SELF-ADHESIVE PATCHES MADE OF FIBRES FOR THE CONTROLLED RELEASE OF BIOACTIVES

Abstract

The present invention falls within the area of polymeric materials based on ultrafine fibres for use in the pharmaceutical, nutraceutical and cosmetic sector, relating to the method of producing self-adhesive patches and the use thereof as a platform for the controlled release of bioactives by means of electrohydrodynamic and/or aerohydrodynamic processing techniques.

Claims

1. A self-adhesive patch as a platform for controlled release of bioactives comprising at least: i) a first block A which is in contact with the corporal mucosa or skin to which it adheres characterised in that it is formed by at least one layer of fibres made of one or more hydrophilic polymers, and in that it has a surface density of at least 0.2 g/m.sup.2; ii) a second block B deposited on the block A, containing the encapsulated bioactive(s), characterised in that it is formed by at least one layer of fibres made of one or more hydrophilic polymers, hydrophobic polymers, or a mixture of both, and in that it has a surface density of at least 0.2 g/m.sup.2; iii) a third block C deposited on the block B, characterised in that it is formed by at least one layer of fibres made of one or more hydrophobic polymers, and in that it has a surface density of at least 0.2 g/m.sup.2.

2. The patch according to the preceding claim, wherein the hydrophilic polymers are independently selected from polyethylene oxide and derivatives thereof as non-ionic water-soluble resins, polyvinylpyrrolidone and the copolymers thereof, polyvinyl alcohols and the copolymers thereof with ethylene, polyacrylates, polyacrylic acid, water-soluble polyacronitriles, lignin and derivatives, acrylic and methacrylic ester polymers, polysaccharides and derivatives, hyaluronic acid, pullulan, alginate, tragacanth, carrageenan, chitin and derivatives, celluloses, gluocogen, starch and polymers derived from it, pectin, guar gum, xanthan gum, fructosan, gellan, collagen, gelatin, soy protein, whey protein, zein, gluten, casein, lectins, thiolated polymers, polyanhydrides, and PAA polyethylene glycol copolymers, as well as the mixtures thereof.

3. The patch according to the preceding claim, wherein the hydrophilic polymers are independently selected from polyvinylpyrrolidone, polyethylene oxide, polyvinyl alcohols, polyacrylates, zeins, gluten derivatives, materials and cellulosics, or combinations thereof.

4. The patch according to any of the preceding claims, wherein the hydrophobic polymers are independently selected from non-water-soluble proteins, polyhydroxyalkanoates, medium-chain-length polyhydroxyalkanoates, and all the possible copolymers thereof, poly-ε-caprolactone and all the copolymers thereof, polylactic acid and all the copolymers thereof, polyphosphazenes, polyorthoesters, polyesters obtained from natural precursors, silicones, polyesters, polyurethanes, polysulphones, halogenated polymers, polycarbonates, acrylonitrile butadiene styrene, latex, and polyamides, as well as the mixtures thereof.

5. The patch according to any of the preceding claims, wherein the hydrophilic polymers of the block A form an emulsified mixture of polyethylene oxide and polyvinylpyrrolidone.

6. The patch according to any of the preceding claims, wherein the hydrophilic polymer of the block A is polyethylene oxide.

7. The patch according to any of claims 5 and 6, wherein block A further contains at least one other polymer which is selected from acrylates, zein, gluten derivatives, ethylcellulose, or a mixture thereof.

8. The patch according to any of the preceding claims, wherein the block B is formed by at least one hydrophobic polymer which is selected from poly-ε-caprolactone, poly-ε-caprolactone copolymers, polylactic acid and the copolymers thereof, and polyhydroxyalkanoates, or any of the mixtures thereof.

9. The patch according to any of claims 1 to 7, wherein the block B is formed by a combination of hydrophilic and hydrophobic polymers.

10. The patch according to any of the preceding claims, wherein the block C is made up of at least one hydrophobic polymer which is selected from poly-ε-caprolactone, poly-ε-caprolactone copolymers, polylactic acid and the copolymers thereof, and polyhydroxyalkanoates, or any of the mixtures thereof.

11. The patch according to any of the preceding claims, wherein block C also contains the same or another bioactive as the one contained in block B.

12. The patch according to any of the preceding claims, wherein the block C further contains other components such as flavours or flavour enhancers if it is applied in the oral cavity, or aromatic substances or flavour enhancers.

13. The patch according to any of the preceding claims, wherein between the blocks B and C, at least one layer (B′) is incorporated which is formed by at least one hydrophilic polymer.

