Method of making an oral film comprising microparticles

Abstract

The present invention relates to a process for preparing an oral film comprising microparticles, comprising the steps of a) preparing a solution comprising a hydrophobic polymer, a hydrophobic pharmaceutically active substance and a 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) and then adding the hydrophilic solvent from b1) immiscible with the solvent from a) to obtain an emulsion, or c2) mixing the solution from a) with the solution from b2) to obtain an emulsion, and d) spreading and drying the emulsion from c1) or c2) to obtain an oral film comprising microparticles.

Description

Invention Field

[0001] This invention relates to a method for preparing an oral film containing microparticles, the oral film obtained by the method, and the use of such an oral film as a medicine. Background Technology

[0002] Oral films containing microparticles typically contain microparticles containing pharmaceutically active substances embedded in a polymer matrix. This polymer matrix containing the microparticles dissolves upon application of the oral film, releasing the pharmaceutically active microparticles, which are then absorbed in the patient's stomach and / or intestines upon swallowing.

[0003] It is known that oral films are water-soluble films containing an internal water-insoluble solid phase in the form of microparticles, within which active substances or flavoring agents are present.

[0004] To prepare such a membrane, microparticles comprising a hydrophobic polymer and a pharmaceutically active substance are typically prepared and separated as described in US 2015 / 0064231A1, so that they can be subsequently incorporated into a hydrophilic polymer matrix in a second process step.

[0005] However, a drawback of this preparation method is that at least two separate process steps are required to prepare the oral film. Secondly, the individually prepared microparticles have a relatively large particle size, which is also relatively difficult to control. The relatively large particle size of the microparticles containing the hydrophobic polymer and the active pharmaceutical ingredient reduces the bioavailability of the active ingredient. Summary of the Invention

[0006] The objective of this invention is to overcome the aforementioned disadvantages of the prior art. In particular, the objective of this invention is to provide a method for preparing an oral film containing microparticles, by which the oral film containing microparticles can be prepared with as few process steps as possible and in as simple and economical a manner as possible. Furthermore, the microparticles in the oral film prepared by this method should have the smallest possible particle size, preferably less than 100 μm, more preferably less than 50 μm, more preferably less than 20 μm, particularly preferably less than 10 μm, and completely particularly preferably less than 5 μm.

[0007] The above task is accomplished by the method according to claim 1, wherein the method includes the following steps:

[0008] a) Prepare a solution comprising a hydrophobic polymer, a hydrophobic pharmaceutical active substance, and a hydrophobic solvent.

[0009] b1) Provide a hydrophilic polymer and a hydrophilic solvent that is immiscible with the solvent from a), or

[0010] b2) Provide a solution comprising a hydrophilic polymer and a hydrophilic solvent immiscible with the solvent from a),

[0011] c1) Mixing the solution from a) with the hydrophilic polymer from b1), and then adding a hydrophilic solvent from b1) that is immiscible with the solvent from a) to obtain an emulsion; or c2) mixing the solution from a) with the solution from b2) to obtain an emulsion.

[0012] d) Spread and dry the emulsion from c1) or c2) to obtain an oral film containing microparticles.

[0013] Using the one-step method according to the invention, the microparticles are not pre-prepared separately and incorporated into a polymer matrix as in known methods, but are generated through a preparation process based on mixing two solutions with different hydrophilic / hydrophobic properties. The components contained in solution a) form small droplets in the hydrophilic environment of solution b) or b2) or a solvent from b1). The resulting emulsion is then spread and dried. Phase separation is maintained during this drying process. This produces stable solid or semi-solid microparticles that may contain hydrophobic pharmaceutical active substances as well as other components.

[0014] Preferably, the method according to the present invention includes the following steps:

[0015] a) Prepare a solution comprising a hydrophobic polymer, a hydrophobic pharmaceutical active substance, and a hydrophobic solvent.

[0016] b) Provide a hydrophilic polymer and a hydrophilic solvent that is immiscible with the solvent from a),

[0017] c) Mix the solution from a) with the hydrophilic polymer from b), then add a hydrophilic solvent from b) that is immiscible with the solvent from a) to obtain an emulsion, and

[0018] d) Spread and dry the emulsion from c) to obtain an oral film containing microparticles.

