WO2008136699A1 - Transdermal patch with microcapsules and a method for the production thereof - Google Patents

Abstract

The invention relates to medicine, in particular to transdermal therapeutic systems in the form of patches which are used for supplying biologically active substances through the epidermal barrier in a prolonged manner. The inventive transdermal patch comprises a substrate, a protective tape and a polymeric layer provided with microcapsules containing biologically active substances and penetration enhancers. The inventive method for producing the patch consists in a) preparing microcapsules containing biologically active substances; b) preparing an adhesive base with the microcapsules; c) applying an adhesive to a substrate; d) removing a solvent (or carrying out a polymerisation reaction in the case of catalyzed polymers); e) laminating (forming the patch required thickness; f) sterilising by means of UV radiation; g) cutting into patches; and in h) packing in moistureproof packaging.

Description

 Transdermal patch with microcapsules and a method for its manufacture

The invention relates to medicine, in particular to transdermal therapeutic systems - patches, designed for prolonged delivery of biologically active substances (BAS) through the epidermal barrier.

Known invention Matrih-ture trapsdertal ratsh for steroid hortopes (WO99 / 66908, 29.12.1999) (Matrix transdermal patch for steroid hormones) in the polymer layer which contains oestradiol solution and 1 to 5% of the activated silicon oxide SiO _2. The disadvantage of the patch is the uneven release of the hormone from the matrix and the insufficiently effective penetration enhancer SiO ₂ .

The invention is known - a transdermal patch for the introduction of fentanyl (Application 2003127841, 03/27/2005 Bull. No. 9), containing a substrate and a reservoir located on the substrate, the contacting surface of the reservoir is sticky; moreover, the specified reservoir consists of a single-phase polymer composition free of undissolved components containing an amount of fentanyl or its analogue sufficient to cause and maintain analgesia in humans for at least three days.

The disadvantage of the above invention is the inconvenience of the practical use of the patch due to its thickness (up to 0.125 mm) and uneven surface. Tank-type plasters (Reservvoir ture) have a reservoir that gives the cumbersome appearance to the patch and creates inconvenience in operation (it comes off and is damaged, clinging to the fabric of clothing).

In the present invention, the most promising model is used - a matrix patch (Matrix tour), in which there is no reservoir

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SUBSTITUTE SHEET (RULE 26) and biologically active substances are directly distributed in the adhesive base ("Drug-ip-adhesive"), which is in contact with human skin. The lack of a reservoir allows the patch to be made thinner.

The principle of operation of the matrix patch is to create an “exclusive effect”, in which the adhesive layer of the patch is hydrated under the action of water constantly evaporating from the skin surface. Hydration of the stratum corneum allows the large molecules of biologically active substances to be introduced into the dermis.

The aim of the invention is the development of a transdermal patch with microencapsulated biologically active substances and the possibility of its production.

This goal is achieved by the fact that for the delivery of biologically active substances in the tissue, a patch is used that creates the conditions for the penetration of microcapsules with biologically active substances into the deeper layers of the skin that deliver the biologically active substances without changes in the required therapeutic dose.

The patch consists of the following components: substrate 1 (Vakipg lauer), adhesive layer 2 (Adhesive lauer) with microcapsules 3 containing microencapsulated biologically active substances and a protective film 4 (Release liper) (Figure 1). Depending on the type of biologically active substances, polymers based on acrylic acid (Rodert ^® brand, Roht apd Naas, USA) and silicone elastomers (DC 7-9800 ^® brand, Dow Co-pipg, USA) were used as a polymer matrix. The principal difference Rodert ^® polymer from DC 7- 9800 ^®, is the presence of a solvent - ethyl acetate, distilled at which the polymer viscosity increases and the adhesive layer is formed. The polymer DC 7- 9800 ^® consists of two parts (Part A: Diethyl silochape, diethyl, test, one of them, one of them, one of them), it’s one, it’s got one, it’s got one, it’s one when two parts are mixed in a 1: 1 ratio, a polymerization reaction occurs and an adhesive layer forms.

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SUBSTITUTE SHEET (RULE 26) To create lipid microcapsules, phospholipids (phosphatidylcholine, phosphatidylethanolamine, phosphadidylserine, phosphatidylinositol), sphingolipids, sphingophospholipids, sterols and glycerides were used. The amphiphilic properties of these lipids allow the formation of bilayer vesicles - liposomes.

One of the microcapsule variants was made from a non-ionic surface-active substance (SAS) of the organosilicon nature PEG-12 Dimethicone (PEG-12 Diethisope) (RF Application JVs 2006128323 dated 08/03/2006). The amphiphilic properties of PEG-12 Dimethicone also allow the formation of bilayer vesicles, which are called niosomes.

Water-soluble polymers were used as biodegradable polymers: polyvinyl alcohol (ruluvipul alcohol), carboxymethyl cellulose (carbohutethul cellulose), gelatin (gelatip) and polylactide-glycolide polymer (polo-teroluta). The polymer has a lactide glycolide ratio of 1: 1 and a molecular weight of 40000-75000 Da.