14. The patch according to any of the preceding claims wherein the block A contains at least one adhesive material.

15. The patch according to the preceding claim wherein the adhesive material is hypoallergenic.

16. The patch according to any of claims 14 to 15 wherein the adhesive material is porous.

17. The patch according to any of claims 14 to 15 wherein the adhesive material is permeable to the bioactive.

18. The patch according to any of the preceding claims wherein the bioactive is an active pharmaceutical ingredient.

19. A method for obtaining a self-adhesive patch as a platform for controlled release of bioactives according to any of claims 1 to 18, comprising the following steps: a) Preparation of the block A starting from a solution of the hydrophilic polymer or polymers at a concentration between 0.01 and 98% by weight, wherein the voltage of the emitter used is between 0.01 and 500 kV and a voltage in the collector between 0 kV and −500 kV, with a flow rate between 0.0001 to 1,000,000 ml/h, at a temperature between 1° C. and 100° C. and a relative humidity between 0% and 100%; b) Preparation of the block B starting from a solution of the hydrophilic and/or hydrophobic polymer or polymers at a concentration between 0.01 and 98% by weight, and at least one bioactive in a concentration between 0 and 98% by weight, wherein the voltage of the emitter used is between 0.01 kV and 500 kV and the voltage in the collector between 0 kV and −500 kV, with a flow rate between 0.0001 to 1,000,000 ml/h at a temperature between 1° C. and 100° C. and a relative humidity between 0% and 100%; c) Preparation of the block C starting from a solution of the hydrophobic polymer or polymers at a concentration between 0.01 and 98% by weight, and optionally one or more bioactives in a concentration between 0 and 98% by weight, wherein the voltage of the emitter used is between 0.01 kV and 500 kV and the voltage in the collector between 0.01 kV and −500 kV, with a flow rate between 0.0001 to 1,000,000 ml/h at a temperature between 1° C. and 100° C. and a relative humidity between 0% and 100%; d) Processing of the blocks produced either continuously or separately in steps (a), (b), and (c) by means of lamination.

20. The method according to the preceding claim, wherein the lamination is carried out by low-temperature calendering.

21. The method according to the preceding claim, wherein the calendering of the layers produced is carried out such that it is the last layer of the block C which is in contact with the roller.

22. The method according to any of the preceding claims wherein each of the blocks are formed by means of the electrospinning technique.

23. The method according to the preceding claim wherein controlled-outlet, multi-outlet or multi-emitter injectors are used.

24. The method according to any of claims 22 to 23 wherein the resulting fibre diameter is less than 35%.

25. The method according to any of claims 22 to 24 wherein the variation in the fibre diameter for a given system with a multi-outlet injector is at least 5% less than that which would be produced with uncontrolled outlet injectors.

26. The method according to any of claims 22 to 24 wherein the variation in the fibre diameter for a given system with a multi-outlet injector is at least 15% less than that which would be produced with uncontrolled outlet injectors.

27. The method according to any of claims 19 to 21 for obtaining a self-adhesive patch as a platform for controlled release of bioactives according to any of claims 14 to 18 wherein the adhesive material is not manufactured by electrohydrodynamic or aerohydrodynamic processing techniques.

28. A pharmaceutical use of the patch according to any of claims 1 to 18 for the controlled release of one or more bioactives.

29. A nutraceutical or cosmetic use of the patch according to any of claims 1 to 18 for the controlled release of one or more bioactives.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0096] FIG. 1. Typical configuration of the patch according to the multilayer system.

[0097] FIG. 2. Release profile of Ropinirole Hydrochloride in three different polymeric matrices.

[0098] FIG. 3. Release profile of Ropinirole Hydrochloride at different concentrations in the PHB matrix.

[0099] FIG. 4. Release profile of Ropinirole Hydrochloride in three different matrix combinations.

[0100] FIG. 5. Release profile of Carvedilol in three different polymeric matrices.

[0101] FIG. 6. Release profile of Carvedilol at different concentrations in the PCL matrix.

[0102] FIG. 7. Release profile of Carvedilol in three different polymeric matrix combinations.

[0103] FIG. 8. Comparison of release profile of Ropinirole Hydrochloride in a multilayer patch vs. a monolayer patch.

[0104] FIG. 9. Comparison of release profile of Ropinirole Hydrochloride in a multilayer patch with a commercial adhesive vs. a monolayer patch.

[0105] FIG. 10. Comparison of release profile of Carvedilol in the release of the multilayer patch vs. monolayer patch.

[0106] FIG. 11. Comparison of release profile of Carvedilol in a multilayer patch with a commercial adhesive vs. a monolayer patch.

EXAMPLES

[0107] Next, the invention will be illustrated by means of examples carried out by the inventors, that demonstrate the effectiveness of the product of the invention. To do so for each example, the controlled release in artificial saliva of each drug in the different matrices is indicated, indicating the degree of controlled release of each system.

