SOLUBLE REAR LAYER FOR OTF

Abstract

The invention relates to a multi-layer oral thin film comprising a matrix layer, which contains at least one polymer and at least one pharmaceutically active agent, and at least one backing layer, wherein the at least one backing layer comprises at least one polymer containing free carboxyl groups, wherein 10 to 100% of the free carboxyl groups of the at least one polymer comprising free carboxyl groups are present in a neutralised form as a salt; to a method for production thereof, and to use thereof as a medicament.

Claims

1. A multi-layer oral thin film comprising a matrix layer, which contains at least one polymer and at least one pharmaceutically active agent, and at least one backing layer, wherein the at least one backing layer comprises at least one polymer containing free carboxyl groups, wherein 10 to 100% of the free carboxyl groups of the at least one polymer comprising free carboxyl groups are present in a neutralised form as a salt.

2. The multi-layer oral thin film according to claim 1, wherein the at least one backing layer has a pH of 3.5 to 7.

3. The multi-layer oral thin film according to claim 1, wherein the at least one polymer comprising free carboxyl groups is provided in the backing layer in an amount of 10 to 99 wt.%, in relation to the total weight of the backing layer.

4. The multi-layer oral thin film according to claim 1, wherein the content of free carboxyl groups in the polymer comprising free carboxyl groups is 10 to 40 wt.%, in relation to the mean polymer mass.

5. The multi-layer oral thin film according to claim 1, wherein the at least one polymer comprising free carboxyl groups comprises a polymer based on (meth)acrylic acid and/or based on a copolymer of (meth)acrylic acid and (meth)acrylates.

6. The multi-layer oral thin film according to claim 1, wherein the at least one polymer comprising free carboxyl groups comprises a (meth)acrylic acid/ethyl acrylate copolymer.

7. The multi-layer oral thin film according to claim 1, wherein the free carboxyl groups of the at least one polymer comprising free carboxyl groups have been neutralised by addition of at least one base.

8. The multi-layer oral thin film according to claim 1, wherein the backing layer comprises at least one plasticiser.

9. The multi-layer oral thin film according to claim 1, wherein the matrix layer comprises at least one water-soluble polymer.

10. The multi-layer oral thin film according to claim 9, wherein the at least one water-soluble polymer is selected from the group consisting of starch and starch derivatives, dextrans, cellulose derivatives, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl ethyl cellulose, sodium carboxymethyl cellulose, ethyl or propyl cellulose, polyacrylic acids, polyacrylates, polyvinylpyrrolidones, vinyl pyrrolidone/vinyl acetate copolymer, polyvinyl alcohols, polyethylene oxide polymers, polyacrylamides, polyethylene glycols, gelatines, collagen, alginates, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan, and natural gums.

11. The multi-layer oral thin film according to claim 1, wherein the at least one pharmaceutically active agent is selected from the group consisting of the active agent classes of analgesics, hormones, hypnotics, sedatives, antiepileptics, analeptics, psychoneurotropic drugs, neuro-muscle blockers, antispasmodics, antihistamines, antiallergics, cardiotonics, antiarrhythmics, diuretics, hypotensives, vasopressors, antidepressants, antitussives, expectorants, thyroid hormones, sexual hormones, antidiabetics, antitumour active agents, antibiotics, chemotherapeutics and narcotics, wherein the at least one pharmaceutically active agent is preferably ketamine, especially preferably (S) ketamine.

12. The multi-layer oral thin film according to claim 1, wherein the matrix layer in each case also comprises at least one auxiliary substance selected from the group comprising colouring agents, flavourings, sweeteners, plasticisers, taste-masking agents, emulsifiers, enhancers, pH regulators, humectants, preservatives and/or antioxidants and the backing layer also comprises at least one auxiliary selected from the group comprising colouring agents, flavourings, sweeteners, taste-masking agents, emulsifiers, enhancers, pH regulators, humectants, preservatives and/or antioxidants.

13. A method for producing a multi-layer oral thin film according to claim 1, comprising the steps of: a) providing at least one active agent-containing matrix layer, comprising the steps of a1) producing a suspension or suspension comprising the at least one polymer and the at least one pharmaceutically active agent, and a2) spreading out and drying the solution or suspension obtained in accordance with step a1); b) providing at least one backing layer, comprising the steps of b1) producing a solution or suspension comprising at least one polymer comprising free carboxyl groups, wherein 10 to 100% of the free carboxyl groups of the at least one polymer comprising free carboxyl groups are present in a neutralised form as a salt; b2) spreading out and drying the solution obtained in accordance with step b1); c) joining together the active agent-containing matrix layer obtained in accordance with a) and the backing layer obtained in accordance with b) in order to obtain a multi-layer oral thin film.