A method of manufacturing a transdermal patch with microencapsulated biologically active substances (hereinafter referred to as the patch) is carried out on special equipment and consists of the following operations:

• Preparation of microcapsules with biologically active substances;

• Preparation of an adhesive base with microcapsules;

• Application of adhesive base on a substrate;

• Solvent removal (or polymerization reaction in the case of catalyzed polymers);

• Lamination (giving the patch the desired thickness);

• UV sterilization;

• Cutting plasters;

• Packaging in waterproof packaging.

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SUBSTITUTE SHEET (RULE 26) The manufacture of microcapsules is carried out from biodegradable materials, which, when ingested in the deeper layers of the skin, do not adversely affect the human body.

Different types of microcapsules make it possible to include a wide range of biologically active substances used in medicine: analgesics, antibiotics, antihistamines, contraceptives and painkillers, hormones, immunomodulators, vaccines, extracts of plant and animal origin, as well as their possible combinations.

Before introducing into the polymer solution, the microcapsules are lyophilized (remove most of the moisture) to a solids content of at least 90%.

The prepared microcapsules with a size of 0.001-50 μm in an amount of 0.1-50% (mass%) are added to the polymer solution used to form the adhesive layer.

The type of microcapsules depends on the type of polymer matrix and the composition of excipients. The use of liposomes in a polymer containing a solvent of ethyl acetate is impossible, due to their destruction in the solvent, therefore, in this case, solvent-resistant niosomes are used. Liposomes are introduced into solvent-free DC 7-9800 ^® silicone polymer.

In order to improve the penetration of microcapsules through the epidermal barrier, excipients were introduced - enhancers (from the English word - strengthen) in the amount of 7-35% (wt.%). Propylene glycol, tetra-glycol, polyvinylpyrrolidone, isopropyl myristate, ethanol, polyethylene glycol monolith were used as enhancers . To obtain liposomes, the mixture was heated under vacuum on a rotary evaporator to remove most of the solvent (ethyl acetate). The mixture was introduced into a glass round bottom flask, and the evaporation process was carried out at a temperature of 40-50 ⁰ C to

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SUBSTITUTE SHEET (RULE 26) a certain viscosity of the mixture (1000 - 3000 Centipoise), at which it is possible to pour the contents from a glass flask. Vacuum evaporation avoids the formation of bubbles in the polymer matrix. In both types of polymers, heating accelerates the process of increasing the viscosity of the mixture, which leads to an increase in the stickiness of the polymer.

Further operations were carried out on special equipment designed for the production of adhesives. The evaporated mixture was deposited on a substrate with a thin layer of up to 150 μm.

Various materials were used as the substrate (ZM Сomrapu, USA): polyurethane {Сotrap ^® 9701), polyethylene {Сotrap ^® 9719, 9720), ethylene vinyl acetate EVA {Сotrap ^® 9726), polyester {Сotсhраск ^® 1109, 9723, 9370, 9732, 9733 , 9735) and non-woven fabric (Сotrap ^® 9700).

The above substrates differ in the degree of occlusivity, that is, the degree of penetration of oxygen through a fixed surface of the material within 24 hours. The choice of material depends on the purpose of the patch and the time of use.

The remaining solvent is removed by heating the substrate to 40-55 ⁰ C. Next, a protective film was applied to the substrate with adhesive and lamination was performed to a predetermined thickness of 200-300 μm.

As a protective film, fluoropolymers with a polyester layer were used (Fliooroluter Composit Rolutester fils, Sotscrap ^® 1020, 1022, 9741.9742, 9744, ZM Comrap, USA).

The resulting tape was sterilized by UV radiation from possible contamination by microorganisms and sent to the cutting of the patches.

The size of the patch ranges from 5-60 cm ² depending on the type of biologically active substances and the necessary therapeutic dose.

Cut plasters were packaged in a moisture-proof package to preserve consumer properties.

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SUBSTITUTE SHEET (RULE 26) The essence of the method is illustrated by a specific example, in which microcapsules include stem cell extract from pig placenta.

Stem cell extract from pig placenta (hereinafter referred to as the extract) can be used to replace damaged cells of the skin and mucous membranes. Superficial application of the extract of cells from healthy placental tissue of porcine tissue ensures the regeneration and restoration of the epidermis due to the growth factors of keratinocytes, cytokines and other biologically active substances contained in the extract (RF application JVs 2006105864/15 from 02.26.2006.).

Microcapsules are prepared on the basis of PEG-12 Dimethicone (PEG-12 Diethisope), which can form bilayer vesicles - niosomes.

The inclusion of the extract in niosomes is done by adding 4% PEG-12 dimethicone to the extract solution in a separate container. The process is carried out at room temperature and intensive mechanical shaking for 5 minutes. A niosome suspension of 0.001 -5 ohm μm containing 15% stem cell extract is lyophilized to a solids content of at least 90%.

Lyophilized niosomes in an amount of 15% (wt.%) Were introduced into the acrylic polymer Roderm brand ^®.