Example 1: Preparation of the Block B for a Release of Water-Soluble Ropinirole Hydrochloride (API) System in Different Matrices (PCL, PDL20 and PHB) by Monoaxial Electrospinning

[0108] The matrices used were polyhydroxybutyrate (PHB), poly(D,L-lactic acid) (PDLA) and poly-ε-caprolactone (PCL) containing an encapsulation of Ropinirole hydrochloride in a polymer:API ratio of 80:20. To this end, the starting point was a solution of PHB at 8% by weight (wt %) in 2,2,2-Trifluoroethanol (TFE), a solution of PDLA at 8 wt % in TFE, and a solution of PCL also at 8% by weight (wt %) in TFE. For each polymeric solution, 2% by weight (wt %) of solution was added, in order to maintain a polymer:API ratio of 80:20.

[0109] Once both components were dissolved, then the fibre sheet was manufactured by means of the electrospinning technique in a 24-needle linear multi-outlet injector.

[0110] In order to produce the PCL fibre mat, a voltage on the emitter of 30 kV was used, as well as a voltage in the collector of −30 kV. A flow rate of 5 ml/h was also used. The fibres were deposited on a rotating collector (200 rpm) covered with a pharmaceutical-grade waxed substrate at a distance of 17 cm. For the case of the PDL20 fibre mat, a voltage on the emitter of 30 kV was used, as well as a voltage in the collector of −10 kV. A flow rate of 5 ml/h was also used. The fibres were also deposited on a rotating collector (200 rpm) covered with a pharmaceutical-grade waxed substrate at a distance of 20 cm. Lastly, in order to produce the PHB fibre mat, a voltage on the emitter of 25 kV was used, as well as a voltage in the collector of −5 kV and a flow rate of 20 ml/h. As in the other cases, the fibres were deposited on a rotating collector (200 rpm) covered with a pharmaceutical-grade waxed substrate at a distance of 25 cm.

[0111] For all cases, a temperature of 20° C. and a relative humidity of 35% were used, in Fluidnatek LE-100 equipment from Bioinicia SL, Valencia, Spain.

[0112] The quantification of the release of the Ropinirole hydrochloride was performed by means of UV-spectrophotometry at a wavelength of 249 nm, measuring 3 patches of each in a circular shape with a surface area of 2 cm.sup.2 for each matrix, in artificial saliva (pH=6.8), under continuous stirring and at 37° C., for 8 h.

[0113] In this example, the PCL resulted in a fast release and the PHB in a more sustained release (see FIG. 2).

Example 2: Preparation of the Block B for a Sustained Release System of Different Concentrations of Water-Soluble Ropinirole Hydrochloride (API) in a PHB Matrix by Monoaxial Electrospinning

[0114] The matrix used for this case was polyhydroxybutyrate (PHB). In this example, the same solution and processing conditions were used for this matrix as the ones discussed in the previous example. In contrast, in this example, a comparison is made based on the concentration of Ropinirole hydrochloride added in the patch. To do so, three solutions were made with different API content, the concentrations being 0.45%, 0.9% and 2% by weight (wt %) of solution, which corresponds to a polymer:API ratio of 95:5, 90:10 and 80:20, respectively. As for the processing conditions for each concentration, they were the same as those set forth in the previous example.

[0115] Also, as in the previous example, the measurements by UV-spectrophotometry were performed by measuring 3 patches of each in a circular shape with a surface of 2 cm.sup.2 for each matrix, in artificial saliva (pH=6.8), under continuous stirring and at 37° C., for 8 h.

[0116] Also, as in the previous example, the quantification of the release of the Ropinirole hydrochloride was performed by means of UV-spectrophotometry at a wavelength of 249 nm, measuring 3 patches of each in a circular shape with a surface area of 2 cm.sup.2 for each concentration, in artificial saliva (pH=6.8), under continuous stirring and at 37° C., for 8 h.

[0117] In the example it can be seen that lower concentrations of the API lead to a more sustained release profile (see FIG. 3).

Example 3: Preparation of the Block B for a Sustained Release System of Water-Soluble Ropinirole Hydrochloride (API) in Matrices of Mixtures of PHB with PCL by Monoaxial Electrospinning

[0118] This example shows how the mixture of matrices affects the release of a water-soluble API such as Ropinirole hydrochloride. To do so, three different combinations of poly-ε-caprolactone (PCL) and polyhydroxybutyrate (PHB) have been selected. The combinations studied were the following: 50/50 PCL/PHB, 80/20 PCL/PHB and 20/80 PCL/PHB. In this example, Ropinirole hydrochloride was encapsulated in a polymer:API ratio of 80:20.

[0119] To this end, the starting point was a solution of at 4% by weight (wt %) of PCL, 4% by weight (wt %) of PHB in a TFE for the 50/50 PCL/PHB combination. Moreover, for the 80/20 PCL/PHB combination, a solution with the same solvent was used, but with 6.4% by weight (wt %) of PCL and 1.6% by weight (wt %) of PHB. For the 20/80 PCL/PHB combination, the same solvent was also used but with 1.6% by weight (wt %) of PCL and 6.4% by weight (wt %) of PHB. For all combinations, 8% by weight (wt %) of Ropinirole hydrochloride was added, in order to maintain the polymer:API ratio of 80:20.

