WO2015101639A1 - Film orodispersible - Google Patents

Film orodispersible Download PDF

Info

Publication number
WO2015101639A1
WO2015101639A1 PCT/EP2014/079475 EP2014079475W WO2015101639A1 WO 2015101639 A1 WO2015101639 A1 WO 2015101639A1 EP 2014079475 W EP2014079475 W EP 2014079475W WO 2015101639 A1 WO2015101639 A1 WO 2015101639A1
Authority
WO
WIPO (PCT)
Prior art keywords
film
water
film forming
rtp
surfactant
Prior art date
Application number
PCT/EP2014/079475
Other languages
English (en)
Inventor
Dimitri Neumann
Andreas Krekeler
Original Assignee
Hexal Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hexal Ag filed Critical Hexal Ag
Publication of WO2015101639A1 publication Critical patent/WO2015101639A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin

Definitions

  • the present invention relates to pharmaceutical compositions, in particular, it relates to orodispersible films.
  • the present invention further relates to film forming suspensions and to processes for preparing the orodispersible films and the film forming suspensions.
  • Oral films are characterized for example by the fact that they have a low thickness and a large surface and are able to disintegrate in short time in the oral cavity. Depending on the patient's needs, they can be taken anytime and anywhere and also discretely. Furthermore, a simultaneous intake of liquid is not necessary, because the salivary fluid in the oral cavity is sufficient to dissolve the film and release the drug.
  • Oral films containing pharmaceutical and non-pharmaceutical active ingredients, and processes for their preparation are described, for example, in WO 2007/009800, WO 2007/009801 and WO 03/01 1259.
  • a homogeneous distribution of the active pharmaceutical ingredient (API) in the oral film is essential to achieve an excellent product complying with regulatory requirements.
  • API active pharmaceutical ingredient
  • a solution can be prepared by dissolving and re-stabilizing it by means of a solid solution with a polymer.
  • the API is poorly soluble a suspension has to be prepared. In such case, suspensions are frequently affected by the problems of sedimentation and aggregation (self- aggregation). The latter may also occur during the film-forming process.
  • Films suffering from the aggregation or conglomeration of particles, i.e., self- aggregation, are inherently non-uniform.
  • agglomerates randomly distributes the film components and any active pharmaceutical ingredient present as well.
  • a small change in the dimensions of the film would lead to a large difference in the amount of API in the film.
  • portions of the film may be substantially devoid of any API.
  • Sheets of film are usually cut into unit doses; certain doses may, therefore, be devoid of or contain an insufficient amount of API for the recommended treatment. Failure to achieve a high degree of accuracy with respect to the amount of API in the cut film can be harmful to the patient.
  • the above mentioned problems are solved by the orodispersible films of the invention.
  • the orodispersible films of the invention comprise a low soluble API and a surfactant having specific solubility characteristics.
  • the orodispersible films of the invention are uniform films free from aggregates, in particular API aggregates.
  • the present invention relates to an orodispersible film comprising:
  • an active pharmaceutical ingredient having a solubility of less than 10 mg/ml in water at RTP;
  • the present invention provides a film forming suspension comprising:
  • an active pharmaceutical ingredient having a solubility of less than 10 mg/ml in water at RTP;
  • solubility of the surfactant in water at RTP is at least 15 times greater than the solubility of the active pharmaceutical ingredient in water at RTP.
  • the present invention is directed to a method for preparing an orodispersible film comprising:
  • step 1 preparing a film forming suspension according to the invention; and 2) drying the suspension of step 1 ) to form the orodispersible film.
  • the present invention is directed to a method for preparing the film forming suspension of the invention.
  • the method comprises mixing the API having a solubility of less than 10 mg/ml in water at RTP with a surfactant and water or a mixture of water and at least a solvent selected from a (Ci-C 5 )-alcohol, acetone and mixtures thereof, wherein the surfactant has a solubility greater than 30 mg/ml in water at RTP, greater than 5 mg/ml in ethanol at RTP; and a solubility in water at RTP at least 15 times greater than the solubility of the active pharmaceutical ingredient in water at RTP.
  • the present invention relates to an orodispersible film obtainable according to a method of the invention.
  • the present invention is directed to an orodispersible film according to the present invention, for use as a medicament.
  • the present invention is directed to a packaging comprising the orodispersible film according to the present invention.
