PHARMACEUTICAL OR COSMETIC COMPOSITIONS COMPRISING A POLYMER AND AN ABSORPTION PROMOTER FOR CONTROLLED RELEASE OF ACTIVE INGREDIENTS

Abstract

Disclosed is a pharmaceutical or cosmetic composition or medical device for topical use including: a) a cosmetically or pharmaceutically active substance; b) a polyvinylcaprolactam/polyvinyl acetate/polyethylene glycol copolymer; and c) a phospholipid. Also disclosed is a method for treatment incorporating such a composition.

Claims

1. A pharmaceutical or cosmetic composition or a medical device for topical use comprising: a) a cosmetically or pharmaceutically active substance; b) a polyvinylcaprolactam/polyvinyl acetate/polyethylene glycol copolymer; c) a phospholipid.

2. The pharmaceutical or cosmetic composition or medical device for topical use according to claim 1 wherein the polyvinylcaprolactam/polyvinyl acetate/polyethylene glycol copolymer is Soluplus®.

3. The pharmaceutical or cosmetic composition or medical device for topical use according to claim 1 wherein the phospholipid is a phosphatidylcholine or a hydrogenated phosphatidylcholine.

4. The pharmaceutical or cosmetic composition or medical device for topical use according to claim 3 wherein the phospholipid is a hydrogenated phosphatidylcholine.

5. The pharmaceutical or cosmetic composition or medical device for topical use according to claim 1 wherein the weight ratio between the polyvinylcaprolactam/polyvinyl acetate/polyethylene glycol copolymer and the phospholipid is 1:1 to 1:1000.

6. The pharmaceutical or cosmetic composition or medical device for topical use according to claim 1, wherein the pharmaceutically or cosmetically active substance is selected from the group consisting of antarcticine, polyglutamic acid, menthol/menthyl lactate, vanillyl butyl ester, escin, hyaluronic acid sodium salt, silver sulfadiazine, troxerutin and diclofenac sodium.

7. A pharmaceutical composition for topical use comprising: a) a pharmaceutically active substance; b) a polyvinylcaprolactam/polyvinyl acetate/polyethylene glycol copolymer; c) a phospholipid for use in the treatment of skin and/or mucosal diseases or lesions.

8. A method for cosmetic treatment of skin, comprising applying an effective amount of a cosmetic composition or a medical device for topical use comprising: a) a cosmetically or pharmaceutically active substance; b) a polyvinylcaprolactam/polyvinyl acetate/polyethylene glycol copolymer; c) a phospholipid.

9. The pharmaceutical or cosmetic composition for topical use according to claim 1 in the form of a liquid solution.

10. A fabric for application to the skin comprising a pharmaceutical or cosmetic composition according to claim 1.

11. A mono- or multi-lamellar film for application to the skin comprising a pharmaceutical or cosmetic composition according to claim 1.

12. The pharmaceutical or cosmetic composition or medical device for topical use according to claim 2 wherein the phospholipid is a phosphatidylcholine or a hydrogenated phosphatidylcholine.

13. The pharmaceutical or cosmetic composition or medical device for topical use according to claim 2 wherein the weight ratio between the polyvinylcaprolactam/polyvinyl acetate/polyethylene glycol copolymer and the phospholipid is 1:1 to 1:1000.

14. The pharmaceutical or cosmetic composition or medical device for topical use according to claim 3 wherein the weight ratio between the polyvinylcaprolactam/polyvinyl acetate/polyethylene glycol copolymer and the phospholipid is 1:1 to 1:1000.

15. The pharmaceutical or cosmetic composition or medical device for topical use according to claim 4 wherein the weight ratio between the polyvinylcaprolactam/polyvinyl acetate/polyethylene glycol copolymer and the phospholipid is 1:1 to 1:1000.

16. The pharmaceutical or cosmetic composition or medical device for topical use according to claim 2, wherein the pharmaceutically or cosmetically active substance is selected from the group consisting of antarcticine, polyglutamic acid, menthol/menthyl lactate, vanillyl butyl ester, escin, hyaluronic acid sodium salt, silver sulfadiazine, troxerutin and diclofenac sodium.