[0120] In order to produce the fibre mats of each combination, a voltage on the emitter of 25 kV was used, as well as a voltage in the collector of −5 kV. A flow rate of 20 ml/h was also used. The fibres were deposited on a rotating collector (200 rpm) covered with a pharmaceutical-grade waxed substrate at a distance of 20 cm in Fluidnatek LE-100 equipment. For all cases, a temperature of 20° C. and a relative humidity of 35% were used.

[0121] Also, as in the previous example, the quantification of the release of the Ropinirole hydrochloride was performed by means of UV-spectrophotometry at a wavelength of 249 nm, measuring 3 patches of each in a circular shape with a surface area of 2 cm.sup.2 for each mixture, in artificial saliva (pH=6.8), under continuous stirring and at 37° C., for 1 h.

[0122] In this example, it is shown that combining materials which lead to a fast release with others that show slow release one can achieve the regulation of the release of the API (see FIG. 4).

Example 4: Preparation of the Block B for a Release System of Water-Insoluble Carvedilol (API) in Different Matrices (PCL, PDLA and PHB) by Monoaxial Electrospinning

[0123] The matrices used were polyhydroxybutyrate (PHB), poly(D,L-lactic acid) (PDLA) and poly-ε-caprolactone (PCL). In this example, Carvedilol was encapsulated in a polymer:API ratio of 90:10. To this end, the starting point was a solution of PHB at 8% by weight (wt %) of TFE, a solution of PDLA at 8 wt % in an 80:20 Acetone/DMF mixture, and a solution of PCL also at 8% by weight (wt %) in a 70:30 Chloroform:Acetone mixture. For each polymeric solution, 0.9% by weight (wt %) of API was added, in order to maintain a polymer drug ratio of 90:10. Once both components were dissolved, then the fibre sheet was manufactured by means of the electrospinning technique in a linear multi-outlet injector.

[0124] In order to produce the PCL fibre mat, a voltage of the emitter of 20 kV was used, as well as a voltage in the collector of −20 kV. A flow rate of 20 ml/h was also used. The fibres were deposited on a rotating collector (200 rpm) coated by a pharmaceutical-grade waxed substrate at a distance of 30 cm. For the case of the PDLA fibre mat, a voltage on the emitter of 20 kV was used, as well as a voltage in the collector of −20 kV, using a flow rate of 15 ml/h. The fibres were also deposited on a rotating collector (200 rpm) coated by a pharmaceutical-grade waxed substrate at a distance of 30 cm. Lastly, in order to produce the PHB fibre mat, a voltage of the emitter of 25 kV was used, as well as a voltage in the collector of −5 kV and flow rate of 20 ml/h. As in the other cases, the fibres were deposited on a rotating collector (200 rpm) covered with a pharmaceutical-grade waxed substrate at a distance of 25 cm.

[0125] For all cases, a temperature of 20° C. and a relative humidity of 35% were used, in Fluidnatek LE-100 equipment.

[0126] The quantification of the release of the Carvedilol was performed by means of UV-spectrophotometry at a wavelength of 240 nm, measuring 3 patches of each in a circular shape with a surface area of 2 cm.sup.2 for each matrix, in artificial saliva (pH=6.8), under continuous stirring and at 37° C., for 8 h.

[0127] In this example, it is observed how the PDLA leads to a very slow release and PHB to a quicker release (see FIG. 5).

Example 5: Preparation of the Block B for a Sustained Release System of Different Concentrations of Water-Insoluble Carvedilol (API) in a PCL Matrix by Monoaxial Electrospinning

[0128] The matrix used for this case was poly-ε-caprolactone (PCL). In this example, the same solution and processing conditions were used for this matrix as the ones discussed in the previous example. In contrast, in this example, a comparison is made based on the concentration of Carvedilol added in the patch. To do so, three solutions were made with different API content, the concentrations being 0.45%, 0.9% and 2% by weight (wt %) of solution, which corresponds to a polymer:API ratio of 95:5, 90:10 and 80:20, respectively.

[0129] Also, as in the previous example, the quantification of the release of the Carvedilol was performed by means of UV-spectrophotometry at a wavelength of 240 nm, measuring 3 patches of each in a circular shape with a surface area of 2 cm.sup.2 for each concentration, in artificial saliva (pH=6.8), under continuous stirring and at 37° C., for 8 h.

[0130] In this example, it is again observed that lower concentrations of the API lead to a more sustained release (see FIG. 6).

Example 6: Preparation of the Block B for a Sustained Release System of Water-Insoluble Carvedilol (API) in Matrices of Mixtures of PCL with PDLA by Monoaxial Electrospinning

[0131] This example shows how the mixture of matrices affects the release of an insoluble drug such as Carvedilol. To do so, three different combinations of poly-ε-caprolactone (PCL) and poly(D,L-lactic acid) (PDLA) have been selected. The combinations studied were the following: 50/50 PCL/PDLA, 80/20 PCL/PDLA, and 20/80 PCL/PDLA. In this example, Carvedilol was encapsulated in a polymer:API ratio of 90:10.

