Composition suitable for the preparation of a medically effective patch

Abstract

A composition suitable for the preparation of a medical patch for delivering the anti-inflammatory active ingredient etofenamate to the skin, said composition comprising at least (i) a self-adhesive polysiloxane, (ii) the pharma- ceutical active ingredient etofenamate contained in component (i) as a dispersion, and (iii) a medium chain (C 10 ~C 16 ) a compound or a mixture of compounds selected from mono-, di- or triester compounds with fatty acids or mixtures of such fatty acids, and (iv) optionally further additives, with component (iii) having an acid number limit of 0.4, preferably 0.2, and a peroxide number limit of 2.0, preferably 1.0.

Description

[Technical field]

[0001] The present invention relates to compositions suitable for the preparation of medically active patches for the delivery to the skin of pharma- ceutical active ingredients that are liquid at room temperature, in particular for the delivery of the anti-inflammatory active ingredient etofenamate. [Background technology]

[0002] The composition according to the present invention contains the highest possible concentration of active ingredient, and allows the active ingredient to be released from the patch to the skin at a pharmacologic effective concentration for a relatively long period of time.This is difficult to achieve for active substances that are liquid at room temperature, because liquid active substances must be stably embedded in carrier material and must be compatible with carrier material.In order to store and use the patch made from the composition for as long as possible, it is important that the composition remains stable for as long as possible. Summary of the Invention

[0003] It has now been found that pharma- ceutical active compositions containing the anti-inflammatory active ingredient etofenamate and the ingredients described below are highly suitable for the manufacture of medicinal patches, such that the pharma- ceutical active ingredient contained in the composition is delivered from the patch to the skin in pharma- ceutical active concentrations over an extended period of time, and such that patches manufactured from the composition remain stable and can be used for a sufficiently extended period of time.

[0004] The present invention relates to a composition suitable for preparing a medical patch for delivering the anti-inflammatory active ingredient etofenamate to the skin, said composition comprising at least (i) a self-adhesive polysiloxane, optionally containing additives known per se for modifying the adhesive properties in order to optimize the adhesive properties, (ii) the pharma- ceutical active ingredient etofenamate contained in component (i) as a dispersion; and (iii) Glycerol and medium chain (C 12 ~C 16) fatty acids or mixtures of such acids, preferably selected from mono-, di- or triester compounds of glycerol and medium chain (C 10 ~C 16 ) a compound or a mixture of compounds selected from mono-, di- or triester compounds with fatty acids or mixtures of such acids, preferably in the form of medium chain triglycerides (MKT) derived from vegetable oils; and (iv) further additives, if necessary Contains For component (iii), it is characterized in that the acid value limit is 0.4, preferably 0.2, and the peroxide value limit is 2.0, preferably 1.0. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0005] Medium chain triglycerides obtained from vegetable oils are, for example, those obtained from palm oil, palm kernel oil, coconut oil, olive oil, castor oil, rapeseed oil, peanut oil, corn oil, hazelnut oil, jojoba oil or wheat germ oil, or from mixtures of such oils, preferably from palm oil, palm kernel oil, coconut oil, olive oil, castor oil or rapeseed oil, or from mixtures of such oils.

[0006] The composition according to the invention is preferably used for the production of a medical patch containing the composition according to the invention as a carrier material from which the active ingredient etofenamate is released to the skin.Such a similar patch is described in EP 2'120'896 (Drossapharm AG).The composition according to the invention is preferably processed into a poultice similarly to the method described in EP 2'120'896 (Drossapharm AG).

[0007] The composition according to the invention contains a self-adhesive polysiloxane as component (i).Self-adhesive polysiloxanes are known per se and are commercially available, for example, from DuPont under the trade name LIVEO® as silicone adhesives of different compositions.According to the invention, they can be used as component (i).Such self-adhesive silicone polymers can further contain additives known per se for modifying adhesive properties, such as, for example, rosin compounds, such as, for example, dehydrogenated or hydrogenated rosin, rosin glycerol esters, terpene resins, polyterpene resins from α- or β-pinene, or low-viscosity silicones or polysiloxanes with terminal silanol groups, or polydimethylsiloxanes, such as, for example, dimethiconol.

