SYSTEM FOR THE IMMEDIATE RELEASE OF ACTIVE AGENTS

Abstract

It relates to a nonwoven fabric membrane for topical use on the skin, which comprises polymeric nanofibres and an active agent in an amount from 25 to 80% by weight with respect to the total weight of the nonwoven fabric membrane, wherein the active agent is soluble in a suitable biocompatible solvent system, and wherein the membrane is capable of releasing the active agent immediately when the membrane is contacted with an appropriate amount of the suitable solvent biocompatible system in which the active agent is completely solubilised. It also relates to a process for the preparation of the nonwoven fabric membrane, to a cosmetic or sanitary product and a kit comprising them and to their therapeutic and cosmetic uses.

Claims

1. A nonwoven fabric membrane for topical use on the skin, which comprises polymeric nanofibres and an active agent comprised in an amount from 25 to 80% by weight with respect to the total weight of the nonwoven fabric membrane, wherein a) the active agent is soluble in a suitable biocompatible solvent system, b) the membrane is capable of releasing an amount equal to or greater than 70% of the total weight of the active agent in a 30-minute period after contacting the membrane with an appropriate amount of the suitable biocompatible solvent system in which the active agent is completely solubilised, and c) the total content of the active agent is arranged externally to the polymeric nanofibres of the membrane.

2. The nonwoven fabric membrane according to claim 1, further comprising a second active agent, which is soluble in a suitable biocompatible solvent system, wherein the membrane is capable of releasing said second active agent immediately when contacted with an appropriate amount of the suitable biocompatible solvent system in which the second active agent is completely solubilised.

3. The nonwoven fabric membrane according to claim 1, wherein the polymeric nanofibres are electrospun nanofibres.

4. The nonwoven fabric membrane according to claim 1, wherein the polymeric nanofibres of the membrane have an average diameter from 50 to 2000 nm.

5. The nonwoven fabric membrane according to claim 1, wherein the polymeric nanofibres comprise one or more polymers selected among polyglycolic acid, poly-D,L-lactic acid, poly-D,L-lactide-co-glycolide, polycaprolactone, polydioxanone, polyvinyl alcohol, collagen, cellulose, hyaluronic acid, polyamide, polyester, polyurethane, polypropylene, elastanes, and a combination thereof.

6. The nonwoven fabric membrane according to claim 1, wherein the active agent comprises an amount from 30 to 70% by weight with respect to the total weight of the nonwoven fabric membrane.

7. The nonwoven fabric membrane according to claim 1, wherein the active agent is a therapeutic and/or cosmetic agent.

8. The nonwoven fabric membrane according to claim 1, wherein the active agent is resveratrol or Vitamin C.

9. The nonwoven fabric membrane according to claim 1, which is capable of releasing an amount which is equal to or greater than 70% of the total weight of the active agent that is contained in the membrane during a period of 30 minutes when contacting the membrane with an appropriate amount of the suitable biocompatible solvent system in which the active agent is completely solubilised.

10. A process for the preparation of the nonwoven fabric membrane defined in claim 1, which comprises the following steps: a) preparing a solution of one or more biocompatible polymers in a suitable solvent system; b) preparing a solution of the active agent in a suitable solvent system, wherein the polymer or polymers from step a) are insoluble; c) carrying out the electrospinning of the solution from step a) and, simultaneously, the spray of the solution from step b) with a flow rate of the solution from step b) and during an appropriate time to obtain a nonwoven fabric membrane comprising the active agent in an amount from 25% to 80% by weight with respect to the total weight of the nonwoven fabric membrane; and d) optionally, drying the nonwoven fabric membrane obtained from step c).

11. A kit comprising the nonwoven fabric membrane defined in any of claim 1 and a suitable biocompatible solvent system capable of solubilising the active agent of the membrane when contacted therewith.

12. The kit according to claim 11, wherein the biocompatible solvent system comprises one or more solvents selected from the group consisting of water, ethanol, ethylene glycol, propylene glycol, butylene glycol, diethylene glycol, tetraethylene glycol, 1,2,3-propanetriol (glycerin), benzyl alcohol, triglycerids of capric/caprylic acid, vegetable oil, mineral oil, animal fat, fractions and mixtures thereof.

13. The kit according to claim 11, wherein the biocompatible solvent system is part of a topical composition that further comprises one or more appropriate topical excipients or carriers.

14. The kit according to claim 13, wherein the topical composition is selected from the group consisting of a liquid, a gel, a paste, a cream, an emulsion, a lotion, a foam, a spray, a patch and a stick.

15. A cosmetic or sanitary product comprising the nonwoven fabric membrane defined in claim 1.

16. A method for the treatment of a mammal, including a human, suffering from a disease, disorder or abnormal condition of the skin, said method comprising the topical application on the skin of said mammal, including a human, of the nonwoven fabric membrane as defined in claim 1, wherein the active agent is a therapeutic agent.

