PROCESS FOR PRODUCING AN ORAL THIN FILM COMPRISING MICROPARTICLES

Abstract

The present invention relates to a process for producing an oral thin film comprising microparticles, comprising the steps of: a) producing a solution comprising a hydrophobic polymer, a hydrophobic pharmaceutically active ingredient and hydrophobic solvent, b1) providing a hydrophilic polymer and providing a hydrophilic solvent immiscible with the solvent from a), or b2) providing a solution comprising a hydrophilic polymer and a hydrophilic solvent immiscible with the solvent from a), c1) mixing the solution from a) with the hydrophilic polymer from b1) followed by the addition of the hydrophilic solvent from b1) immiscible with the solvent from a) to obtain an emulsion, or c2) mixing the solution from a) and the solution from b2) to obtain an emulsion, and d) spreading and drying the emulsion from c1) or c2) to obtain an oral thin film comprising microparticles.

Claims

1. A process for producing an oral thin film comprising microparticles, comprising the steps of: a) producing a solution comprising a hydrophobic polymer, a hydrophobic pharmaceutically active ingredient and hydrophobic solvent, b1) providing a hydrophilic polymer and providing a hydrophilic solvent immiscible with the solvent from a), or b2) providing a solution comprising a hydrophilic polymer and a hydrophilic solvent immiscible with the solvent from a), c1) mixing the solution from a) with the hydrophilic polymer from b1) followed by the addition of the hydrophilic solvent from b1) immiscible with the solvent from a) to obtain an emulsion, or c2) mixing the solution from a) and the solution from b2) to obtain an emulsion, and d) spreading and drying the emulsion from c1) or c2) to obtain an oral thin film comprising microparticles.

2. The process according to claim 1, characterised in that the hydrophilic solvent is water or an aqueous solvent.

3. The process according to claim 1, characterised in that the hydrophobic solvent comprises ethyl acetate, methyl acetate, propyl acetate, liquid alkanes, liquid alkenes, aromatics, carboxylic acid esters, ethers and/or gasoline.

4. The process according to claim 1, characterised in that the hydrophilic polymer is selected from the group comprising agar-agar, gelatin and other gel-forming proteins, cellulose and derivatives thereof, alginic acid, galactomannan, carrageenan and other vegetable gums, pullulan, xanthan, pectin and other glucans, dextran, polyvinylpyrrolidone, polyvinyl alcohol, poly(meth)acrylates, polyalkylene glycols, carboxyvinyl polymers, polyethylene glycol-polyvinyl alcohol copolymers, shellac, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft and/or co-polymers thereof, chitosan, polyoxyethylene alkyl ether and/or co-polymers thereof.

5. The process according to claim 1, characterised in that the hydrophobic polymer has a log P value of greater than about 1.

6. The process according to claim 1, characterised in that the hydrophobic polymer comprises polymer cellulose acetate phthalate, hypromellose acetate succinate, poly(meth)acrylate, hypromellose acetate phthalate, polyvinyl acetate phthalate, ethyl cellulose, cellulose acetate butyrate, collophonium, polyoxyethylene alkyl ethers, polyvinyl acetate phthalate and/or cellulose nitrate.

7. The process according to claim 1, characterised in that the hydrophilic polymer is added in an amount such that it constitutes from 30 to 99 wt. % in relation to the total weight of the dried oral thin film.

8. The process according to claim 1, characterised in that the hydrophobic polymer is added in an amount such that it constitutes from 1 to 70 wt. % in relation to the total weight of the dried oral thin film.

9. The process according to claim 1, characterised in that the hydrophobic pharmaceutically active ingredient is added in an amount such that it constitutes 0.01 to 20 wt. % in relation to the total weight of the dried oral thin film.