[0008] Self-adhesive polysiloxanes suitable for processing the compositions according to the invention as "hot melts" without the addition of solvents are commercially available, for example, from DuPont as LIVEO® BIO-PSA 7-4560 silicone adhesive. Such siloxane compounds are known, for example, under CAS number 68440-70-0 and CAS number 63148-62-9 and mixtures thereof, for example the compound under CAS number 68440-70-0 in a concentration of at least 60% by weight and the compound under CAS number 63148-62-9 in a concentration of 10.0% to 30.0% by weight.

[0009] Self-adhesive polysiloxanes suitable for preparing compositions according to the invention by adding a solvent are commercially available, for example, from DuPont as LIVEO® BIO-PSA 7-4603 or LIVEO® BIO-PSA 7-4201. Suitable polysiloxanes for preparing compositions according to the invention can be readily selected by those skilled in the art.

[0010] Suitable self-adhesive polysiloxanes can be obtained, for example, by condensation of dimethylpolysiloxanes containing silanol groups with organic solvent-soluble silicate resins and subsequent reaction of the remaining silanol groups with reactive trimethylsilyl compounds. Such polysiloxanes are soluble in organic solvents such as ethyl acetate, propyl acetate, saturated and aromatic hydrocarbons such as hexane, heptane, octane, benzene or toluene.

[0011] A preferred embodiment consists in that the self-adhesive polysiloxane of the composition according to the invention contains a compound or mixture of compounds [component (iii)] which reduces the viscosity of the self-adhesive polysiloxane containing the active ingredient, without adversely affecting the other properties of the self-adhesive polysiloxane.

[0012] The compound [component (iii)] is composed of glycerol and medium-chain (C 10 ~C 16 ) fatty acids or mixtures of such acids, preferably selected from mono-, di- or triester compounds of glycerol and medium chain (C 12 ~C 16 ) fatty acids or mixtures of such acids, preferably in the form of medium chain triglycerides (MKT), preferably obtained from vegetable oils, preferably from palm oil, palm kernel oil, coconut oil, olive oil, castor oil and / or rapeseed oil.

[0013] Vegetable oils having a stated analysis are also called "refined" or "semi-synthetic" oils and have a higher purity compared to the corresponding natural oils, as indicated, for example, by stated acid and peroxide value values.

[0014] Such refined or semi-synthetic oils are described as vegetable oils and preferably contain up to 2% caproic acid (C6), 50-80% caprylic acid (C8), and capric acid (C 10 ) at 20-50%, lauric acid (C 12 ) up to 3% and myristic acid (C 14) at a maximum of 1%.

[0015] Acid number (according to European ISO standard 660) refers to the mass of potassium hydroxide in milligrams required to neutralize the free fatty acids present in one (1) gram of fat or oil.

[0016] The peroxide value is expressed according to the DIN standard as "milliequivalents of oxygen per kilogram of fat". This value corresponds to the amount of oxygen atoms bound as peroxide in millimoles per kilogram of fat.

[0017] To produce vegetable oils with defined analysis values, it is possible, for example, to hydrolytically cleave the starting products, such as coconut or palm oil, and re-esterify the medium-chain saturated fatty acids obtained after fractional distillation with glycerol in the desired ratio. These methods are known.

[0018] The self-adhesive polysiloxane [component (i)] used preferably contains about 2 to 15% by weight, preferably about 5 to 10% by weight, of the compound of component (iii), based on the total weight of the composition.

[0019] The composition according to the present invention has the chemical formula: [ka] That is, 2-(2-hydroxyethoxy)ethyl (α,α,α-trifluoro-m-tolyl)anthranilate (etofenamate) The pharmaceutical composition contains the pharmacologic active ingredient etofenamate [ingredient (ii)] corresponding to

[0020] The composition according to the invention contains the active ingredient etofenamate in an amount ranging from 1.0% to 25.0% by weight, preferably from 2.0% to 20% by weight, preferably from 2.5% to 15% by weight, preferably in an amount of about 5% to about 10% by weight, calculated relative to the total weight of the composition.

[0021] The compositions according to the invention contain the active ingredient in a highly dispersed distribution with an average droplet size in the range of 0.1 μm to 500 μm, preferably 1.0 μm to 100 μm.

[0022] The adhesive strength of the processed composition, ie the adhesive strength of the carrier layer, which is to be directly adhered to the skin in the finished poultice, is preferably in the range of 0.8 N / 25 mm to 1.4 N / 25 mm.

[0023] The adhesive strength of the applied composition, which is used as an intermediate layer in the finished poultice, is preferably in the range of 0.8N / 25mm to 2.0N / 25mm, preferably in the range of 0.9N / 25mm to 1.7N / 25mm.