14. A multi-layer oral thin film obtained by the method according to claim 13.

15. A method for providing a pharmaceutically active agent comprising administering the multi-layer oral thin film according to claim 1.

16. The multi-layer oral thin film according to claim 1, wherein the free carboxyl groups of the at least one polymer comprising free carboxyl groups have been neutralised by addition of at least NaOH.

17. The multi-layer oral thin film according to claim 1, wherein the backing layer comprises at least triethyl citrate.

Description

DESCRIPTION OF THE DRAWINGS

[0081] FIG. 1: Dissolution times of formulations without a backing layer,` with a PET backing layer, and with a backing layer according to the invention.

[0082] The invention will be described in greater detail hereinafter on the basis of non-limiting examples.

EXAMPLES

Example 1

[0083] A backing layer is produced as follows: Formulation of the composition:

TABLE-US-00002 Ingredient Function Proportion [%] Kollicoat MAE 100-55 Polymer 42 Kollicoat MAE 100 P Polymer 42 Triethyl citrate Plasticiser 10 Sucralose Taste corrector 3 Saccharin Na Taste corrector 2 Cherry Flavour Taste corrector 1 Solvent: ethanol:water 80:20 Target area density: approx. 50 g/m2

Production Sequence

[0084] The solvents are put together and the plasticiser and flavouring are added. Sweeteners are then dissolved one after the other and the polymers are sprinkled in and dissolved. The mass is now left to rest until it is bubble-free.

[0085] The result is a homogeneous, slightly cloudy mass.

Coating/Drying

[0086] The mass is applied to a siliconised liner and the resulting film is dried.

[0087] The result is a thin, stable, clear film.

Further Processing

[0088] The resultant coating can now be further processed. For example, a further film, such as the matrix layer, can be applied to this backing layer by means of coating, bonding or heat.

Example 2

[0089] In an initial investigation, three formulation variants were tested. Formulation 1 was the base without a backing layer. A formulation with PET backing (insoluble, 2) and the dissolving backing layer (3) according to the invention was then formed from the same mass.

TABLE-US-00003 Material 1 2 3 Matrix layer S ketamine HCI 30.0 % 30.0 % 30.0 % Kollidon VA 64.sup.1 20.5 % 20.5 % 20.5 % Kollicoat MAE.sup.2 35.0 % 35.0 % 35.0 % NaOH 1.0 % 1.0 % 1.0 % Saccharin Na 2.0 % 2.0 % 2.0 % Sucralose 1.0 % 1.0 % 1.0 % Cherry Flavour 3.0 % 3.0 % 3.0 % Glycerol 7.5 % 7.5 % 7.5 % Solvent Purified water / ethanol Purified water / ethanol Purified water / ethanol Backing layer PET backing layer FO PET 15 .Math.m tsp. Kollicoat MAE backing layer Kollicoat MAE backing layer: Kollicoat MAE 100-55 42.0 % Kollicoat MAE 100 P 42.0 % Triethyl citrate 10.0 % Cherry EU 3.0 % Saccharin Na 2.0 % Sucralose 1.0 % Solvent Purified water / ethanol .sup.1: Vinylpyrrolidone/vinyl acetate copolymer .sup.2: (Meth)acrylic acid/ethyl acrylate copolymer

TABLE-US-00004 Formulation Disintegration time [s] Fully dissolved* [s] 1 341 425 2 773 1122 3 Not detectable 742 * The full dissolution time refers to the dissolution of the matrix layer containing at least one pharmaceutically active agent.

[0090] The disintegration rate and the release of the active agent were examined.

[0091] The disintegration time was examined by means of a standard disintegration tester with sinker and is sufficiently known and described in the pharmacopoeias. The active agent was released by means of a standard dissolution tester using the “rotating cylinder” method. For this purpose, the OTFs were glued onto a cylinder that rotated in the release medium. The analysis was carried out via HPLC.

[0092] The tests confirmed that the backing layer of formulation 3 according to the invention dissolved and significantly slowed down the disintegration and the release of the active agent compared to the reference (1). The results are also shown in FIG. 1.

[0093] The polymer is neutralised by adding, dropwise, caustic soda (preferably as a solution in the appropriate solvent, which was also used for the polymer solution) to a polymer suspended in water or dissolved in a mixture of organic solvent and water (in this case Kollicoat L100-55). The increasing neutralisation reduces the solubility in the organic solvent and increases the solubility in water.

[0094] Here it is preferred that a certain amount of water is present, otherwise phase separation will occur and the polymer may precipitate as a solid component.