17. The pharmaceutical or cosmetic composition or medical device for topical use according to claim 3, wherein the pharmaceutically or cosmetically active substance is selected from the group consisting of antarcticine, polyglutamic acid, menthol/menthyl lactate, vanillyl butyl ester, escin, hyaluronic acid sodium salt, silver sulfadiazine, troxerutin and diclofenac sodium.

18. The pharmaceutical or cosmetic composition or medical device for topical use according to claim 4, wherein the pharmaceutically or cosmetically active substance is selected from the group consisting of antarcticine, polyglutamic acid, menthol/menthyl lactate, vanillyl butyl ester, escin, hyaluronic acid sodium salt, silver sulfadiazine, troxerutin and diclofenac sodium.

19. The pharmaceutical or cosmetic composition or medical device for topical use according to claim 5, wherein the pharmaceutically or cosmetically active substance is selected from the group consisting of antarcticine, polyglutamic acid, menthol/menthyl lactate, vanillyl butyl ester, escin, hyaluronic acid sodium salt, silver sulfadiazine, troxerutin and diclofenac sodium.

20. The pharmaceutical or cosmetic composition for topical use according to claim 2 in the form of a liquid solution.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0024] FIG. 1 is the schematic representation of the Franz cells used in the Permeation Test reported in Example 5 consisting of a receptor chamber and a donor compartment.

[0025] FIG. 2 is a graph showing the permeability profiles at 37° C. of a film A (comparison profile) and a film B (according to the invention) as reported in Example 5.

DESCRIPTION OF THE INVENTION

[0026] The Object of the present invention is a pharmaceutical or cosmetic composition or medical device for topical use comprising: [0027] a) a cosmetically or pharmaceutically active substance; [0028] b) a polyvinylcaprolactam/polyvinyl acetate/polyethylene glycol copolymer; [0029] c) a phospholipid.

[0030] The polyvinylcaprolactam/polyvinyl acetate/polyethylene glycol copolymer is preferably Soluplus®, made by BASF.

[0031] The phospholipid used in the composition according to the present invention is preferably selected from the group consisting of phosphatidylcholine and hydrogenated phosphatidylcholines with different degrees of purity, ranging from 50% to 90% purity.

[0032] In particular the phospholipid is hydrogenated phosphatidylcholine such as Phospholipon 80H, manufactured and marketed by the company Lipoid GmbH FrigenstraBe 4, 67065 Ludwigshafen am Rhein, Germany.

[0033] The weight ratio between the copolymer (polyvinylcaprolactam/polyvinyl acetate/polyethylene glycol) and the phospholipid ranges from 1:1 to 1:1000, preferably from 100:10 to 100:1.

[0034] The pharmaceutically and/or cosmetically active substance used in the composition for topical use according to the invention is preferably selected from the group consisting of antarcticine, polyglutamic acid, menthol/menthyl lactate, vanillyl butyl ester, escin, hyaluronic acid sodium salt, silver sulfadiazine, troxerutin and diclofenac sodium.

[0035] The active substance and the polymer are preferably solubilised in the preparation, and the absorption promoter is present in microdispersed form.

[0036] The composition according to the invention can be formulated as: [0037] a) solution to be applied directly to the skin [0038] b) solution to be sprayed directly onto the skin [0039] c) solution to be sprayed onto a medium (fabric) which, after evaporation of the solvent, is applied to the skin [0040] d) monolamellar film to be applied to the skin [0041] e) multilamellar (e.g. two-layer) film to be applied to the skin.

[0042] The compositions for topical use according to the present invention can be used in the treatment of diseases or lesions of the skin and/or mucosa, or for cosmetic treatment of the skin.

[0043] As regards liquid preparations, Soluplus has been used at concentrations ranging between 0.5% and 20% w/w.