17. A method for the treatment of a mammal, including a human, suffering from a disease, disorder or abnormal condition of the skin, said method comprising the topical application on the skin of said mammal, including a human, of the product as defined in claim 15, wherein the active agent is a therapeutic agent.

18. The method according to claim 16, wherein the disease, skin disorder or anomalous condition is selected from the group consisting of cellulitis, acne, skin aging, hyperpigmentation, keratosis, dandruff, warts, photodamaged skin, chronic dermatosis, dryness, ichthyosis, wound healing and skin infections caused by viruses, fungi or bacteria.

19. A cosmetic method for the skin care of a mammal, including a human, said method comprising the topical application on the skin of said mammal, including a human, of the nonwoven fabric membrane according to claim 1, wherein the active agent is a cosmetic agent, where skin care comprises improving at least one of the following symptoms: aging, wrinkles, skin blemishes, cellulite, skin imperfections, roughness, scaling, dehydration, strain, cracking and lack of elasticity.

20. The method according to claim 17, wherein the disease, skin disorder or anomalous condition is selected from the group consisting of cellulitis, acne, skin aging, hyperpigmentation, keratosis, dandruff, warts, photodamaged skin, chronic dermatosis, dryness, ichthyosis, wound healing and skin infections caused by viruses, fungi or bacteria.

21. A cosmetic method for the skin care of a mammal, including a human, said method comprising the topical application on the skin of said mammal, including a human, of the product according to claim 16, wherein the active agent is a cosmetic agent, where skin care comprises improving at least one of the following symptoms: aging, wrinkles, skin blemishes, cellulite, skin imperfections, roughness, scaling, dehydration, strain, cracking and lack of elasticity.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0081] FIG. 1 shows a diagram (A: side view; B: front view) of a particular embodiment of a system for the preparation of the nonwoven fabric membranes of the invention, wherein a) is the electrospray system of the active agent, b) the obtained nonwoven fabric membrane, c) the rotatory collector and d) is the electrospinning system of the polymeric nanofibres.

[0082] FIG. 2 shows images obtained by scanning electron microscopy (SEM) of the membrane of the invention of Example 1 at different magnifications.

[0083] FIG. 3 shows images obtained by scanning electron microscopy (SEM) of the membrane of the invention of Example 2 at different magnifications.

[0084] FIG. 4 shows images obtained by scanning electron microscopy (SEM) of the membrane of the Comparative Example 1, prepared according to the process of the state of the art, at different magnifications.

[0085] FIG. 5 shows the amount of L-ascorbic acid released as fraction (%) with respect to the total theoretical amount of a nanofibre membrane prepared according to Example 1 (A) and of a nanofibre membrane prepared according to Comparative Example 1 (B) over time.

[0086] FIG. 6 shows a particular embodiment of the application of a nonwoven fabric membrane of the invention on human skin, said membrane having 15 mm diameter, loaded with 10 mg of vitamin C on a gel of carbopol at different stages of the membrane wetting: 5 minutes (A), 15 minutes (B) and 25 minutes (C) after contacting the membrane with the gel.

EXAMPLES

Technique of High-Performance Liquid Chromatography (HPLC) for Quantification of L-ascorbic Acid

[0087] Selected conditions for the HPLC technique of detection of L-ascorbic acid were the following ones: [0088] HPLC Shimadzu equipment consisting of isocratic pump LC 20 AD, SIL HT 20A autoinjector, 20A SPD UV detector. [0089] HPLC Column Tracer Excel 120 ODSA, particle size 5 m, 150.4 cm. [0090] Mobile phase 65% methanol, 35% water, flow 0.75 mL/min. [0091] Sample volume 10 L. [0092] Standard concentrations: 50, 100, 250 and 500 g/mL (prepared in phosphate buffered saline, PBS). [0093] Quality Control Concentration: 150 ng/mL (prepared in PBS).

[0094] Under these conditions, the peak of L-ascorbic acid appears at retention time=2.1 min. The calibration line is linear in the range of concentrations studied.

Example 1

Preparation of a Nonwoven Fabric Membrane with L-Ascorbic Acid

[0095] A solution of 17% (by mass) of PLA was prepared in a mixture of 40% dioxane and 60% acetone. The solution was stirred during 24 h to ensure its regularity. This solution was used for the electrospinning (creation of the fibres) on a cylindrical rotatory collector at a distance of 100 mm and a voltage difference of 15 kV (positive in the needle). The injection flow rate of the polymer solution was 15.5 mUh. Simultaneously, on the same cylinder and in a disposition at 180 (as shown in FIG. 1) the electrospraying of the active agent solution was performed. This solution was prepared by dissolving 2.6% (by mass) of vitamin C in ethanol and stirring for 6 hours. The electrospray was performed at a distance of 25 mm from the collector and with a voltage of 10 kV (positive in the needle). The 80 mm-diameter cylinder, rotated at an angular velocity of 16 min.sup.1. The simultaneous process of electrospinning and electrospraying was maintained during 56 min obtaining membranes with an average thickness of 0.352 mm and with a ratio of active agent in the membrane of 51% (w/w). FIG. 2 shows images obtained by scanning electron microscopy (SEM) of the membrane obtained at different magnifications.