[0019] Preferably, the method according to the present invention includes the following steps:

[0020] a) Prepare a solution comprising a hydrophobic polymer, a hydrophobic pharmaceutical active substance, and a hydrophobic solvent.

[0021] b) Provide a solution comprising a hydrophilic polymer and a hydrophilic solvent immiscible with the solvent from a),

[0022] c) Mix the solution from a) and the solution from b) to obtain an emulsion, and

[0023] d) Spread and dry the emulsion from c) to obtain an oral film containing microparticles.

[0024] Advantageously, hydrophobic polymers can be selected, allowing for control over the release of at least one hydrophobic pharmaceutically active substance. For example, polymers that do not dissolve in the acidic environment of the stomach but rather in the more alkaline environment of the intestine can be selected.

[0025] The term "includes / contains" can also mean "composed of".

[0026] The term "solution" also includes the term "suspension".

[0027] The method according to the invention is preferably characterized as the solvent in step b), b1), or b2) being water or an aqueous solvent.

[0028] Water is particularly preferred as a solvent because it dissolves the polymer required to form the film, on which the aqueous environment exists at the application site, causing decomposition. Furthermore, a significant difference in polarity is required to prevent the mixing of the two solvents necessary for the formation of the two phases.

[0029] The hydrophobic solvent preferably includes ethyl acetate, methyl acetate-propyl acetate, liquid alkanes, liquid olefins, aromatic compounds, carboxylic acid esters, ethers, and / or gasoline.

[0030] The solutions in steps b) and b2) or the solvent provided in step b1) contain a hydrophilic polymer. A hydrophilic polymer is a polymer containing polar and / or charged groups that make the polymer water-soluble.

[0031] The hydrophilic polymer may be selected from the group consisting of: starch and its derivatives, agar-agar, gelatin and other gel-forming proteins, cellulose and its derivatives, alginic acid, galactomannan, carrageenan and other plant gums, amylopectin and other disaccharides or polysaccharides, xanthan gum, pectin and other dextran, dextran, polyvinylpyrrolidone, polyvinyl alcohol, poly(meth)acrylate, polyalkylene glycol, carboxyvinyl polymers, polyethylene glycol-polyvinyl alcohol copolymers (available, for example, under the BASF trade name Kollicoat IR), shellac, polyethylene-caprolactam-polyvinyl acetate-polyethylene glycol-graft polymers and / or copolymers thereof (available, for example, under the BASF trade name Soloplus) and / or copolymers thereof, chitosan, and polyoxyethylene alkyl ethers.

[0032] In a preferred embodiment, the at least one hydrophilic polymer includes polyvinylpyrrolidone, polyvinyl alcohol, cellulose derivatives and / or copolymers thereof, and polyethylene glycol-polyvinyl alcohol copolymers (available, for example, under the trade name KollicoatIR).

[0033] The advantage of these hydrophilic polymers is that they form a thin, stable film upon drying, which decomposes and releases microparticles within a pharmaceutically acceptable timeframe upon application. This offers the advantages of relatively rapid availability of microparticles or hydrophobic pharmaceutical active substances and residue-free application.

[0034] The solution in step a) contains at least one hydrophobic polymer.

[0035] The term hydrophobicity refers to the property of molecules to prefer polar or nonpolar media. As the nonpolarity of a compound increases, hydrophobicity (i.e., the water repulsion of the molecule) increases. Hydrophobic polymers exhibit correspondingly low hydrophilicity.

[0036] In a preferred embodiment, the at least one hydrophobic polymer has a logP value greater than about 1, preferably greater than about 1.5, and particularly preferably greater than about 2.

[0037] octanol-water partition coefficient K ow (The notation of octanol / water partition coefficient, for example, is common and correct.) It is a dimensionless partition coefficient known to those skilled in the art, representing the concentration ratio of a chemical in a two-phase system of n-octanol and water, and therefore a measure of the hydrophobicity or hydrophilicity of a substance. The logP value is the n-octanol-water partition coefficient K. ow The logarithm to the base 10. It conforms to:

[0038] and

[0039] c o Si =Concentration of chemicals in the octanol phase

[0040] c w Si = The concentration of chemicals in the aqueous phase.