[0132] To this end, the starting point was a solution of at 4% by weight (wt %) of PCL, 4% by weight (wt %) of PDLA in a 70:30 Chloroform:Acetone mixture for the 50/50 PCL/PDLA combination. Moreover, for the 80/20 PCL/PDLA combination, a solution with the same mixture of solvents was used, but with 6.4% by weight (wt %) of PCL and 1.6% by weight (wt %) of PDLA. For the 20/80 PCL/PDLA combination, the same mixture of solvents was also used but with 1.6% by weight (wt %) of PCL and 6.4% by weight (wt %) of PDLA.

[0133] In order to produce the fibre mats of each combination, a voltage on the emitter of 20 kV was used, as well as a voltage in the collector of −5 kV. A flow rate of 20 ml/h was also used. The fibres were deposited on a rotating collector (200 rpm) covered with a pharmaceutical-grade waxed substrate at a distance of 30 cm in Fluidnatek LE-100 equipment. For all cases, a temperature of 20° C. and a relative humidity of 35% were used.

[0134] Also, as in the previous example, the quantification of the release of the Carvedilol was performed by means of UV-spectrophotometry at a wavelength of 240 nm, measuring 3 patches of each in a circular shape with a surface area of 2 cm.sup.2 for each mixture, in artificial saliva (pH=6.8), under continuous stirring and at 37° C., for 8 h.

[0135] In FIG. 7, it is observed again how the mixture with the highest content of PDLA leads to a slower release.

Example 7: Release System of a Water-Soluble API (Ropinirole) in a Tri-Layer Patch Format. Water-Soluble Inner Layer (Block A) of PEO/PVP/EC, Interlayer of PHB with API and Protective Outer Layer (Block C) of PCL

[0136] This example shows how the release of a tri-layer patch is.

Preparation of the First Inner Hydrophilic Layer (Block A)

[0137] A solution was used of 8% by weight of polyethylene oxide (PEO), 4% by weight of polyvinylpyrrolidone (PVP) and 1% by weight of ethyl cellulose (EC) in a mixture of ethanol/water in a ratio of 5:5. The manufacturing conditions used were a voltage on the emitter of 30V and a voltage in the collector of −20 kV, a flow rate of 26 ml/h was also used, through a multi-outlet linear injector. The fibres were deposited on a rotating collector (200 rpm) coated by a waxed paper substrate and at a distance of 28 cm. Such manufacturing process was performed at a temperature of 25° C. and a relative humidity of 30%. In this case, the surface density is 20 g/m.sup.2.

Preparation of the Second Hydrophobic Layer with Encapsulated API (Block B)

[0138] This layer was made following the conditions of example 1 for PHB. This layer has a surface density of 10 g/m.sup.2.

Preparation of the Third External Hydrophobic Layer (Block C)

[0139] A solution is made of Poly-ε-caprolactone (PCL) at 12% by weight, in 79% by weight of Chloroform and 9% Methanol. For the production of this layer on the PVP/Perfume layer, a voltage on the emitter of 23 kV and a voltage in the collector of −1 kV were used, a flow rate of 10 ml/h was also used, through a multi-outlet linear injector. This last layer must have a surface density near 12 g/m.sup.2 since the main function thereof is protection and a barrier towards the outlet of the API.

[0140] Once each layer has been manufactured independently, they are joined together by the calendering technique at a speed of 2.56 rpm and by heating only the roller which is in contact with the external layer to 40° C. In this manner, the adhesion between layers is ensured and a coalescence of the fibres is performed, reducing the porosity of the external layer of PCL so that the barrier effect is more effective.

[0141] Also, as in the previous example, the quantification of the release of the Ropinirole hydrochloride was performed by means of UV-spectrophotometry at a wavelength of 249 nm, measuring 3 patches with a surface area of 2 cm.sup.2, in artificial saliva (pH=6.8), under continuous stirring and at 37° C., for 6 h.

[0142] FIG. 8 shows how the release of the API is regulated in a more sustained manner than in example 1 of the monolayer, reaching a constant release speed.

Example 8: Release System of a Water-Soluble API (Ropinirole) in a Tri-Layer Patch Format. Porous Commercial Adhesive Internal Layer (Block A), Intermediate Layer (Block B) of PHB with API and External Protective Layer (Block C) of PCL

[0143] This example shows how the release of the sandwich-like tri-layer patch is.

[0144] This case is similar to the previous one, but the first layer is based on a 3M commercial double-sided adhesive tape (Ref No. 9917), which is hypoallergenic and especially porous for the contact with the mucosa. The rest of the layers were produced as described in the previous example.