[0095] As the proportion of added caustic soda becomes very high at higher concentrations, a blend of pre-neutralised polymer (Kollicoat MAE 100P pre-neutralised by the manufacturer using NaOH) and non-neutralised polymer (Kollicoat MAE 100-55) was also used (see Table 4). The pH value of the polymer mixtures summarised in Table 4 is shown in FIG. 2.

TABLE-US-00005 Formulation Kollicoat MAE 100-55 Kollicoat MAE 100P Ratio NaOH [%] pH value 1 72.21 72.21/13.14 13.14 7.61 2 71.9 71.9//12.1 12.1 6.93 3 74 74.0//10.0 10 6.76 4 73.2 73.2//10.8 10.8 6.64 5 72.4 72.4//11.6 11.6 6.51 6 82.5 82.5//1.5 1.5 5.9 7 100 100+/0.25 0.25 6.04 8 0 100 0/100 0 6.2 9 17 83 17/83 0 6 10 25 75 25/75 0 5.9 11 50 50 50/50 0 5.6 12 75 25 75/25 0 5.3 13 79 21 79/21 0 4.9 14 85 15 85/15 0 4.6 15 100 0 100/0 0 3.5

Example 3

[0096] In a further test, the differences between different pH values were shown. For this purpose, a film of active agent with a similar composition as in previous tests was provided with backing layers with different degrees of neutralisation (pH values). The compositions (in wt.%) are summarised in Table 5.

TABLE-US-00006 Formulation 1 2 3 4 Matrix layer S ketamine HCI 30.0 % 30.0 % 30.0 % 30.0 % Kollidon VA 64 20.5 % 20.5 % 20.5 % 20.5 % Kollicoat MAE 35.0 % 35.0 % 35.0 % 35.0 % NaOH 1.0 % 1.0 % 1.0 % 1.0 % Saccharin Na 2.0 % 2.0 % 2.0 % 2.0 % Sucralose 1.0 % 1.0 % 1.0 % 1.0 % Cherry Flavour 3.0 % 3.0 % 3.0 % 3.0 % Glycerol 7.5 % 7.5 % 7.5 % 7.5 % Solvent Purified water / ethanol Purified water / ethanol Purified water / ethanol Purified water / ethanol Kollicoat MAE backing layer Kollicoat MAE pH 3.5: Kollicoat MAE pH 5.0: Kollicoat MAE pH 6.0: Kollicoat MAE pH 7.0: Kollicoat MAE 100-55 84.0 % 66.4 % 14.3 % Kollicoat MAE 100 P 17.6 % 69.7% 71.9 % Triethyl citrate 10.0 % 10.0 % 10.0 % 10.0 % Cherry EU 3.0 % 3.0 % 3.0 % 3.0 % Saccharin Na 2.0 % 2.0 % 2.0 % 2.0 % Sucralose 1.0 % 1.0 % 1.0 % 1.0 % NaOH 12.1 % Solvent Purified water / ethanol Purified water / ethanol Purified water / ethanol Purified water / ethanol

[0097] The release was tested in two set-ups with the paddle over disk (TTS holder). In a first variation, the OTF was tested with a USP 5 TTS holder mesh size 40 (35 mm diameter) with the API side to a PET film and the backing layer to the release medium. The effect of the backing layer was able to be tested here. The measurement results are summarised in FIG. 3.

[0098] In a second variant, the set-up was basically the same, with the difference that the backing layer of the OTF was applied to the PET side to show the release profiles of the API matrix. The measurement results are summarised in FIG. 4.

Example 5

[0099] Oral thin films were also prepared with agomelatine as the pharmaceutically active agent of the compositions shown in Tables 6 and 7.

TABLE-US-00007 Agomelatine-containing matrix layer Ingredient Ex. 3a Ex. 3b, 3c and 3d Amount [g] Solid [%] Amount [g] Solid [%] Agomelatine 0.50 9.96 3.50 9.98 Eucalyptol 0.04 0.83 0.17 0.49 Menthol 0.05 1.00 0.35 1.00 Methyl salicylate 0.03 0.52 0.18 0.51 Novamint Fresh Peppermint 0.18 3.52 1.24 3.52 Kolliphor RH 40 (Cremophor) 0.12 2.43 0.72 2.06 FD&C Red #40 0.004 0.09 0.04 0.10 Sucralose 0.03 0.50 0.18 0.50 Polyvinylpyrrolidone (Povidone K90) 4.00 79.14 27.98 79.80 Polysorbate 80 (Tween 80) 0.10 2.02 0.71 2.03 Ethanol 21.89 155.60 Total 26.94 100.01 190.67 99.99 Area density [g/m.sup.2] 55.4 50.0 Agomelatine content [.Math.g/cm.sup.z] 551.6 499.2 Size of the OTF [cm.sup.2] 0.522 Backing layer Ex. 3a Ex. 3b Ex. 3c Ex. 3d Ingredient Amount [g] Solid [%] FO-PET 15 .Math.m Ethylcellulose N50F 5.22 65.09 Castor oil 2.80 34.91 Ethanol 45.33 Total 53.35 100.00 Area density [g/m.sup.2] 12.3 Size of the OTF [cm.sup.z] 0,522