[0044] The solvents preferably used are: purified water and/or water/ethanol mixtures on the basis of 100% water, or aqueous solutions with an alcohol content ranging between 5% and 30% weight/weight.

[0045] Technological adjuvants such as plasticisers, e.g. propylene glycol, glycerol, PEG-3, PEG 400 and PEG 3500, can also be used, at weight/weight concentrations ranging between 0.1% and 45%, preferably 20-30%.

[0046] In the case of films for topical use, the same substances, such as Soluplus, Phospholipon 80H and plasticisers, are used in the following ratios: [0047] Soluplus: Phospholipon 80H from 1:1 to 1:1000, preferably from 100:5 to 100:0.1, by weight. [0048] Soluplus: Plasticiser ranging between 1:0.05 and 1:0.4.

Examples

Example No. 1—Topical Cosmetic Film Based on Antarcticine

[0049]

TABLE-US-00001 % content % Quantity by weight of compo- % by for 1 kg of dry matter in sition Substance weight solution the solution of film Antarcticine 3.00 30.00 g 0.75% 5.00 solution with (equal to 25% dry matter 7.5% dry matter) Phospholipon 80H 1.00 10.00 g 1.00% 6.67 Propylene glycol 4.00 40.00 g 4.00% 26.67 Soluplus ® 10.00 925.00 9.25% 61.66 Purified water q.s. to 100% 820.00 g  = =

[0050] Preparation Method:

[0051] Preparation of Solution:

[0052] Step #1: The required quantity of deionised water was introduced into a 2-litre glass beaker and weighed. The beaker was placed on a hotplate fitted with electromagnetic stirrer, and the water temperature was increased to 80° C.

[0053] Step #2: The Phospholipon 80 H was added to the water of step #1 and dispersed, maintaining the dispersion under stirring for about 30 minutes at the temperature of 80° C., until a complete microdispersion without lumps was obtained.

[0054] Step #3: The microdispersion of step #2 was cooled to room temperature, and the Soluplus® was then added under vigorous stirring. Stirring was maintained for at least 3 hours, until the Soluplus had completely dissolved. The antarcticine and propylene glycol were then added.

[0055] Step #4: The resulting solution was then filtered through an 8.0 micron filter membrane.

[0056] Step #5: The solution was then stored in a glass bottle with a usable capacity of 1 litre.

[0057] Film Preparation:

[0058] The film is prepared by spreading the solution on glass containers positioned perfectly horizontally on a surface and then placed in a thermostatic stove until a film is obtained by complete evaporation of the solvent.

[0059] Preparation of a Topical Film with 10 mg of Film/Cm.sup.2: [0060] A glass dish with an area of 56.7 cm.sup.2 was prepared, and 3.78 g of the solution resulting from step #5 was weighed in it. [0061] The dish thus filled was placed in a thermostatic stove under vacuum at the temperature of 30° C. for 8 hours. [0062] The dish containing the film was then removed and left to cool at room temperature. [0063] The resulting film was collected and placed in an aluminium/polythene sachet. The sachet was then heat-sealed.

[0064] Preparation of Topical Film with 20 mg of Film/Cm.sup.2: [0065] glass dish with an area of 56.7 cm.sup.2 was prepared, and 7.56 g of the solution resulting from step #5 was weighed in it. [0066] The dish thus filled was placed in a thermostatic stove under vacuum at the temperature of 30° C. for 8 hours. [0067] The dish containing the film was then removed and left to cool at room temperature. [0068] The resulting film was collected and placed in an aluminium/polythene sachet. The sachet was then heat-sealed.

Example no. 2—Topical gel for cosmetic use based on hyaluronic acid

[0069]

TABLE-US-00002 % by Quantity for Substance weight 1 kg of solution Hyaluronic acid with a molecular 0.10 1.00 g weight of 1 million daltons Phospholipon 80H 0.10 1.00 g Propylene glycol 3.00 30.00 g Soluplus ® 20.00 200.00 Purified water q.s. to 100% 768.00 g

[0070] Preparation Method:

[0071] Preparation of Solution:

[0072] Step #1: The required quantity of deionised water was introduced into a 2-litre glass beaker and weighed. The beaker was placed on a hotplate fitted with electromagnetic stirrer, and the water temperature was increased to 80° C.

