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.

Claims

1. Topical transdermal controlled release systems of medicaments consisting of: a polymeric matrix for said controlled release of said medicaments, said polymeric matrix comprising copolymers of acrylic or metacrylic acid and/or esters thereof having a Tg lower than 0 C., wherein the free carboxylic groups are salified with stoichiometric amounts of compatible organic bases, the organic bases comprising at least one ammonia, amino methyl-acrylate copolymers, ethylenediamine, and lysine.

2. The system as claimed in claim 1, wherein the copolymers are selected from poly(2-ethyl-hexyl acrylate-co-acrylic acid), poly(2-hydroxy ehtylacrylate-co-acrylic acid-co-methyl acrylates), poly(2-ethyl-hexyl acrylate-co-acrylic acid-co-methyl acrylates), poly(2-ethyl-hexyl acrylate-co-acrylic acid-co-butyl acrylate-co-vinyl acetate).

3. The system as claimed in claim 1, wherein the acrylic or methacrylic copolymers have a percentage of free carboxy groups ranging from 0.1 to 15%.

4. The system as claimed in claim 3 wherein the acrylic or methacrylic copolymers have a percentage of free carboxy groups ranging from 1 to 10%.

5. Topical transdermal controlled release systems of medicaments consisting of: 0.1 to 20% by weight of water, and a polymeric matrix for said controlled release of said medicaments, said polymeric matrix comprising copolymers of acrylic or metacrylic acid and/or esters thereof having a Tg lower than 0 C., wherein the free carboxylic groups are salified with stoichiometric amounts of compatible organic bases, the organic bases comprising at least one ammonia, amino methyl-acrylate copolymers, ethylenediamine, and lysine.

6. The system as claimed in claim 5, wherein water is present in an amount of between 1 to 5% by weight.

7. The system as claimed in claim 1 as adhesive layer in a transdermal patch.

8. A process for the preparation of a topical transdermal controlled release systems of medicaments which comprises the treatment-of-a the copolymer of claim 1 having a Tg lower than 0 C. and free carboxy groups suspended in an organic solvent with an aqueous solution of organic bases in stoichiometric amounts in respect of the carboxylic groups, followed by addition of an active ingredient and any other excipients.

9. Topical transdermal controlled release systems of medicaments consisting of: a polymeric matrix for said controlled release of said medicaments, said polymeric matrix comprising copolymers of acrylic or metacrylic acid and/or esters thereof having a Tg lower than 0 C., wherein the free carboxylic groups are salified with stoichiometric amounts of compatible organic bases, the organic bases comprising at least one ammonia, amino methyl-acrylate copolymers, ethylenediamine, and lysine and a medicament selected from the group consisting of non-steroidal anti-inflammatory agents, corticosteroids, local anesthetics, alpha-adrenergic agonists, analgesics, antimigraine drugs, anti-allergics, antihistaminics, antimicrobials, antiemetics, anticholinergics, bronchodilators, antivirals, myorelaxants, cholinergic agents, central nervous system stimulators, cardioactive agents, beta-adrenergic agonists, hormones, anxiolytics, antidepressants, antipsychotics, opioid antagonists, and coronary dilators.

10. The system as claimed in claim 9, wherein the non-steroidal anti-inflammatory is selected from the group consisting of diclofenac, fenoprofen, flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, ketorolac, naproxen, oxametacine, oxyphanbutazone, piroxicam, suprofen, and celecoxib.

Description

DETAILED DISCLOSURE OF THE INVENTION

[0036] 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.

[0037] The acidic groups are neutralized with stoichiometric amounts of inorganic (alkali and transition metal hydroxides, e.g. sodium hydroxide, 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.

[0038] 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.

[0039] In this way the acidic functions are neutralised and interactions with the active principle are avoided.

[0040] 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.

[0041] 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.

[0042] 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%.

[0043] The invention is illustrated in greater detail in the following examples.

EXAMPLE 1

[0044] 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.

[0045] Thereafter, 90 g of Diclofenac are added, and stirring is continued until complete dissolution.

[0046] 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/m.sup.2. After coupling to a polyethylene film, the patch is formed with a suitable punch.

[0047] EXAMPLE 2

[0048] 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.

[0049] Thereafter, 90 g of Ketoprofen are added, and stirring is continued until complete dissolution.

[0050] 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/m.sup.2. After coupling to a polyethylene film, the patch is formed with a suitable punch.

EXAMPLE 3

[0051] 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.

[0052] Thereafter, 100 g of Diclofenac are added, and stirring is continued until complete dissolution.

[0053] 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/m.sup.2. After coupling to a polyethylene film, the patch is formed with a suitable punch.