10. The process according to claim 1, characterised in that no emulsifier and/or pH regulator is added.

11. The process according to claim 1, characterised in that the process further comprises the addition of at least one excipient selected from the group comprising colourants, flavourings, sweeteners, taste-masking agents, enhancers, humectants, preservatives and/or antioxidants to the solution a) and/or to the solution b) and/or to the emulsion c).

12. The process according to claim 1, characterised in that the hydrophobic pharmaceutically active ingredient comprises a pharmaceutically active ingredient having a log P of greater than 1.

13. The process according to claim 1, characterised in that the emulsion from c) is spread and dried so that the dried emulsion has a basis weight of about 20 to about 250 g/m.sup.2.

14. An oral thin film obtainable by the process according to claim 1.

15. A method of delivering a pharmaceutically active ingredient comprising administrating the oral thin film according to claim 14 to a patient.

Description

EXAMPLES

Example 1

[0061]

TABLE-US-00001 TABLE 1 Material Function Amount [wt. %] Polyvinyl alcohol Hydrophilic polymer 68.85 (PVA 4-88) Hypromellose acetate Hydrophobic polymer 24.89 succinate Idebenone Pharmaceutically 6.24 active ingredient

[0062] For the production of an oral thin film according to the invention of the composition according to Table 1, 68.85 wt. % polyvinyl alcohol were dissolved in water.

[0063] In parallel, 24.89 wt. % hypromellose acetate succinate and 6.24 wt. % idebenone were dissolved in methyl acetate.

[0064] The polyvinyl alcohol solution and the solution comprising hypromellose acetate succinate and idebenone were then mixed to obtain an emulsion.

[0065] The emulsion obtained was spread out and dried.

[0066] The oral thin film obtained has a solid hydrophilic polymer matrix in which the hydrophobic microparticles are present as a separate stable phase. The microparticles have a mean particle size of less than 5 μm (determined by light microscopy).

Example 2

[0067]

TABLE-US-00002 TABLE 2 Amount Amount [wt. %] [wt. %] in relation to in relation the dry to the Material Function constituents solution HPMC 603 Hydrophilic 38.5 15.4 polymer HPMC 60SH60 Hydrophilic 0.75 0.30 polymer Orange flavour Flavouring 3.00 1.20 Mint flavour Flavouring 1.00 0.40 Polysorbate 80 Emulsifier 3.00 1.20 Span 85 Emulsifier 2.00 0.80 Miglyol Carrier Flavour- 4.00 1.60 Phase Sucralose Sweetener 1.00 0.40 Saccharin sodium Sweetener 2.00 0.80 BHT Preservative 0.25 0.10 Flavouring Isomalt Disintegrant 10.00 4.00 Eudragit Hydrophobic 9.50 3.80 Smartseal polymer Ketoprofen Pharmaceutically 25.00 10.00 active ingredient Water Solvent — 45.00 Methyl acetate Solvent — 15.00

[0068] To produce an oral thin film according to the invention of the composition according to Table 2, 10.00 wt. % ketoprofen were dissolved in 15.00 wt. % hydrophobic solvent (methyl acetate). To this there were added 3.80 wt. % hydrophobic polymer (Eudragit Smartseal), and the mixture was stirred until the ketoprofen was dissolved.

[0069] To this solution there were added the hydrophilic polymers (Σ15.7%) according to Table 2.

[0070] Then 45% water was added as a hydrophilic solvent with rapid stirring to obtain an emulsion.

[0071] The remaining ingredients were added to this emulsion. HPMC 60SH50, isomalt, saccharin and sucralose were added one after the other. Separately, BHT, miglyol, Span 85, PS80, mint flavour and orange flavour were dissolved and added dropwise to the mass. Rinsing was performed with 1.314 g water and the mass was stirred at 2000 rpm for 5 min to degas. A homogeneous, milky emulsion was formed. The emulsion obtained was spread out and dried.

[0072] The oral thin film obtained has a solid hydrophilic polymer matrix in which the hydrophobic microparticles are present as a separate stable phase.