TABLE-US-00008 Agomelatine-containing matrix layer Ingredient Ex. 3e - 3h Amount [g] Solid [%] Agomelatine 3.50 9.98 Eucalyptol 0.17 0.49 Menthol 0.35 1.00 Methyl salicylate 0.18 0.51 Novamint Fresh Peppermint 1.24 3.52 Kolliphor RH 40 (Cremophor) 0.72 2.06 FD&C Red #40 0.04 0.10 Sucralose 0.18 0.50 Polyvinylpyrrolidone (Povidone K90) 27.98 79.80 Polysorbate 80 (Tween 80) 0.71 2.03 Ethanol 155.60 Total 190.67 99.99 Area density [g/m.sup.2] 50.0 Agomelatine content [.Math.g/cm.sup.2] 499.2 Size of the OTF [cm.sup.2] 0,522 Backing layer Ex. 3e Ex. 3f Ex. 3g Ex. 3h Ingredient Amount [g] Solid [%] Amount [g] Solid [%] Amount [g] Solid [%] Amount [g] Solid [%] Kollidon VA 64 9.29 46.36 9.31 39.63 8.40 42.11 8.50 42.50 Eudragit L100-55 9.22 46.01 9.21 39.21 8.40 42.11 8.50 42.50 Glycerol (99.5%) 1.54 7.63 1.51 6.39 1.55 7.72 3.02 15.00 NaOH 0.1N 3.47 14.77 1.61 8.07 Ethanol 22.49 22.53 22.5 22.49 Purified water 7.50 7.55 7.52 7.56 Total 50.04 100.00 53.58 100.00 49.98 100.01 50.07 100.00 Area density [g/m.sup.2] 26.8 26.0 20.5 22.9 pH 3.75 5.01 4.46 3.62 Size of the OTF [cm.sup.2] 0.522

[0100] For Example 3a, a glass beaker was loaded with agomelatine. Ethanol, eucalyptol, menthol, methyl salicylate, Novamint Fresh Peppermint, Kolliphor RH 40, FD&C Red #40, sucralose and polysorbate 80 were added and the mixture was then stirred. The polyvinylpyrrolidone was added with stirring, and after about 2.5 hours of stirring a clear red solution was obtained.

[0101] For Examples 3b to 3h, the same coating composition was used for the agomelatine-containing layer, which was prepared as follows: A glass beaker was filled with agomelatine. Ethanol, menthol, eucalyptol, methyl salicylate, Kolliphor RH 40, FD&C Red #40, sucralose and polysorbate 80 were added and the mixture was then stirred. A clear solution was obtained. The polyvinylpyrrolidone was added and, after further stirring, the Novamint Fresh Peppermint was added dropwise with stirring to obtain a clear, red solution.

Preparation of a Second Coating Composition (Backing Layer)

[0102] For Example 3c, a glass beaker was loaded with ethyl cellulose. Ethanol was added and the mixture was then stirred. Castor oil was added while stirring to obtain a slightly opaque mixture.

[0103] For Examples 3e to 3h, a glass beaker was loaded with ethanol. Purified water and Kollidon were added and the mixture was then stirred to obtain a solution. Eudragit and glycerol were added while stirring and a clear mixture was obtained.

[0104] For Examples 3f and 3g, sodium hydroxide solution was added to obtain a pH value as given in Table 7.

[0105] The resulting second coating composition of Examples 3c and 3e to 3h was applied to a polyester film (polyethylene terephthalate film, siliconised on one side, 75 .Math.m thick, which can act as a separation layer) and dried for about 10 min at room temperature and 20 min at 70° C. (Ex. 3c) and for about 5 min at room temperature, 10 min at 35° C. and 2 min at 80° C. (Ex. 3e to 3h). The film thickness resulted in an area density of 12.3 g/m.sup.2 (Ex. 3c), 26.8 g/m.sup.2 (Ex. 3e), 26.0 g/m.sup.2 (Ex. 3f), 20.5 g/m.sup.2 (Ex. 3g) and 22.9 g/m.sup.2 (Ex. 3h), respectively.