[0024] The composition may optionally contain further additives [component (iv)].Thus, compounds that also reduce the viscosity of the self-adhesive polysiloxane containing active ingredient can also be used, such as liquid paraffin, polysorbates (i.e. polyoxyethylene sorbitan fatty acid ester compounds), such as Tween® 60 (polyoxyethylene sorbitan monostearate) or Tween® 80 (polyoxyethylene sorbitan monooleate), polyethylene glycols, such as polyethylene glycol 400, propylene glycol and polypropylene glycol, esters of polybasic acids and alcohols, such as triethyl citrate, and mixtures of these compounds.

[0025] The composition may contain other additives, such as compounds that enhance the penetration of the pharma- ceutical active ingredient through the skin, stabilizers and fragrances, the corresponding compounds being known per se, although their presence is not absolutely necessary.

[0026] The present invention also relates to a method for preparing a composition according to the invention comprising at least one self-adhesive polysiloxane [component (i)], the active ingredient etofenamate [component (ii)], a compound or a mixture of compounds selected from mono-, di- or triester compounds according to component (iii) and optionally one or more additives according to component (iv), which comprises heating the self-adhesive polysiloxane [component (i)] together with the active ingredient etofenamate [component (ii)] and at least one compound of component (iii), optionally together with at least one compound of component (iv), under vigorous stirring, to a temperature in the range of 80°C to 200°C, preferably in the range of 140°C to 190°C, in particular in the range of 160°C to 190°C, until the desired dispersion is formed. If necessary, the formed dispersion can then be cooled.

[0027] This dispersion can be further processed without solvent at a specified temperature range, preferably in the range of 120°C to 140°C, preferably in the range of 80°C to 120°C, especially about 100°C, and applied as a thin layer in the desired amount to the intended substrate.

[0028] A further method for preparing a composition according to the invention comprising at least one self-adhesive polysiloxane and the active ingredient etofenamate, optionally together with an agent that promotes penetration through the skin and optionally further additives, is characterized in that the self-adhesive polysiloxane is heated in the presence of a solvent at elevated temperature, preferably in the range of 40°C to 90°C, preferably in the range of the boiling point of said solvent, together with the active ingredient, optionally with an agent that promotes penetration through the skin and optionally with further additives, under vigorous stirring, until the desired dispersion is formed; preferably a large amount of solvent is added such that the resulting dispersion can be processed into a poultice at room temperature, i.e. the resulting dispersion can be applied as a thin layer in the desired amount to the intended substrate at room temperature.

[0029] Alternatively, the solvent can be largely or completely removed from the formed dispersion, and the remaining dispersion can be further processed at elevated temperatures largely or completely free of solvent, and then applied as a thin layer in the desired amount to the intended substrate.

[0030] The solvent used is preferably an organic solvent such as, for example, ethyl acetate, propyl acetate, saturated and / or aromatic hydrocarbons such as, for example, hexane, heptane, octane, benzene or toluene, etc. The solvent is preferably evaporated either from the obtained dispersion or from the layer applied to the patch at a temperature ranging from 50° C. to 90° C. depending on the boiling point of the solvent, preferably at a temperature of about 60° C. to 70° C., for a time of about 30 minutes to 60 minutes.

[0031] In the patches produced therefrom, the coating of the surface or adhesive layer and / or the carrier layer is in each case 30 g / m 2 ~300g / m 2 in the range of 40 g / m 2 ~200g / m 2 In particular, in the range of about 40 g / m 2 ~100g / m 2 The range is.

[0032] The compounds of component (iii) mentioned can also act as penetration enhancers in some cases. Compounds that enhance penetration through the skin are additives that enhance the administration of active ingredients to the skin or their penetration through the stratum corneum. The weight ratio of active ingredient: penetration enhancer is preferably in the range of 98:2 to 2:8, preferably in the range of 9:1 to 3:7, preferably about 1:2. EXAMPLES

[0033] The following examples illustrate the invention without limiting it.

[0034] Example 1 70 parts of etofenamate [component (ii)] are placed in a glass round-bottom flask with 1,274 parts of a self-adhesive polysiloxane (*LIVEO® BIO-PSA 7-4560 from DuPont) dissolved in ethyl acetate [component (i)] and 28 parts of refined olive oil [component (iii)] and 600 parts of pure ethyl acetate [component (iv)] and vigorously mixed on a magnetic stir plate at a temperature of 70°C to 77°C until a sufficient dispersion is formed. This is cooled and vigorously stirred at room temperature for 2.5 hours. The resulting mixture can then be processed into a poultice. *Trimethylsilylated polysilicate α-hydro-ω-hydroxypoly(dimethylsiloxane) polycondensate with dimethicone

[0035] Example 2 Example 1 is repeated using a starting mixture additionally containing 28 parts of macrogol 400 (peg400).