[0041] If a substance is more soluble in fatty solvents (such as n-octanol), then K ow If K is greater than 1, then K is more soluble in water. ow Less than 1. Correspondingly, logP is positive for lipophilic substances and negative for hydrophilic substances.

[0042] In a particularly preferred embodiment, the at least one hydrophobic polymer includes cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, poly(meth)acrylate, hydroxypropyl methylcellulose acetate phthalate, polyvinyl acetate phthalate, ethyl cellulose, cellulose acetate butyrate, rosin, polyoxyethylene alkyl ether, polyvinyl acetate phthalate, and / or nitrocellulose.

[0043] The method according to the invention is further preferably characterized in that the hydrophilic polymer is added in an amount of 30 to 99% by weight, preferably 35 to 90% by weight, relative to the total weight of the dried oral film.

[0044] The method according to the invention is further preferably characterized in that the hydrophobic polymer is added in an amount of 1 to 70% by weight, preferably 10 to 65% by weight, relative to the total weight of the dried oral film.

[0045] The method according to the invention is further preferably characterized in that the hydrophobic pharmaceutically active substance is added in an amount of 0.01 to 40% by weight, preferably 5 to 30% by weight, relative to the total weight of the dried oral film.

[0046] As defined above, the hydrophobic pharmaceutical active substance preferably comprises a hydrophobic active substance having a logP value greater than about 1, preferably greater than about 1.5, and particularly preferably greater than about 2.

[0047] The term "pharmaceutical active substance" also includes all pharmaceutically acceptable salts and solvates of each pharmaceutical active substance.

[0048] The hydrophobic active substance is preferably substantially present in the hydrophobic microparticles. The term "substantially" is understood to mean that, relative to the total amount of active substance in the system, the active substance is present in the microparticles of the oral membrane at a proportion greater than 85% by weight, preferably greater than 90% by weight, particularly preferably greater than 95% by weight or greater than 99% by weight.

[0049] Very particularly preferred, the hydrophobic pharmaceutically active substance includes idebenone, ulilistat acetate, and / or ketoprofen.

[0050] Idebenone refers to, for example, the brand name of Santhera Pharmaceuticals. The product sold is 2-(10-hydroxydecyl)-5,6-dimethoxy-3-methyl-cyclohexane-2,5-diene-1,4-dione.

[0051] Ulistat acetate refers to (8S,11S,13S,14R,17R)-17-acetoxy-11-[4-(dimethylamino)phenyl]-19-norpregn-4,9-diene-3,20-dione.

[0052] Ketoprofen refers to (RS)-2-(3-benzoylphenyl)propionic acid.

[0053] In addition, fragrances and / or essential oils may preferably be present in the microparticles.

[0054] The method according to the invention is also preferably characterized by the absence of emulsifiers and / or pH adjusters, resulting in the absence of emulsifiers and / or pH adjusters in the obtained oral film containing microparticles.

[0055] Emulsifiers are the term for additives used to prepare and stabilize emulsions. In a narrower sense, they can also be described as surfactants or surface-active substances, and are typically found in oily to waxy forms as well as powders.

[0056] pH adjusters are all substances or mixtures of substances that have a buffering effect and are therefore used to adjust or maintain a certain pH value.

[0057] The method according to the invention is also preferably characterized as further comprising adding at least one auxiliary agent selected from the group consisting of colorants, fragrances, sweeteners, flavor maskers, enhancers, humectants, preservatives and / or antioxidants to solutions a) and / or b) or b2) or to the solvent from b1) and / or to emulsions c), c1) or c2).

[0058] The method according to the invention is also preferably characterized in that, relative to the total weight of the dried oral film, the amount of these adjuvants added is such that each is contained in an amount of 0.01 to 25% by weight.

[0059] The method according to the invention is also preferably characterized by spreading and drying the emulsion from c), c1), or c2), such that the basis weight of the dried emulsion is about 20 to about 250 g / m³. 2 .

[0060] The method according to the invention is also preferably characterized as spreading and drying an emulsion from c), c1), or c2), such that the dried emulsion has a layer thickness of preferably about 10 μm to about 500 μm, preferably about 50 μm to about 300 μm.