[0073] Step #2: The Phospholipon 80 H was added to the water of step #1 and dispersed, maintaining the dispersion under stirring for about 30 minutes at the temperature of 80° C., until a complete microdispersion without lumps was obtained.

[0074] Step #3: The microdispersion of step #2 was cooled to room temperature, and the Soluplus® was then added under vigorous stirring. Stirring was maintained for at least 3 hours, until the Soluplus had completely dissolved. The hyaluronic acid and propylene glycol were then added, and stirring was maintained for a further 3 hours.

[0075] Step #4: The resulting solution was then filtered through an 8.0 micron filter membrane.

[0076] Packaging: The resulting gel was used to fill bottles fitted with a dispenser pump, which were then sealed.

Example No. 3—Caffeine-Based Cosmetic Solution for Spraying onto

[0077] Undergarments

TABLE-US-00003 % by Quantity for Substance weight 1 kg of solution Caffeine 0.50 5.00 g Phospholipon 80H 1.50 15.00 g Soluplus ® 0.10 1.00 g Denatured ethanol 30.00 300.00 Purified water q.s. to 100% 679.00 g

[0078] Preparation Method:

[0079] Preparation of Solution:

[0080] Step #1: The required quantity of deionised water was introduced into a 2-litre glass beaker and weighed. The beaker was placed on a hotplate fitted with electromagnetic stirrer, and the water temperature was increased to 80° C.

[0081] Step #2: The Phospholipon 80 H was added to the water of step #1 and dispersed, maintaining the dispersion under stirring for about 30 minutes at the temperature of 80° C., until a complete microdispersion without lumps was obtained.

[0082] Step #3: The microdispersion of step #2 was cooled to room temperature, and the Soluplus® was then added under vigorous stirring. Stirring was maintained for at least 3 hours, until the Soluplus had completely dissolved. The caffeine and denaturated ethanol were then added, and stirring was maintained for about 1 hour.

[0083] Step #4: The resulting solution was then filtered through an 8.0 micron filter membrane.

[0084] Packaging: The resulting solution was then used to fill bottles fitted with a spray pump.

Example No. 4—Topical Film Based on Diclofenac Sodium

[0085]

TABLE-US-00004 % content % Quantity by weight of compo- % by for 1 kg of dry matter in sition Substance weight solution the solution of film Diclofenac sodium 1.00 10.00 g 1.00% 3.846 Phospholipon 80H 1.00 10.00 g 1.00% 3.846 Propylene glycol 4.00 40.00 g 4.00% 15.384 Soluplus ® 20.00 200.00 g 20.00% 76.924 Purified water q.s. to 100% 740.00 g = =

[0086] Preparation Method:

[0087] Preparation of Solution:

[0088] Step #1: The required quantity of deionised water was introduced into a 2-litre glass beaker and weighed. The beaker was placed on a hotplate fitted with electromagnetic stirrer, and the water temperature was increased to 80° C.

[0089] Step #2: The Phospholipon 80 H was added to the water of step #1 and dispersed, maintaining the dispersion under stirring for about 30 minutes at the temperature of 80° C., until a complete microdispersion without lumps was obtained.

[0090] Step #3: The microdispersion of step #2 was cooled to room temperature, and the Soluplus® was then added under vigorous stirring. Stirring was maintained for at least 3 hours, until the Soluplus had completely dissolved. The diclofenac sodium and propylene glycol were then added, and stirring was maintained for about 30 minutes.

[0091] Step #4: The resulting solution was then filtered through an 8.0 micron filter membrane.

[0092] Step #5: The solution was then stored in a glass bottle with a usable capacity of 1 litre.