Claims

1. A composition suitable for the preparation of a medicinal patch for delivering the anti-inflammatory active ingredient etofenamate to the skin, said composition comprising at least, (i) a self-adhesive polysiloxane, and (ii) the pharmaceutically active substance etofenamate, contained as a dispersion in component (i), (iii) a compound or mixture of compounds selected from mono-, di- or triester compounds of glycerol and medium-chain (C １２ ~C １６ ) fatty acids or mixtures of such acids and characterized in that for component (iii), the acid value limit is 0.4 and the peroxide value limit is 2.0, Composition.

2. The composition according to claim 1, characterized in that the medium-chain triglyceride of component (iii) is obtained from palm oil, palm kernel oil, coconut oil, olive oil, castor oil, rapeseed oil, peanut oil, corn oil, hazelnut oil, jojoba oil or wheat germ oil, or a mixture of such oils.

3. The composition according to claim 1, characterized in that it contains at least one self-adhesive polysiloxane known per se as component (i).

4. The composition according to claim 1, characterized in that it further contains at least one additive known per se for modifying the adhesion properties, and contains at least one self-adhesive polysiloxane known per se as component (i), wherein the at least one additive is selected from the rosin compound, rosin glycerol ester, and / or from terpene resin, polyterpene resin, from α- or β-pinene, or from low-viscosity silicone, and / or from polydimethylsiloxane, Composition.

5. The composition according to claim 1, characterized in that the self-adhesive polysiloxane of component (i) contains a compound or a mixture of compounds [component (iii)] that reduces the viscosity of the self-adhesive polysiloxane containing the active ingredient without adversely affecting other properties of the self-adhesive polysiloxane.

6. The composition according to claim 1, characterized in that the self-adhesive polysiloxane of component (i) contains 2 to 15% by weight of the compound of component (iii) based on the total weight of the composition.

7. A composition which is the composition according to claim 1 and contains the active ingredient etofenamate in an amount of 1.0% to 25.0% by weight, calculated based on the total weight of the composition.

8. ​ The composition according to claim 1, characterized in that it contains the active ingredient etofenamate in a highly dispersed distribution having an average droplet size in the range of 0.1 μm to 500 μm.

9. The composition according to claim 1, characterized in that the adhesion of this composition to be processed, which is intended to adhere directly to the skin in the finished patch, is in the range of 0.8 N / 25 mm to 1.4 N / 25 mm.

10. The composition according to claim 1, characterized in that the adhesion of this composition to be processed, which is used as an intermediate layer in the finished patch, is in the range of 0.8 N / 25 mm to 2.0 N / 25 mm.

11. A composition according to claim 1, characterized in that the composition contains a further additive [component (iv)], a stabilizer and / or a fragrance that promotes the penetration of the pharmaceutically active substance through the skin.

12. A composition according to claim 1, characterized in that the composition contains a compound of component (iii) that acts as a penetration enhancer in a weight ratio of active ingredient to penetration enhancer in the range of 98:2 to 2:

8.

13. A method for preparing the composition according to any one of claims 1 to 12, characterized in that the self-adhesive polysiloxane [component (i)] is heated to a temperature in the range of 80 °C to 200 °C while stirring vigorously until a desired dispersion is formed, together with at least one compound of the active ingredient etofenamate [component (ii)] and component (iii).

14. A method for preparing the composition according to any one of claims 1 to 12, characterized in that the self-adhesive polysiloxane is heated together with the active ingredient while stirring vigorously at a high temperature in the range of 40 °C to 90 °C in the presence of a solvent until the desired dispersion is formed.

15. The method according to claim 14, characterized in that an amount of solvent sufficient to process the resulting dispersion into a patch at room temperature is added.

16. The method according to claim 14, characterized in that the medium-chain triglyceride of component (iii) is obtained from palm oil, palm kernel oil, coconut oil, olive oil, castor oil, rapeseed oil, peanut oil, corn oil, hazelnut oil, jojoba oil or wheat germ oil, or a mixture of such oils.