Example 2

Preparation of a Nonwoven Fabric Membrane with Resveratrol

[0096] A solution of 15.8% (by mass) of PLA was prepared in a mixture of 40% dioxane and 60% acetone. The solution was stirred during 24 h to ensure its regularity. This solution was used for the electrospinning (creation of the fibres) on a cylindrical rotatory collector at a distance of 100 mm and a voltage difference of 15 kV (positive in the needle). The injection flow rate of the polymer solution was 15.5 mL/h. Simultaneously, on the same cylinder and in a disposition at 180 (as shown in FIG.1) the electrospraying of the active agent solution was performed. This solution was prepared by dissolving 1.47% (by mass) of resveratrol in ethanol and stirring for 6 hours. The electrospray was performed at a distance of 25 mm from the collector and with a voltage of 10 kV (positive in the needle). The 80 mm-diameter cylinder, rotated at an angular velocity of 16 min.sup.1. The simultaneous process of electrospinning and electrospraying was maintained during 60 min obtaining membranes with an average thickness of 0.326 mm and with a ratio of active agent in the membrane of 30% (w/w). FIG. 3 shows images obtained by scanning electron microscopy (SEM) of the membrane obtained at different magnifications.

Comparative Example 1

Preparation of a Nonwoven Membrane With L-Ascorbic Acid According to the Corresponding Process to that Described in the State of the Art (JP2008179629)

[0097] A solution of 11.3% (by mass) of PLA was prepared in a mixture of 40% dioxane and 60% acetone. A 5.7% (by mass) of vitamin C was added to the solution. The solution was stirred during 24 h to ensure its regularity. This solution was used for the electrospinning (creation of the fibres with Vitamin C in them) on a cylindrical rotatory collector at a distance of 100 mm and a voltage difference of 15 kV (positive in the needle). The injection flow rate of the polymer solution was 15.5 mL/h. The 80 mm-diameter cylinder, rotated at an angular velocity of 16 min.sup.1. The process of electrospinning was maintained during 117 min obtaining membranes with an average thickness of 0.306 mm and with a ratio of active agent in the membrane of 33% (w/w). FIG. 4 shows images obtained by scanning electron microscopy (SEM) of the membrane of the Comparative Example 1 at different magnifications.

Example 3

Release Assay

[0098] In culture plates in plastic material, of 6 wells, 0.50 grams of carbopol gel (carbopol gel 940 to 1% w/v in distilled water) per well were deposited, and then on the gel a nanofibre membrane (of 15 mm diameter) loaded with 10 mg of L-ascorbic acid (theoretical load) prepared according to Example 1 or a nanofibre membrane (15 mm diameter) loaded with 12 mg of L-ascorbic acid (theoretical load) prepared as Comparative Example 1. In the case of the membrane of the invention, it was tested by HPLC technique that the theoretical charge and the actual total load (calculated as the sum of the amount of L-ascorbic acid released and the amount of L-ascorbic acid remaining in the membrane) were equivalent. The plates were incubated, covered from that moment, at 37 C. To measure the amount of L-ascorbic acid released at set times (30 minutes in the case of the membrane prepared according to Example 1) and 30, 60, 90 and 120 minutes in the case of the membrane prepared according to Comparative Example 1) the membranes were removed, 9.5 mL of phosphate buffered saline (PBS) were added to each well and they were mixed by pipetting the gel in the same well. From there, a sample of 1 mL was taken and was diluted with 1 mL of PBS in a 12 mL-amber vial. With a 1 mL-disposable syringe, part of the vial content was aspirated and that content was filtered to an HPLC vial with a 0.45 m-disposable filter to remove insolubles compounds. The sample in the vial was injected into the HPLC apparatus under the conditions previously described. The amount of ascorbic acid released at each time was represented as fraction (%) with respect to the total amount (theoretical load of the manufacturing process). Studies were performed in triplicate.

[0099] FIG. 4 shows the amount of ascorbic acid released at each time represented as fraction (%) with respect to the theoretical total amount. It has been observed that the release of L-ascorbic acid from the nanofibre membranes of the invention (prepared according to Example 1) was 8724% after 30 minutes. Moreover, it was proved by HPLC that the active agent was released in unaltered form. Furthermore, the release of L-ascorbic acid from the nanofibre membranes of the state of the art (prepared according to Comparative Example 1) was inferior to 5% after 30 minutes, 10.20.7% after 60 minutes, 11.00.7% after 90 minutes, and 12.77.0% after 120 minutes.

Analysis of Results:

[0100] While the membranes of the invention are capable of quickly releasing practically the total amount of active agent contained in the membrane when contacted with the gel base, the membranes of the state of art with a comparable loading of active agent are only capable of immediately releasing small fractions (less than 5%) and even with prolonged incubations (120 minutes) only a very moderated release of 13% is achieved.

REFERENCES CITED IN THE APPLICATION

[0101] JP2008179629