To enhance the penetration of niosomes through the skin, 10% (mass%) of propylene glycol and 5% (mass%) of isopropyl myristate are introduced. The mixture is thoroughly mixed for 5 minutes until the components are uniformly distributed in the polymer and evaporated under vacuum on a rotary evaporator to a viscosity of 1500-2000 cps.

Further operations were carried out on special equipment for the production of adhesives. The resulting polymer is applied to a substrate of polyethylene (Сotrap ^® 9719) using a knife, allowing to apply

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SUBSTITUTE SHEET (RULE 26) polymer with a thickness of 120-150 microns. The substrate was heated to 45-50 ° C for 5-10 minutes until complete evaporation of ethyl acetate.

The protective film was applied from a fluoropolymer with a layer of polyester (Flororuloter Composite rostester, Shothrask ^® 1020) was carried out immediately after evaporation of the solvent and the tape was laminated with adhesive to a thickness of 220-250 μm.

The tape was sterilized by UV irradiation for 5 minutes to eliminate possible contamination by microorganisms and sent to cutting the patches.

The size of the patch was 30 cm ² , which provided the necessary therapeutic effect.

Cut plasters were packaged in a moisture-proof package to preserve consumer properties.

A patch with stem cell extract is used to prevent and treat various skin diseases by improving the regeneration of skin cells. The transdermal route of administration of AB is an alternative to injections and allows you to dose biologically active substances for a long time, providing the necessary therapeutic effect.

SUBSTITUTE SHEET (RULE 26)

Claims

Claim 1. Transdermal patch containing a substrate, a protective tape and a polymer layer located on the substrate, the contacting surface of the polymer layer is sticky; moreover, the specified polymer layer consists of a single-phase polymer composition, characterized by the content of microcapsules with biologically active substance (BAS) included and penetration enhancers (enhancers). 2. The transdermal patch of claim 1, wherein the substrate is made of polyurethane, polyethylene, ethylene vinyl acetate (EVA), polyester or non-woven fabric. 3. The transdermal patch according to claim 1, wherein the polymer layer is an acrylic polymer of the rodent ^® brand. 4. The transdermal patch according to claim 1, wherein the polymer layer is a two-phase catalyzed silicone polymer of the DC 7-9800 ^® grade: Part A: Diethyl silo-compound, Part B: Diethyl silo-polymer, di-teluto-thermal, tertipate, Diethousl soslosilokhapes, satalust. 5. The transdermal patch according to claim 1, wherein the polymer layer has a thickness of 100-150 microns. 6. The transdermal patch according to claim 1, wherein the protective tape is a fluoropolymer with a layer of polyester (Fliooroleter Coatered filters). 7. The transdermal patch according to claim 1, wherein the patch has a thickness of 150-300 microns. 8. The transdermal patch according to claim 1, wherein the size of the patch ranges from 5-60 cm ² . 8 SUBSTITUTE SHEET (RULE 26) 9. A method of manufacturing a patch is carried out on special equipment and consists of the following operations: a) Preparation of microcapsules with B AB; b) Preparation of an adhesive base with microcapsules; c) Application of an adhesive base on a substrate; d) Solvent removal (or polymerization reaction in the case of catalyzed polymers); d) Lamination (giving the patch the desired thickness); e) UV sterilization; g) cutting plasters; h) Packaging in waterproof packaging. 10. The method according to claim 7, where the microcapsules are made of sphingolipids, sphingophospholipids, sterols, glycerides, phospholipids: phosphatidylcholine, phosphatidylethanolamine, phosphadidylserine or phosphatidylinositol, and are liposomes. 11. The method according to claim 7, where the microcapsules are made from esters of polydimethylsiloxane and polyethylene glycol (dimethicone copolyols), and in particular from PEG-12 Dimethicone, which are niosomes. 12. The method according to claim 7, where the microcapsules are made from biodegradable polymers: polyvinyl alcohol, carboxymethyl cellulose, gelatin or polylactide-glycolide polymer. 13. The method according to claim 7, where the biologically active substances are analgesics, antibiotics, antihistamines, contraceptives and painkillers, hormones, immunomodulators, vaccines, extracts of plant and animal origin, as well as their possible combinations. SUBSTITUTE SHEET (RULE 26) 14. The method according to claim 7, where the enhancers are introduced in an amount of 5-35% (wt.%) And are: propylene glycol, tetra-glycol, polyvinylpyrrolidone, isopropyl myristate, ethanol, polyethylene glycol monolaurate, glycerol or methyl laurate, as well as their possible combinations. 15. The method according to claim 7, where the microcapsules have a size of 0.001 -5 Ohm and introduced in an amount of 0.1-50% (mass.%). 16. The method according to claim 7, where the process of evaporation of the solvent is carried out at a temperature of 40-50 ⁰ C to a viscosity of the mixture 1000 - 3000 Centipoise. 17. The method according to claim 7, where the sterilization of the patch is performed by UV irradiation for 5 minutes. 18. The method according to claim 7, where the patches are packaged in a moisture-proof package of polyethylene, polyethylene terephthalate (PET), polypropylene or polyvinyl chloride. 10 SUBSTITUTE SHEET (RULE 26)