

417/KOLNP/2007

PG Journal Number

51/2011

Publication Date

23-Dec-2011

Grant Date

21-Dec-2011

Date of Filing

05-Feb-2007

Name of Patentee

BOUTY S.P.A.

Applicant Address

VIA VANVIETELLI, 4 I-20129, MILANO

Inventors:

#	Inventor's Name	Inventor's Address
1	STEFANELLI, PAOLA	VIALE MONTENARO, 46 I-20135,MILANO
2	DI GRIGOLI, MAURIZIO	VIA DEGLI ACERI ROSSI,5 I-20050 , VEDUGGIO CON COLZANO
3	ROMELLI, PIERBRUNO	VIA PERFETTI, 1 I-20017, RHO
4	SCARSETTO, ALBERTO	VIA PICASSO, 26, I-20092 CINISELLO BALSAMO

PCT International Classification Number

A61K 9/70, A61K31/00

PCT International Application Number

PCT/EP2005/007293

PCT International Filing date

2005-07-06

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	MI2004A 001628	2004-08-06	Italy