[0145] Once each layer has been manufactured independently, they are joined together by the calendering technique at a speed of 2.56 rpm and by heating only the roller which is in contact with the external layer at 40° C. In this manner, the adhesion between layers is ensured and a coalescence of the fibres is performed, reducing the porosity of the external layer of PCL so that the barrier effect is more effective.

[0146] Also, as in the previous example, the quantification of the release of the Ropinirole hydrochloride was performed by means of UV-spectrophotometry at a wavelength of 249 nm, measuring 3 patches with a surface area of 2 cm.sup.2, in artificial saliva (pH=6.8), under continuous stirring and at 37° C., for 6 h.

[0147] FIG. 9 shows how the release of the API is regulated in a much more sustained manner than in example 1 witnthe monolayer, showing two constant release rates.

Example 9: Release System of a Water-Insoluble API (Carvedilol) in a Four-Layer Patch Format. Water-Soluble Layer (Block A) of PEO/PVP/EC, Intermediate Layer (Block B) of PHB with API, Protective Layer (B′) of PEO/PVP/EC and External Protective Layer (Block C) of PCL

[0148] This example shows how the release of the sandwich-like four-layer patch is. The first water-soluble layer of PEO/PVP/EC and the last protective layer of PCL were produced under conditions similar to those of example 7.

[0149] In this case, the hydrophobic intermediate layer was made following the conditions of example 5 for PHB. This layer has a surface density of 10 g/m.sup.2.

[0150] Furthermore, a hydrophilic layer was added between the intermediate layer containing the API and the external protective layer. To do so, the same conditions were used as the first hydrophilic layer. The function of this layer is to limit the outlet of the API in the direction opposite from the mucosa or skin.

[0151] The quantification of the release of the Carvedilol was performed by means of UV-spectrophotometry at a wavelength of 240 nm, measuring 3 in a circular shape with a surface area of 2 cm.sup.2, in artificial saliva (pH=6.8), under continuous stirring and at 37° C., for 6 h.

[0152] FIG. 10 shows how the release of the API is regulated in a more sustained manner than in the monolayer, showing two constant release speeds.

Example 10: Release System of a Water-Insoluble API (Carvedilol) in a Four-Layer Patch Format. Inner Layer (Block A) with Porous Commercial Adhesive, Intermediate Layer (Block B) of PHB with API, Protective Layer (B′) of PEO/PVP/EC and External Protective Layer (Block C) of PCL

[0153] This example shows how the release of a four layer-sandwich-like patch is. This case is similar to the previous one, but the first layer is based on a commercial double-sided adhesive tape, which is hypoallergenic and especially porous for the contact with the mucosa. The rest of the layers were produced as described in the previous example.

[0154] The quantification of the release of the Carvedilol was performed by means of UV-spectrophotometry at a wavelength of 240 nm, measuring 3 in a circular shape with a surface area of 2 cm.sup.2, in artificial saliva (pH=6.8), under continuous stirring and at 37° C., for 6 h.

[0155] FIG. 11 shows how the release of the API is regulated much more slowly than in the monolayer, with a constant speed from the start.

Example 11: Tri-Layer Release System of a Water-Insoluble API (Carvedilol) Wherein the Intermediate Layer (Block B) is Made by Monoaxial Co-Electrospinning of PCL and PDLA Matrices

[0156] This example shows how the release of the sandwich-like tri-layer patch is.

[0157] The first water-soluble layer (block A) of PEO/PVP/EC and the last protective layer (block C) of PCL were produced under conditions similar to those of example 7.

[0158] In this case, for the intermediate layer which contains the API, two different matrices are deposited simultaneously by codeposition. To do so, the starting point is the same solutions mentioned in example 5 for the PCL and PDLA matrices. The processing conditions were also the same as those set forth in example 5. This layer of combination of fibres made of PCL/Carvedilol and PDLA/Carvedilol has a surface density of 20 g/m.sup.2. of the use of a roll-to-roll system enables the substrate to pass under both injectors continuously, in other words, depositions of PCL/Carvedilol and PDLA/Carvedilol are performed simultaneously in Fluidnatek LE-500 equipment from Bioinicia S. L. Such manufacturing process was performed at a temperature of 25° C. and a relative humidity of 30%.

[0159] Also, as in the previous example, the quantification of the release of the Carvedilol was performed by means of UV-spectrophotometry at a wavelength of 240 nm, measuring 3 patches with a surface area of 2 cm.sup.2, in artificial saliva (pH=6.8), under continuous stirring and at 37° C., for 8 h. The results showed a behaviour similar to the 50PCL/50PDLA mixture, but in this case the total release (100%) of the Carvedilol was at 8 h.