  • the present invention relates to an orodispersible film comprising a low soluble API, which is, nevertheless, uniform and free from aggregates.
  • Uniform/uniformity in the present context means that the API is homogenously distributed in the film. Uniformity is determined in accordance with Ph. Eur. 7.4 chapter 2.9.40 (content uniformity).
  • the orodispersible film of the invention has the desired dissolution time and excellent mechanical properties. Indeed, during its production the film is required to adhere to the support liner, but at the same time needs to be easily removable from the support liner (pull-off ability) without being damaged. Generally, it is difficult to achieve this balance as it mainly depends on the composition of the film and its viscosity. Advantageously, it has been found that the orodispersible film of the invention meets this balance.
  • the orodispersible film of the invention is prepared by film forming suspensions.
  • the present inventors have surprisingly found that by selecting a specific class of surfactants to be added to the suspension, the problem of the sedimentation of the suspension is solved, the suspension is stable and the API is homogeneously distributed in the suspension. Additionally, the problem of the aggregation of the API particles during the film-forming process is avoided.
  • the selected surfactant preferably has a good solubility not only in the solvent system of the suspension, but also in the solvent system formed during the drying step. For example, if a solvent system such as a water/ethanol system is used, the composition of the solvent system may change during the drying step, because the more volatile solvent (ethanol) evaporates first.
  • the evaporation causes the solvent system to become enriched in the solvent having the highest boiling point (i.e., water). Additionally, since the solvent(s) evaporate, the viscosity of the suspension during the drying step changes: the suspension tends to become more viscous.
  • a non-aggregated orodispersible film and a stable suspension are provided by the present invention. Additionally, the orodispersible film has the desired dissolution properties and excellent pull-off properties.
  • the present invention provides an orodispersible film comprising:
  • the orodispersible film of the present invention comprises
  • an active pharmaceutical ingredient having a solubility of from 0.01 to less than 10 mg/ml in water at RTP;
  • solubility greater than 30 to 10000 mg/ml in water at RTP; preferably greater than 30 to 1000mg/ml, more preferably greater than 30 to 100mg/ml
  • solubility of the surfactant in water at RTP is at least 15 times greater than the solubility of the active pharmaceutical ingredient in water at RTP.
  • the orodispersible film of the present invention comprises:
  • the problem of avoiding APIs sedimentation in the film forming suspension and the aggregation problem during the film-forming process is solved by the selection of surfactants having a solubility greater than 30 mg/ml in water at RTP and a solubility greater than 5 mg/ml in ethanol at RTP.
  • the solubility of the surfactant in water at RTP is at least 15 times greater than the solubility of the API in water at RTP.
  • the surfactants of the invention decrease the interfacial tension between API particles and water or the solvent system.
  • water or the solvent system penetrates in the pores of the API particles, displaces air from them and ensures wettability, leading then to a stable suspension.
  • variations in the solvent system composition may alter the wetting properties of the surfactant.
  • the surfactants of the invention are able to maintain excellent wettability throughout the entire film forming process.
  • the surfactants of the present invention have a solubility in water at RTP that is greater than 40 mg/ml, more preferably is greater than 80 mg/ml, even more preferably is greater than 100 mg/ml in (all the solubility values refer to water at RTP).
  • the surfactants of the invention have a solubility in water at RTP that is at least 15 times greater than the solubility of the selected API in water at RTP.
  • a solubility in water at RTP that is at least 15 times greater than the solubility of the selected API in water at RTP.
  • the solubility of Tween 80 is at least 500 times greater than the solubility of olanzapine.
  • Tween 80 has a solubility in ethanol greater than 5 mg/ml and hence meets the requirements of a surfactant according to the present invention.
  • the solubility values are in water at RTP.
  • (homogenous) film forming suspension can be prepared. Uniformity is maintained during the film-forming process despite the increased viscosity of the suspension and the change in solvent composition.
  • Surfactants having the required solubility are preferably selected from anionic or non-ionic surfactants.
  • Anionic and non-ionic surfactants have a high water solubility and good wettability property that allow the API to be uniformly suspended in the film forming suspension and through all the variations of solvent compositions occurring during the film-forming process.
  • Non-ionic surfactants offer the additional advantages of no change in pH and reduced or no foam formation. Foam formation is generally caused by the incorporation of air bubbles during the initial stirring of the film forming suspension.