[0106] For Example 3d, a commercially available polyethylene terephthalate film with a thickness of 15 .Math.m was used as the carrier layer.

[0107] The resultant agomelatine-containing first coating composition of Examples 3a and 3b was applied to a polyester film (polyethylene terephthalate film, siliconised on one side, 75 .Math.m thick, which can act as a separation layer) and dried for about 15 min at room temperature and 5 min at 70° C. (Example 3a) or for about 5 min at room temperature, 10 min at 50° C. and 2 min at 90° C. (Example 3b). For Examples 3a and 3b, the dried film is the final agomelatine-containing layered structure.

[0108] The resultant agomelatine-containing initial coating compositions of Examples 3c and 3e to 3h were applied to the dried carrier layer and dried for about 5 min at room temperature, 10 min at 50° C. and 2 min at 90° C. (Ex. 3c and 3e to 3h).

[0109] The coating thickness resulted in an area density of 55.4 g/m.sup.2 (Ex. 3a) or 50.0 g/m.sup.2 (3b, 3c and 3e to 3h). The coating process of 3d was identical to that of Examples 3b, 3c and 3e to 3h, except that the coating composition was applied to a polyethylene terephthalate film of 15 .Math.m thickness, resulting in an OTF with a carrier layer (of polyethylene terephthalate film).

[0110] The OTFs of Examples 3b, 3c and 3e to 3h were prepared by laminating the carrier layers to the agomelatine-containing layers. The separation layer was removed before lamination.

Measurement of the Mucosal Permeation Rate

[0111] The permeate amount and the corresponding mucosal permeation rates of the OTFs prepared according to Examples 3a to 3h were determined by in vitro experiments according to the OECD guideline (adopted on 13 Apr. 2004) with porcine mucosa (mucosal oesophagus). A dermatome was used to produce mucous membrane up to a thickness of 400 .Math.m with an intact barrier function. The OTFs were applied to the mucous membrane with an area of 0.522 cm.sup.2 and the mucous membrane with the OTF on the upper side was immersed in artificial saliva (the underside is in contact with the receptor medium, the upper side is divided into a mucosal area of 1.145 cm.sup.2). The agomelatine permeated amount in the receptor medium (phosphate buffer solution pH 7.4) at a temperature of 37 ± 1° C. was measured and the corresponding mucosal permeation rate calculated.

[0112] The results are shown in Tables 8 and 9 and in FIGS. 3a and 3b. The standard deviation (SD) was calculated in this example using the n-method.

TABLE-US-00009 Time [h] Ex. 3a (n = 3) Ex. 3b (n = 3) Ex. 3c (n = 3) Ex. 3d (n = 3) Rate SD Rate SD Rate SD Rate SD 0.5 23.19 5.57 55.30 46.92 17.07 6.03 5.44 3.18 1 91.36 7.68 131.57 84.76 63.94 8.91 29.20 12.09 2 105.02 3.93 115.97 51.31 75.98 11.34 45.16 9.80 4 64.60 0.46 45.71 15.35 59.38 0.99 37.46 2.22 6 34.53 1.21 32.42 6.60 37.75 1.01 35.10 3.86

TABLE-US-00010 Time [h] Ex. 3e (n = 3) Ex. 3f (n = 3) Ex. 3g (n = 3) Ex. 3h (n = 3) Rate SD Rate SD Rate SD Rate SD 0.5 24.26 1.05 12.66 7.08 11.06 3.42 17.28 7.68 1 61.51 2.48 41.72 12.24 35.91 4.34 47.51 11.58 2 63.17 1.45 50.58 6.03 44.57 3.58 53.13 7.70 4 58.15 2.65 52.93 3.42 46.19 2.17 50.98 4.52 6 43.26 3.14 45.01 0.75 37.46 2.54 45.56 2.35

Use of Agomelatine

[0113] The use of agomelatine after 6 hours was calculated based on the cumulative permeate amount after 6 hours and based on the initial agomelatine content. The results are shown in Table 10.

TABLE-US-00011 Use of aqomelatine after 6 hours [%] Ex. 3a (n = 3) Ex. 3b (n = 3) Ex. 3c (n = 3) Ex. 3d (n = 3) Ex. 3e (n = 3) Ex. 3f (n = 3) Ex. 3g (n = 3) Ex. 3h (n = 3) 65.4 68.9 62.3 41.6 61.9 54.8 47.2 55.8

[0114] The in vitro experiments show a good mucosal permeation rate and a good use of the active agent. Examples 3c to 3h compared to Examples 3a and 3b show that even when a backing layer is used, a lower but still good permeation can be achieved.