Example 12: Release System of a Water-Insoluble Bioactive (Ketoprofen) in a Tri-Layer Patch Format. Water-Soluble Layer (Block A) of PEO/PVP/EC, Intermediate Layer (Block B) of PCL/Gelatin in Emulsion with Bioactive, and Protective External Layer (Block C) of PCL

[0160] This example shows how the release of the sandwich-like tri-layer patch is.

[0161] The first water-soluble layer of PEO/PVP/EC and the last protective layer of PCL were produced under conditions similar to those of example 7.

[0162] The PCL/gelatin layer with ketoprofen was manufactured maintaining a bioactive-polymer ratio of 5:95. To this end, the starting point was a solution of PCL at 8% by weight (wt %) in chloroform/methanol in a ratio of 4:1 (vol/vol), with a concentration of ketoprofen of 5% by weight (wt %) in relation to the amount of polymers and a concentration of Span80 of 1% by weight (wt %). A solution of gelatin in acetic acid at 25% by weight (wt %) was also prepared. The concentration of gelatin was 32.5% by weight (wt %). In order to produce the emulsion, the PCL solution was added onto the gelatin solution in a ratio of 3:7 (wt./wt.). The resulting mixture was stirred by an Ultra-Turrax in order to generate the emulsion.

[0163] Once the emulsion was prepared, the fibre sheet was manufactured by means of the electrospinning technique. In order to produce the fibre mat, a voltage of 18 kV, a flow rate of 1.1 ml/h and a distance between the injector and the rotating collector (200 rpm) located at 13 cm were used. For all cases, a temperature of 30° C. and a relative humidity of 30% were used.

[0164] In order to prevent the gelatin layer from dissolving in the water during release tests, a cross-linking was performed by placing the fibre mat in contact with the gaseous phase of a glutaraldehyde solution in water at 25% for 1 h.

[0165] The quantification of the release of the Ketoprofen was performed by means of UV-spectrophotometry at a wavelength of 260 nm, measuring 3 circular patches of each sample with a surface area of 2 cm.sup.2, in artificial saliva (pH=6.8), under continuous stirring and at 37° C., for 8 h. The tests demonstrated a sustained release with a diffusion constant of 5.4.Math.10.sup.−15 m.sup.2/s.

Example 13: Tri-Layer Patch of a Water-Insoluble Bioactive (DHA-Rich Algae Oil). Water-Soluble Layer (Block A) of PEO/PVP/EC, Intermediate Layer (Block B) of Whey Protein with Bioactive, and Protective External Layer (Block C) of PCL

[0166] This example shows how the release of the sandwich-like tri-layer patch is.

[0167] The first water-soluble layer of PEO/PVP/EC and the last protective layer of PCL were produced under conditions similar to those of example 7.

[0168] The layer composed of an amorphous solid dispersion of PDLA with DHA-rich algae oil was manufactured maintaining a bioactive-polymer ratio of 33:67. To this end, the starting point was a solution of PDLA at 8 wt % in an 80:20 Acetone/DMF mixture, with a concentration of DHA-rich algae oil of 33% by weight (wt %) in relation to the PDLA. The resulting mixture was thoroughly stirred in order to generate a homogeneous solution.

[0169] In order to produce the fibre mat, a voltage of 15 kV, a flow rate of 0.6 ml/h and a distance between the injector and the flat collector located at 12 cm were used. For all cases, a temperature of 30° C. and a relative humidity of 30% were used.

[0170] The quantification of the release of the DHA-rich algae oil was performed by means of UV-spectrophotometry at a wavelength of 285 nm, measuring 3 circular patches of each sample with a surface area of 2 cm.sup.2, in artificial saliva (pH=6.8), under continuous stirring and at 37° C., for 8 h. The tests demonstrated that the total release was produced in a sustained manner for 6 hours.

Example 14: Continuous Tri-Layer Core-Shell Fibre System of PCL with Soluble API (Ropinirole Hydrochloride)

[0171] This example shows how the release of the sandwich-like tri-layer patch is.

[0172] The first water-soluble layer (block A) of PEO/PVP/EC and the last protective layer (block C) of PCL were produced under conditions similar to those of example 7.

[0173] In this case, the layer which stores the API is produced by means of a device formed by coaxial nozzles. Through the external nozzle (shell), a PCL solution is injected in a 70:30 Chloroform/Methanol mixture at 8% by weight (wt %), using a voltage on the emitter of 20 kV and a voltage in the collector of −10 kV, a flow rate of 10 ml/h was also used. This results in the formation of tubular fibres. Through the internal nozzle (core), a solution of the API at 2% by weight (wt %) in Methanol is injected such that the API is encapsulated in the tubular fibres. The flow rate introduced is 10 ml/h, while obviously the rest of the parameters are the same since it is the same nozzle support. This layer has a surface density of 25 g/m.sup.2.