  • the surfactant is selected from:
  • alkoxylated fatty alcohols of formula RO(Ci-C 4 alkyl-0) n H wherein R is a (C 6 -Ci 8 )alkyl and n is 10 to 50, preferably R is (Ci 2 -Ci 8 )alkyl, C C 4 alkyl-0 is ethoxy (EO) and n is 20,
  • polyoxyethylene glycols and polyoxyethylene glycolethers (macrogols); block polymer surfactants; and
  • alkyl sulfates alkyl sulfates
  • Polyoxyalkylene sorbitan esters are, for example, polyethylene 20 sorbitan monolaurate (polysorbate 20), polyethylene 20 sorbitan monopalmitate (polysorbate 40), polyethylene 20 sorbitan monostearate (polysorbate 60) and polyethylene 20 sorbitan monooleate (polysorbate 80).
  • these surfactant are known as TWEENS®.
  • Alkoxylated fatty alcohols are commercially known as Brij®, for example polyoxyethylene 10 stearyl ether is commercially available as Brij 98 and is preferably used.
  • Polyoxyethylene glycols and polyoxyethylene glycol ethers are commercially known as "macrogol”.
  • a suitable and good macrogol according to the invention is Cetomacrogol 1000 (macrogol cetostearyl ether).
  • Block copolymer surfactants are also known as polyoxyalkylene block copolymers. They are prepared by block copolymerization of ethylene oxide (EO), propylene oxide (PO) or butylene oxide (BO). Polyoxyalkylene block copolymers of the invention are polaxamers (synthetic polyoxyethylene-polyoxypropylene block copolymers) which are commercially known as Pluronics®. Pluronic F68 is the preferred Pluronics of the invention.
  • the (Ci 0 -Ci 8 )alkyl sulfates are a known class of ionic surfactants.
  • Sodium lauryl (d 2 ) sulfate is an example of a pharmaceutically acceptable surfactant of this family of surfactants.
  • the surfactant of the invention is selected from polysorbates and (C-io-C-i 8 )-alkyl sulfates. More preferably, the polysorbate is selected from polysorbate 80 (polyoxyethylene (20) sorbitan monooleate) and polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate). More preferably, the (Ci 0 -Ci 8 )-alkyl sulfate is sodium lauryl sulfate. Even more preferably, the surfactant is Polysorbate 80 (also known as TWEEN® 80).
  • Surfactants of the invention have a hydrophilic-lipophilic balance (HLB) greater than 10. It is known that the hydrophilic-lipophilic balance of a surfactant is a measure of the degree to which it is hydrophilic or lipophilic and hence it is a measure of the solubility of the surfactant in oil/water.
  • the HLB according to the present invention is calculated according to the Davies' method. As mentioned above, the surfactants according to the present invention have a solubility in water that allows keeping the API uniformly distributed in the film forming suspension and the viscosity variations that occur during the drying step. It was found that surfactants having a HLB greater than 7 meet this need.
  • the surfactant of the invention has an HLB greater than 14, more preferably greater than 15.
  • Surfactants such as alkyl sulfates having a high HLB can have effects on foaming.
  • this problem may be overcome by employing a lower concentration of the surfactant, preferably less than 0.10 mg/ml, provided that the chosen concentration does not affect the purpose of preparing stable suspension and avoiding aggregation.
  • the amount of surfactant present in the film of the invention is preferably from 0.01 % wt. to 0.5% wt., more preferably from 0.1 % wt. to 0.2% wt.
  • the weight value refers to the dry weight of the orodispersible film.
  • concentration of the surfactant varies and depends on the solid content intended for the suspension. However, it is not suggested using a surfactant at a concentration less than 0.01 % wt. as it can result in an incomplete wetting, loss in stability of the suspension and formation of aggregates in the film. On the other hand, concentrations above 0.5% wt. may increasingly solubilize or dissolve the API particles or lead to a change in the API particle size distribution, once again, causing instability and aggregation.
  • APIs Active Pharmaceutical Ingredients
  • the APIs of the present invention are “slightly soluble” “very slightly soluble” or “practically insoluble” APIs.
  • the three classes are defined in the European Pharmacopoeia.
  • the solubility in the present context unless otherwise specified, refers to the solubility measured at RTP:
  • the APIs of the present invention have a solubility of less than 10 mg/ml in water at RTP.