[0061] It is preferable to use a spatula (Rakel) to spread the emulsion.

[0062] Alternatively, a coating box (Streichkasten), a spiral scraper (Spiralrakelstab), a grooving nozzle, or a roller (Rollenauftragswerk) can be used for spreading.

[0063] The spread emulsion is preferably dried in a drying oven, or alternatively in a climate chamber, preferably in a preferred temperature range of 40°C to 100°C for 10 minutes.

[0064] The method according to the invention is also preferably characterized as stirring or otherwise mixing the emulsions from c), c1), or c2). The intensity of stirring or mixing can affect the particle size. In principle, the stronger the stirring or mixing, the smaller the resulting particles.

[0065] In one implementation, a turbine agitator is used to agitate the emulsion. Suitable turbine agitators can be obtained, for example, from IKA or Heidolph.

[0066] Alternatively, propeller mixers, anchor mixers, dissolvers, homogenizers, colloid mills, ultrasonic mixers, or microfluidics can be used. Used for stirring or mixing.

[0067] It is preferable to stir or mix the provided emulsion for at least 15 minutes and up to 24 hours.

[0068] The provided emulsion is preferably stirred or mixed at a speed of at least 50 rpm and at most 8000 rpm.

[0069] The provided emulsion is preferably stirred or mixed at a temperature of 4°C to 50°C.

[0070] Preferably, the particles have an average particle size of less than 100 μm, more preferably less than 50 μm, more preferably less than 20 μm, more preferably less than 10 μm, and most preferably less than 5 μm or less than 3 μm. The average particle size is determined by optical microscopy.

[0071] The present invention also relates to oral films comprising microparticles obtainable by the above methods.

[0072] The definitions disclosed in the method according to the invention also apply to the oral films obtained by the above method.

[0073] The oral film containing microparticles obtainable by the method is particularly characterized in that the microparticles have an average particle size of less than 100 μm, preferably less than 50 μm, preferably less than 20 μm, preferably less than 10 μm, and especially preferably less than 5 μm or less than 3 μm. The average particle size is determined by optical microscopy.

[0074] The advantage of these microparticles lies in the improved bioavailability of the hydrophobic active pharmaceutical substances they contain.

[0075] Finally, the present invention relates to the use of an oral film comprising microparticles obtainable by the above method as a medicine, particularly for the treatment of Friedreichscher-Ataxie, Duchenne-Muskeldystrophie, primary progressive multiple sclerosis and / or Leberscher optic neuropathy. Optikusneuropathie).

[0076] The present invention will now be explained through non-limiting embodiments.

[0077] Specific implementation form

[0078] Example 1:

[0079] Table 1

[0080] Material Function Quantity [weight %] Polyvinyl alcohol (PVA 4-88) hydrophilic polymers 68.85 Hydroxypropyl methylcellulose acetate succinate Hydrophobic polymers 24.89 Idebenone Pharmacological active substances 6.24

[0081] To prepare the oral film according to the invention with the composition according to Table 1, 68.85% by weight of polyvinyl alcohol was dissolved in water.

[0082] In parallel, 24.89% by weight of hydroxypropyl methylcellulose acetate succinate and 6.24% by weight of idebenone were dissolved in methyl acetate.

[0083] The polyvinyl alcohol solution was then mixed with a solution containing hydroxypropyl methylcellulose acetate succinate and idebenone to obtain an emulsion.

[0084] Spread out the obtained emulsion and let it dry.

[0085] The obtained oral membrane has a solid hydrophilic polymer matrix in which hydrophobic microparticles exist as a separate stable phase. The microparticles have an average particle size of less than 5 μm (measured by optical microscopy).

[0086] Example 2:

[0087] Table 2

[0088]

[0089] To prepare the oral film according to the invention with the composition shown in Table 2, 10.00 wt% ketoprofen was dissolved in 15.00 wt% of a hydrophobic solvent (methyl acetate). 3.80 wt% of a hydrophobic polymer (Eudragit Smartseal) was added and stirred until the ketoprofen dissolved.

[0090] According to Table 2, a hydrophilic polymer (∑15.7%) was added to the solution.