[0174] Also, as in the previous example, the quantification of the release of the Ropinirole hydrochloride was performed by means of UV-spectrophotometry at a wavelength of 249 nm, measuring 3 patches with a surface area of 2 cm.sup.2, in artificial saliva (pH=6.8), under continuous stirring and at 37° C., for 8 h. In this case, the release process is slower than the one reflected in example 1, in fact, the total release (100%) of the Ropinirole hydrochloride was completed at 8 h.

Example 15: Release System of a Water-Insoluble API (Carvedilol) in a Four-Layer Patch Format by Means of Solution Blow Spinning. Water-Soluble Layer (Block A) of PEO/PVP/EC, Intermediate Layer (Block B) of PHB with API, Protective Layer (B′) of PEO/PVP/EC and External Layer (Block C) of PCL. Produced by Solution Blow Spinning

[0175] This example shows how the release of the sandwich-like four-layer patch is. In this example, it was manufactured by means of the solution blow spinning technique.

Preparation of the First Inner Hydrophilic Layer (Block A)

[0176] As in the previous examples, by a first layer of PEO which is the one which adheres to the skin. This is manufactured by using a 10% by weight solution of PEO in a Chloroform/Acetone mixture in a ratio of 8:2 by weight. To do so, a coaxial injector was used, through which the external nozzle (1 mm in diameter) circulates an air flow at a pressure of 0.5 bar, while through the internal nozzle (0.5 mm in diameter) the polymeric solution circulates with a flow rate of 15 ml/h. These fibres are deposited on a rotating collector (120 rpm) located at 20 cm from the nozzle. This layer has a surface density of 50 g/m.sup.2.

Preparation of the Second Hydrophobic Layer with API (Block B)

[0177] To do so, the starting point is a PCL solution at 8% by weight (wt %) in a Chloroform/Acetone mixture at 70:30. In this polymeric solution, 0.9% by weight (wt %) of Carvedilol was added, in order to maintain a polymer drug ratio of 90:10. For the production of this layer, a pressure of 0.5 bar and a flow rate of 0.25 ml/h were used, through a coaxial injector. This layer was deposited at a distance of 10 cm on the previous layer. This layer must have a surface density of 10 g/m.sup.2.

Preparation of the Third Hydrophilic Barrier Layer (B′)

[0178] This layer is produced in a similar manner to the first hydrophilic layer on the PCL layer with Carvedilol. In contrast, this layer must have a surface area of 30 g/m.sup.2.

Preparation of the Last Protective Hydrophobic Layer (Block C)

[0179] Lastly, a fourth layer of PCL was deposited. To do so, a solution of PCL at 12% by weight, in 79% by weight of Chloroform and 9% Methanol was used. For the production of this layer on the previous layer, a pressure of 1 bar and a flow rate of 10 ml/h were used, through a coaxial injector. This layer was deposited at a distance of 10 cm. This last layer must have a surface density between 12 g/m.sup.2 since the main function thereof is protection and a barrier.

[0180] Said manufacturing was performed at a temperature of 25° C. and a relative humidity of 30%, in Fluidnatek LE-100 equipment.

[0181] Also, as in the previous example, the quantification of the release of the Carvedilol was performed by means of UV-spectrophotometry at a wavelength of 240 nm, measuring 3 patches with a surface area of 2 cm.sup.2, in artificial saliva (pH=6.8), under continuous stirring and at 37° C., taking 8 h to be completely released at a speed close to constant.

Example 16: Four-Layer Continuous System of PCL Fibres Filled with PVP Particles with Encapsulated Water-Insoluble API (Carvedilol)

[0182] This example shows how the release of the sandwich-like four-layer patch is, which is similar to the one shown in example 9. But in this case, the hydrophobic layer (block B) which contains the API is made of PCL fibres filled with PVP particles with Carvedilol.

[0183] The starting point is a solution of 1% by weight (wt %) of Carvedilol and 0.25% by weight (wt %) of PVP, in a mixture of Acetone/Water in a ratio of 70:30 by volume. Furthermore, a surfactant such as Span20 was added to it at a concentration of 0.15 by weight. The particles were processed in Capsultek equipment from Bioinicia S. L. at 25° C. and 30% RH, the dissolution at a speed of 1 ml/min with a voltage of 10 kV and a flow of carrier gas of 10 l/min.

[0184] These particles are added in a solution of PCL at 15% by weight in a mixture of Chloroform/Methanol in a ratio of 90:10. Starting from this solution, the second layer of fibres is deposited on the first hydrophilic layer, using a voltage of, flow rate of 25 ml/h, at a height of 20 cm. The deposition was performed at a temperature of 25° C. and a relative humidity of 30%. This layer has a surface density of 60 g/m.sup.2.

[0185] Also, as in the previous example, the quantification of the release of the Carvedilol was performed by means of UV-spectrophotometry at a wavelength of 240 nm, measuring 3 patches with a surface area of 2 cm.sup.2, in artificial saliva (pH=6.8), under continuous stirring and at 37° C., for 8 h. The results showed a total release (100%) of Carvedilol at 12 h.