  • the solubility of the API is less than 5 mg/ml, more preferably the solubility is less than 1 mg/ml, even more preferably the solubility is less than 0.1 mg/ml.
  • the solubility of a "practically insoluble" API is less than 0.1 mg/ml according to the European Pharmacopoeia.
  • practically insoluble APIs are contemplated by the present invention.
  • olanzapine which is considered “practically insoluble" in water at RTP is an API according to the present invention.
  • APIs are also contemplated according to the invention.
  • Each API has a solubility of less than 10 mg/ml in water at RTP, preferably has a solubility of less than 5 mg/ml, more preferably has a solubility of less than 1 mg/ml, even more preferably of less than 0.1 mg/ml. All the solubility values are "in water at RTP".
  • APIs suitable according to the present invention are for example olanzapine, sildenafil, ambroxol, citalopram, losartan, mirtazapine, verapamil, buprenorphine, risperidone, fentanyl, loperamide, loratadine and/or pharmaceutically acceptable salts thereof, provided that the salts have a solubility of less than 10 mg/ml in water at RTP.
  • a particularly preferred API is olanzapine, more preferably olanzapine free base, even more preferably olanzapine polymorphic form I or olanzapine polymorphic form II.
  • Olanzapine polymorphic forms I and II are disclosed in patent application WO1996/030375.
  • form II obtainable by the process disclosed in WO1996/030375, is characterized by an X-ray powder diffraction pattern as represented by the following interplanar spacings: d (A) 10.2689, 8.577, 7.4721 , 7.125, 6.1459, 6.071 , 5.4849, 5.2181 , 5.1251 , 4.9874, 4.7665, 4.7158, 4.4787, 4.3307, 4.2294, 4.141 , 3.9873, 3.7206, 3.5645, 3.5366, 3.3828, 3.2516, 3.134, 3.0848, 3.0638, 3.01 1 1 , 2.8739, 2.8102, 2.7217, 2.6432, 2.6007.
  • Form I has a typical x-ray powder diffraction pattern substantially represented by the following interplanar spacings: d (A) 9.9463, 8.5579, 8.2445, 6.8862, 6.3787, 6.2439, 5.5895, 5.3055, 4.9815, 4.8333, 4.7255, 4.6286, 4.533, 4.4624, 4.2915, 4.2346, 4.0855, 3.8254, 3.7489, 3.6983, 3.5817, 3.5064, 3.3392, 3.2806, 3.2138, 3.1 1 18, 3.0507, 2.948, 2.8172, 2.7589, 2.6597, 2.6336, 2.5956.
  • the spectra have been obtained using a Siemens D5000 x-ray powder diffractometer.
  • the amount of API per single dosage form is from 2.5 mg to 70 mg, preferably from 2.5 mg to 50 mg.
  • Olanzapine is preferably present in the film in an amount of from 2.5 mg to 20 mg per oral dosage form.
  • the content of the API in the film of the invention is from 20 to 70% wt., preferably from 20 to 50% wt., even more preferably from 20 to 40% wt. related to the dry weight of the film.
  • the API is preferably micronized in the form of nano- or microparticles.
  • the micronized form is especially preferred, because nano- or microparticles of the API are stabilized against agglomeration by the surfactant surface adsorption.
  • the particles provide a higher surface and hence a greater surfactant surface adsorption. This improves wettability of the API particles.
  • the mean particle size of the micronized API is from 1 ⁇ to 20 ⁇ , preferably from 1 ⁇ to 15 ⁇ , even more preferably from 5 ⁇ to 10 ⁇ .
  • the orodispersible film of the invention rapidly disintegrates in the oral cavity of a patient.
  • the disintegration time is preferably less than 100 seconds, more preferably less than 60 seconds, even more preferably less than 20 seconds.
  • the disintegration time is determined as described below in the context of the Examples.
  • the orodispersible film of the invention has a dry film thicknesses ranging from 50 ⁇ to 500 ⁇ , preferably from 100 ⁇ to 200 ⁇ , more preferably from 140 ⁇ to 180 ⁇ .
  • a dry film thickness within and including the mentioned limits ensures rapid disintegration of the film within the oral cavity. This ensures that the API is completely absorbed by the patient.
  • films with lower or higher layer thicknesses can be provided, which are encompassed by the invention as well.
  • a surfactant of the invention in particular, polyoxyalkylene sobitan esters, and preferably polyoxyethylene (20) sorbitan monooleate (polysorbate 80), advantageously allows having a thinner orodispersible film.