[0091] Then, 45% water is added as a hydrophilic solvent under rapid stirring to obtain an emulsion.

[0092] Add the remaining ingredients to the emulsion. Add HPMC 60SH50, isomalt, saccharin, and sucralose sequentially. Separately dissolve and add BHT, Miglyol, Span 85, PS80, peppermint, and orange extracts dropwise to the material. Rinse with 1.314g of water and agitate the material at 2000 rpm for 5 minutes to deaerate. A homogeneous emulsion is produced. Spread and dry the resulting emulsion.

[0093] The obtained oral film has a solid hydrophilic polymer matrix, wherein the hydrophobic microparticles exist as a separate stable phase.

Claims

1. A method for preparing an oral film containing microparticles, comprising the following steps: a) Prepare a solution comprising a hydrophobic polymer, a hydrophobic pharmaceutical active substance, and a hydrophobic solvent. b1) Provide a hydrophilic polymer and a hydrophilic solvent that is immiscible with the solvent from a), or b2) Provide a solution comprising a hydrophilic polymer and a hydrophilic solvent immiscible with the solvent from a), c1) Mix the solution from a) with the hydrophilic polymer from b1), then add a hydrophilic solvent from b1) that is immiscible with the solvent from a) to obtain an emulsion, or c2) The solution from a) is mixed with the solution from b2) to obtain an emulsion, and d) Spread and dry the emulsion from c1) or c2) to obtain an oral film containing microparticles. in The hydrophobic polymer has a logP value greater than 1. The hydrophilic polymer has a negative logP value. The hydrophilic polymer is added in an amount of 30 to 99% by weight relative to the total weight of the dried oral film. The hydrophobic polymer is added in an amount of 1 to 70% by weight relative to the total weight of the dried oral film.

2. The method according to claim 1, characterized in that, The hydrophilic solvent is water or an aqueous solvent.

3. The method according to claim 1, characterized in that, The hydrophobic solvents include ethyl acetate, methyl acetate, propyl acetate, liquid alkanes, liquid olefins, aromatic compounds, carboxylic acid esters, ethers, and / or gasoline.

4. The method according to claim 1, characterized in that, The hydrophilic polymer is selected from the group consisting of: agar-agar, gelatin and other gel-forming proteins, cellulose and its derivatives, alginic acid, galactomannan, carrageenan and other plant gums, amylopectin, xanthan gum, pectin and other dextran, dextran, polyvinylpyrrolidone, polyvinyl alcohol, poly(meth)acrylate, polyalkylene glycol, carboxyvinyl polymers, polyethylene glycol-polyvinyl alcohol copolymers, shellac, polyethylene-caprolactam-polyvinyl acetate-polyethylene glycol-grafted polymers and / or copolymers thereof, chitosan, polyoxyethylene-alkyl ethers and / or copolymers thereof.

5. The method according to claim 1, characterized in that, The hydrophobic polymers include polymeric cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, poly(meth)acrylate, hydroxypropyl methylcellulose acetate phthalate, polyvinyl acetate phthalate, ethyl cellulose, cellulose acetate butyrate, rosin, polyoxyethylene alkyl ether, polyvinyl acetate phthalate, and / or nitrocellulose.

6. The method according to claim 1, characterized in that, The hydrophobic pharmaceutical active substance is added in an amount of 0.01 to 20% by weight relative to the total weight of the dry oral film.

7. The method according to claim 1, characterized in that, No emulsifiers and / or pH adjusters are added.

8. The method according to claim 1, characterized in that, The method further includes adding at least one adjuvant selected from the group consisting of colorants, fragrances, sweeteners, flavor maskers, enhancers, humectants, preservatives, and / or antioxidants to the solution a) and / or the solution b) and / or the emulsion c).

9. The method according to claim 1, characterized in that, The hydrophobic pharmaceutical active substance comprises a pharmaceutical active substance with logP greater than 1.

10. The method according to claim 1, characterized in that, The emulsion from c) is applied and dried, such that the dried emulsion has a density of 20 to 250 g / m³. 2 The base weight.

11. An oral film obtained by the method according to any one of claims 1 to 10.

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