[0093] Preparation of Film:

[0094] Preparation of Topical Film with 10 mg of Film/Cm.sup.2:

[0095] The film is prepared by spreading the solution on glass containers positioned perfectly horizontally on a surface and then placed in a thermostatic stove until a film is obtained by complete evaporation of the solvent.

[0096] Preparation of a Topical Film with 10 mg of Film/Cm.sup.2: [0097] A glass dish with an area of 56.7 cm.sup.2 was prepared, and 3.78 g of the solution resulting from step #5 was weighed in it. [0098] The dish thus filled was placed in a thermostatic stove under vacuum at the temperature of 30° C. for 8 hours. [0099] The dish containing the film was then removed and left to cool at room temperature.

[0100] The resulting film was collected and placed in an aluminium/polythene sachet. The sachet was then heat-sealed.

Example No. 5—Comparison of Diclofenac Permeation in Two Different Films Through Porcine Ear Skin at 37° C.

[0101] Two formulations based on diclofenac sodium salt in Soluplus®-based film (Film A: comparison film) and Soluplus combined with phospholipids (Phospholipon 80H) (Film B: film according to the invention) were prepared for evaluation of the ex vivo permeation test with Franz cells using pig skin.

[0102] The two formulations differ in terms of the presence or absence of Phospholipon 80H as active ingredient absorption promoter.

[0103] Qualitative/Quantitative Composition of the Two Anhydrous Films:

TABLE-US-00005 Ingredient Film A (% w/w) Film B (% w/w) Diclofenac sodium 3.0 3.0 Phospholipon 80H = 5.0 Propylene glycol 19.9 19.9 Antifoam 0.1 0.1 Soluplus 77 72 100.0 100.0

[0104] Film Preparation:

[0105] Films A and B were produced with the ingredients and quantities set out in the table below:

TABLE-US-00006 Ingredient Film A (% w/w) Film B (% w/w) Diclofenac sodium 0.6 0.6 Phospholipon 80H 1.0 Propylene glycol 3.98 3.98 Antifoam (30% emulsion) 0.02 0.02 Soluplus 15.4 14.4 Purified water 79.82 79.82 100 100

[0106] Preparation of Film A:

[0107] Step #1: The diclofenac sodium was dissolved in the specified quantity of water.

[0108] Step #2: The Soluplus® was weighed in a glass beaker, and the propylene glycol and antifoam were added. The propylene glycol was left to absorb the Soluplus.

[0109] Step #3: The solution obtained in step #1 was added slowly to the mixture obtained in step #2. The resulting mixture was maintained under stirring until the Soluplus had completely dissolved, to give a slightly opalescent solution.

[0110] Step #4: 1.960 g of the solution resulting from step #3 was spread on a PVCD film with a circular mould having a radius of 5 cm and an area of 78.5 cm.sup.2, and placed in a forced-air stove at the temperature of 60° C. for 45 minutes.

[0111] At the end of the drying process the film was extracted from the PVCD support and cooled at room temperature for about 6 hours.

[0112] The film formed weighed 5 mg/cm.sup.2.

[0113] Step #5: The film was packaged in sachets and hermetically sealed.

[0114] Preparation of Film B:

[0115] Step #1: The diclofenac sodium was dissolved in the specified quantity of water.

[0116] Step #2: The Soluplus® was weighed in a glass beaker, and the propylene glycol, Phospholipon 80H and antifoam were added. The propylene glycol was left to absorb the Soluplus, and the mixture was then mixed until the Phospholipon 80H was incorporated in the Soluplus.

[0117] Step #3: The solution obtained in step #1 was added slowly to the mixture obtained in step #2. The resulting mixture was maintained under stirring until the Soluplus® was completely dissolved and the Phospholipon 80H dispersed. The resulting mixture was ultrasonicated in an ultrasonic bath to give a homogeneous opalescent microdispersion.

[0118] Step #4: 1.960 g of the solution resulting from step #3 was spread on a PVCD film with a circular mould having a radius of 5 cm and an area of 78.5 cm.sup.2′ and placed in a forced-air stove at the temperature of 60° C. for 45 minutes.