  • a surfactant of the invention in particular, polyoxyalkylene sobitan esters, and preferably polyoxyethylene (20) sorbitan monooleate (polysorbate 80), advantageously allows having a thinner orodispersible film.
  • One problem in film production is the tendency of the film to be damaged during the pull-off step. Thicker films are less affected by this problem. However, thick films have a longer disintegration time and are generally less favorable in relation to patient compliance.
  • the above surfactants solve this problem by sticking a balance between film thickness requirements and pull-off integrity.
  • the orodispersible film of the invention may further comprise one or more excipients selected from a film forming polymer/agent, a plasticizer, a wetting agent, a flavoring, a taste masker, a preservative, a sweetener, a coloring agent and a filler. These are disclosed in details in the section below: "Additional pharmaceutical acceptable excipients”.
  • the orodispersible film comprises
  • the above embodiment further comprises, preferably: c) 15 to 60% wt. of film forming polymer(s); and
  • the percentages refer to the dry weight of the orodispersible film.
  • the orodispersible film comprises a) 20 to 40% wt., preferably 25 to 35% wt. of active pharmaceutical ingredient, wherein the active pharmaceutical ingredient is selected from olanzapine, olanzapine free base, olanzapine free base polymorphic form I and olanzapine free base polymorphic form II ;
  • surfactant 0.01 to 0.5% wt., preferably 0.10 to 0.20% wt. of surfactant, wherein the surfactant is selected from a polyethylene sorbitan mono-oleate or sodium alkyl sulfate, more preferably is Polysorbate 80;
  • the film forming polymer is selected from cellulose derivatives, preferably cellulose ethers, more preferably hydroxy propyl cellulose, hydroxy propyl methyl cellulose and mixtures thereof, even more preferably the film forming polymer is hydroxy propyl methyl cellulose (such as Methocel E5LV); an additional film forming polymer may be present; the additional film forming polymer is preferably polyvinylpyrrolidone (PVP).
  • the cellulose derivative is in an amount ranging from 20% wt. to 40% wt., preferably 25 to 35% wt. and PVP is present in an amount ranging from 15 to 35% wt., preferably 15 to 20% wt.
  • the sum of the weight percentages of the cellulose derivative and of PVP preferably does not exceed 60% wt.
  • plasticizer 5 to 35% wt. of plasticizer, wherein the plasticizer is selected from propylene glycol or glycerol, preferably propylene glycol.
  • the weight percentages refer to the dry weight of the orodispersible film.
  • the surfactant is selected from polysorbate 80 and sodium lauryl sulfate. More preferably, the active pharmaceutical ingredient is olanzapine, the surfactant is polysorbate 80 or sodium lauryl sulfate, the film forming agent is hydroxy propyl methyl cellulose and/or povidone, and the plasticizer is glycerol and/or propylene glycol; even more preferably, the active pharmaceutical ingredient is olanzapine, the surfactant is polysorbate 80, the film forming agent is hydroxy propyl methyl cellulose and/or povidone, and the plasticizer is glycerol and/or propylene glycol.
  • the present invention is directed to a film forming suspension comprising:
  • an active pharmaceutical ingredient having a solubility of less than 10 mg/ml in water at RTP;
  • solubility of the surfactant in water at RTP is at least 15 times greater than the solubility of the active pharmaceutical ingredient in water at RTP.
  • the surfactants of the film forming suspension are as disclosed in the first aspect of the invention and its embodiments.
  • the amount of surfactant present in the film forming suspension of the invention is from 0.01 % wt. to 0.5% wt. of the suspension, preferably 0.1 % wt. to 0.2% wt. of the suspension.
  • the percentage amounts refer to the dry weight of the suspension and solvent(s) are not considered in this calculation.
  • APIs are as disclosed above in the first aspect of the invention and its embodiments.
  • the content of the API in the film forming suspension of the invention is preferably from 20 to 70% wt., preferably from 20 to 50% wt., even more preferably from 20 to 40% wt. related to the dry weight of the suspension.
  • Solvents suitable according to the invention are water, (CrC 5 )-alcohol or acetone. Water may be present as sole solvent or may be present in a mixture with one or more solvents selected from a (Ci-C 5 )-alcohol and acetone. The mixture of solvents in the present context may be referred to as "solvent system”.
  • a solvent system is used to prepare the film forming suspension of the invention.
  • Preferred solvents (in addition to water) of the solvent system are ethanol or isopropanol; hence, the solvent system is preferably a mixture of 1 ) water and ethanol or 2) water and isopropanol. Even more preferably, the solvent system is a mixture of water and ethanol.
  • the amount of solvent other than water in the solvent system is from 0% wt. to 65% wt., preferably from 20% wt. to 40% wt., even more preferably from 25% wt. to 35% wt. of the solvent system.
  • the amount of ethanol is from 0% wt. to 65% wt., preferably from 20% wt. to 40% wt., even more preferably from 25% wt. to 35% wt.
  • Acetone can also be present in the solvent system.
  • acetone preferably does not exceed the 5% wt. of the solvent system.
  • the quantity of solvent or the solvent system is such that a suspension is formed.
  • the ratio dry/solid component to solvent/solvent system is from 1 :3 to 1 :1 , preferably 1 :2.5 to 1 :1 .5, more preferably 1 :2.2 to 1 :2.
  • the ratio refers to the weight: for example 100g of the total solid component of the suspension is mixed with 200g of the solvent system i.e. with a ratio of 1 :2.
  • the film forming suspension of the invention has a viscosity (dynamic viscosity) at RTP from 1000 mPa * s to 5000 mPa * s, preferably 2000 mPa * s to 4000 mPa * s, even more preferably 2000 mPa * s to 2500 mPa * s (measured with a cone- plate viscometer at a shear rate of 1 /100 sec according to Ph. Eur. 7.0 chapter 2.2.10).
  • a high viscosity of the film forming suspension is preferable in general to obtain a stable suspension free from sedimentation problems.
  • a highly viscous suspension will result in a non-homogeneous film with aggregate formation observed during the film-forming process and in the final film.
  • the use of the surfactant of the invention allows suspensions with a lower viscosity and yet stable suspensions free from sedimentation problems. Since suspensions with lower viscosity can be advantageously used due to the presence of the surfactant of the invention, the above mentioned problems connected with a high viscosity are avoided by the film forming suspension of the invention.
  • the film forming suspension of the invention may further comprise one or more components selected from a film forming polymer/agent, a plasticizer, a wetting agent, a flavoring, a taste masker, a preservative, a sweetener, a coloring agent and a filler. These are disclosed in details in the below section "Additional pharmaceutical acceptable excipients”.
  • the film forming suspension comprises
  • the above embodiment further comprises, preferably: c) 15 to 60% wt. of film forming polymer(s); and
  • the percentage amounts refer to the dry weight of the film forming suspension.
  • the suspension comprises water or a solvent system.
  • Preferred solvent systems are a water/ethanol solvent system and a water/isopropanol solvent system; even more preferred is the water/ethanol solvent system.
  • the amount of solvent other than water in the solvent system is from 0% wt. to 65% wt., preferably from 20% wt. to 40% wt., even more preferably from 25% wt. to 35% wt. of the solvent system.
  • the amount of ethanol is from 0% wt. to 65% wt., preferably from 20% wt.
  • the film forming suspension comprises a) 20 to 40% wt., preferably 25 to 35% wt. of active pharmaceutical ingredient, wherein the active pharmaceutical ingredient is selected from olanzapine, olanzapine free base, olanzapine free base polymorph form I and olanzapine free base polymorph form II ;
  • surfactant 0.01 to 0.5% wt., preferably 0.10 to 0.20% wt. of surfactant, wherein the surfactant is selected from a polyethylene sorbitan mono-oleate or sodium alkyl sulfate, more preferably Polysorbate 80;
  • film forming polymer 15 to 60% wt. preferably 30 to 55% wt. of film forming polymer wherein the film forming polymer is selected from cellulose derivatives, preferably cellulose ethers, more preferably hydroxy propyl cellulose, hydroxy propyl methyl cellulose and mixtures thereof, even more preferably the film forming polymer is hydroxy propyl methyl cellulose (such as Methocel E5LV); an additional film forming polymer may be present; the additional film forming polymer is polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • the cellulose derivative When present in combination, the cellulose derivative is in amount ranging from 20 to 40% wt., preferably 25 to 35% wt and PVP is present in an amount ranging from 15 to 35% wt., preferably 15 to 20% wt.