[0119] At the end of the drying process the film was extracted from the PVCD support and cooled at room temperature for about 6 hours.

[0120] The film formed weighed 5 mg/cm.sup.2.

[0121] Step #5: The film was packaged in sachets and hermetically sealed.

[0122] Permeation Test:

[0123] The apparatus used consisted of: [0124] Franz cells (FIG. 1): receptor chamber volume 11 ml; donor compartment diameter 1.5 cm; [0125] Stirring and temperature control system.

[0126] Procedure

[0127] After the removal of subcutaneous fat, portions of porcine ear skin were thoroughly cleaned with 0.9% saline solution. Before storage at −20° C., the thickness of each disc of skin was determined.

[0128] Before each permeability experiment, the tissue samples were thawed at room temperature in saline solution (0.9% w/v of NaCl).

[0129] The samples were then mounted in the diffusion cells (exposed area 1.8 cm.sup.2) with the stratum corneum facing towards the donor compartment and the dermis facing towards the receptor compartment. The receptor compartment of the cell was filled with the selected medium (0.9% w/v of NaCl). During the experiments, the receptor solution was maintained under stirring at 37° C. A quantity of film corresponding to 15 mg was applied to the surface of the skin/membrane in the donor compartment. 200 μl aliquots were collected from the receptor side at the specified time intervals (0.5, 1, 2, 4 and 6 hours), and immediately replaced with 200 μl of fresh medium solution. The permeated diclofenac concentration was determined by the HPLC-ES-MS/MS method.

[0130] HPLC-ES-MS/MS Method

[0131] The HPLC System used was the 2690 Alliance System (Waters, Milford, Mass., USA), combined with a QUATTRO-LC triple-quadrupole mass spectrometer (Micromass; Waters) with electrospray (ES) interface. The diclofenac concentration was determined by HPLC-ES-MS/MS under the following experimental conditions:

[0132] HPLC column: Waters XSELECT CSH C18 column (5 μm, 150 mm×2.1 mm i.d.).

[0133] Composition of mobile phase and elution mode: Solvent A: 15 mM ammonium acetate buffer; Solvent B: Acetonitrile: methanol=75:25 v/v; Isocratic elution Solvent A: Solvent B=40:60 v/v

[0134] Column temperature: 40° C.

[0135] Flow rate: 0.15 ml/min

[0136] Injection volume: 10 μL

[0137] Linearity range: 0.05-20 μg/mL

[0138] Under the conditions reported above, the retention time of diclofenac is about 6.1±0.1 min

[0139] Data Processing and Results

[0140] The cumulative quantity permeated per surface unit is plotted in the graph vs. time for the two films. The permeability profiles at 37° C. are shown in FIG. 2. The steady-state flux (J, μg cm.sup.−2 h.sup.−1) and lag time were estimated by extrapolation from the straight line on the graph. The quantity of diclofenac permeated through the porcine ear skin (expressed as μg/cm.sup.2) and steady-state flux J for the two films are shown in the table below. These values are the mean of three independently replicate experiments for each film.

[0141] Quantity of diclofenac permeated (μg/cm.sup.2) for the two films at 37° C.

TABLE-US-00007 Time Film A Film B (hours) Mean (n: 3) SD Mean (n: 3) SD 0.5 n.d. n.c. n.d. n.c. 1 n.d. n.c. n.d. n.c. 2 0.12 0.06 0.59 0.31 4 3.80 1.17 6.44 2.20 6 7.92 1.58 12.43 3.04 J (μg cm.sup.−2 h.sup.−1) 1.95 ± 0.21 2.96 ± 0.41 n.d. not detected; n.c. not calculated

[0142] A paired t-test (two tailed) test was conducted to compare the two films. The slopes of the two formulations are significantly different (P<0.05), and the differences between the elevations are significant.

CONCLUSIONS

[0143] The permeation of diclofenac through the two membranes was significantly greater for film B according to the invention, while the lag time of the two formulations tested was similar (approximately 2 hours).