  • the sum of the weight percentages of the cellulose derivative and of PVP preferably does not exceed the 60% wt.
  • plasticizer 5 to 35% wt. of plasticizer, wherein the plasticizer is selected from propylene glycol or glycerol, preferably propylene glycol.
  • the weight percentages refer to the dry weight of the film forming suspension.
  • the suspension comprises water or a solvent system.
  • Preferred solvent systems are a water/ethanol solvent system and a water/isopropanol solvent system; even more preferred is the water/ethanol solvent system.
  • the amount of solvent other than water in the solvent system is from 0% wt. to 65% wt., preferably from 20% wt. to 40% wt., even more preferably from 25% wt. to 35% wt. of the solvent system.
  • the amount of ethanol is from 0% wt. to 65% wt., preferably from 20% wt. to 40% wt., even more preferably from 25% wt. to 35% wt.
  • the percentage amounts refer to the solvent system.
  • the present invention provides a method for preparing an orodispersible film comprising:
  • the suspension is homogeneously spread out on a foil (carrier liner) and dried.
  • a second foil backing foil
  • the foil or foils are removed afterwards.
  • the drying of the film is done by application of heat.
  • the application of heat can for example be done by a hot air blower.
  • the film is dried in an oven or a comparable drying device.
  • the film is preferably dried for 15 to 30 minutes, more preferably for 15 to 20 minutes.
  • the drying temperature may preferably range from 40 to 70°C.
  • the thus formed film can be cut into the final form representing the single dosage unit, for example into a round, any rounded, oval, elliptical, triangular, rectangular, square or polygonal shape.
  • the present invention is directed to a method for preparing the film forming suspension as defined in the second aspect of the invention and its embodiments.
  • the method comprises mixing the API having a solubility of less than 10 mg/ml in water at RTP, with the surfactant and water or the mixture of water and a solvent selected from a (Ci-C 5 )-alcohol, acetone and mixtures thereof, wherein the surfactant has a solubility greater than 30 mg/ml in water at RTP and greater than 5 mg/ml in ethanol at RTP; and a solubility in water at RTP at least 15 times greater than the solubility of the API in water at RTP.
  • the API can be added to the water or the solvent system already containing the surfactant. Alternatively, the surfactant can be added after the API was added to the water or the solvent system.
  • the API and the surfactant can be added to the water or the solvent system simultaneously.
  • Further substance(s) can be added before, after or simultaneously with the API to the solvent or solvent mixture of the suspension.
  • Film forming agents, flavorings, sweeteners and/or plasticizers can be dissolved or dispersed, for example prior to the addition of the API, in the solvent or solvent mixture. The mixture thus obtained can then be used as solvent for the suspension.
  • further substances may be added to the suspension later, i.e. for example, after the addition of the API.
  • the present invention is directed to an orodispersible film obtainable according to a method as defined in the third aspect of the invention and its embodiments.
  • the orodispersible films of the invention are obtainable from film forming suspensions according to the second aspect of the invention and its embodiments in a process that comprises drying the film forming suspension.
  • the present invention is directed to the orodispersible film of the invention as defined in the first aspect and its embodiments and in the fifth aspect and its embodiments, for use as a medicament.
  • the present invention is directed to a package comprising the orodispersible film of the invention as defined in the first aspect and its embodiments and in the fifth aspect and its embodiments.
  • the packaging materials used for oral films are, for example, sachets made from flexible multilayer foils which preferably may have an aluminum barrier layer and a heat sealer layer.
  • the orodispersible film of the invention and the film forming suspension of the invention may further comprise one or more additional components selected from a film forming polymer/agent, a plasticizer, a wetting agent, a flavoring, a taste masker, a preservative, a sweetener, a coloring agent and a filler.
  • Preferred film forming polymers are selected from cellulose, cellulose derivatives, starch, starch derivatives (preferably semisynthetic derivatives), pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, sodium alginate, and mixtures thereof.
  • Suitable cellulose derivatives include carboxy methylcellulose, hydroxy ethylcellulose, hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), methyl cellulose (MC) and ethyl cellulose (EC).
  • HMPC is preferred as the film forming polymer of the invention.
  • HMPCs are, for example, commercially available as Methocel® and Pharmacoat®. Examples of Methocels are Methocel E5LV and Methocel E15LV. Examples of Pharmacoats are Pharmacoat 603 and Pharmacoat 606. Methocel E5LV and E15LV are particularly preferred film forming polymers of the present invention.
  • HPC is commercially available as Klucel®.
  • a preferred Klucel® is Klucel® EF.
  • Mixtures of MC/HPMC are commercially known as Metolose®.
  • Preferred Metolose® polymers are Metolose SM-100, SM-15 and SM4.
  • mixtures of film forming polymers can be used to prepare the orodispersible film of the invention. It has been seen that preferably mixtures of cellulose derivatives and polyvinyl pyrrolidone (PVP) together with the surfactant of the invention provide a film forming dispersion that has excellent stability and leads to a non-aggregating orodispersible film with excellent pull-off properties and the desired disintegration time.
  • PVPs are commercially known as Kollidon®.
  • Preferred Kollidons are Kollidon 25 and Kollidon CL.
  • the preferred percentage amount of the film forming polymer in the orodispersible film or in the film forming suspension of the invention is from 15 to 60% wt., preferably 30 to 55% wt., even more preferably 30 to 40% wt. of the dry weight of the film or suspension.
  • the sum of the weight percentages of each film forming component preferably does not exceed the 60% wt. of the dry weight of the orodispersible film and is more preferably in the range of from 45 to 60% wt. of the dry weight of the film or suspension.
  • the first film forming polymer is in amount ranging from 20 to 40% wt., preferably 25 to 35% and the second film forming polymer is present in an amount ranging from 15 to 35% wt., preferably 15 to 20% wt. of the dry weight of the film or suspension.
  • a wetting agent may be present in the film and in the film forming suspension of the invention.
  • the wetting agents are useful to retain water in the dosage form.
  • a certain amount of water remaining in the film (0.5 to 10% wt., preferably 1 to 8% wt.) is preferable in view of the elasticity, which facilitates the processing of the product and the handling by the patient.
  • Any wetting agent suitable for the purpose of retaining water in the film is contemplated by the present invention.
  • Preferred wetting agents include sorbitols, xylitols and malto-dextrine.
  • the percentage amount of the wetting agent, when present, ranges from 0.5 to 10% wt., preferably 5 to 10% wt.
  • the weight both of the film and the suspension refers to the dry weight of the film or of the suspension.
  • a plasticizer is optionally comprised in the film and suspension of the invention.
  • the plasticizer may serve to reduce the brittleness of the composition provided in the form of a film and to increase its flexibility.
  • the plasticizers may be selected from glycerol, propylene glycol, dibutyl sebacate, triacetin, triethyl citrate and isopropyl myristate. The use of propylene glycol and glycerol is particularly preferred.
  • the percentage amount in the orodispersible film or film forming suspension of the invention is from 5 to 35% wt., preferably 10 to 20% wt.
  • the weight both of the film and the suspension refers to the dry weight of the film or of the suspension.
  • taste masking may be advantageous for APIs with a bitter or otherwise unpleasant taste.
  • a flavoring agent may be optionally a further component of the orodispersible film and of the suspension of the invention. Normally, liquid flavors are used, although amounts of flavors may be lost during drying.
  • the proportion in the orodispersible film or in the film forming suspension of the invention is from 0.1 to 10% wt., preferably 0.1 to 5% wt., more preferably 0.2 to 2% wt. related to the dry weight of the composition.
  • Peppermint oil, peppermint flavor, menthol, and/or levomenthol are flavors according to the invention.
  • flavors with sour fresh taste especially grapefruit flavor, lemon and/or orange flavor can be present.
  • the taste of the orodispersible film and the taste sensation occurring after ingestion can thus be made more comfortable for the patient.
  • the flavoring agent can also be selected from flavoring agents with sweet, nutty taste, in particular from those flavoring agents that produce a nut flavor, a chocolate flavor, a cinnamon or spice flavor or the like.
  • any other suitable flavoring agents can be used to determine or define the flavor of respective compositions to thereby increase patient's compliance.
  • taste receptor competitors e.g. sodium chloride
  • bitter masking substances e.g. sodium chloride
  • Ion exchange resins e.g. Amberlite types
  • a sweetener can be used.
  • the sweetener may support taste masking and enhance acceptability of the film.
  • Sweeteners can be selected from monosaccharides, disaccharides, polysaccharides, in particular maltodextrin, sucralose, neotame, alitame, cyclamate, sorbitol, xylitol, saccharin, aspartame, and mixtures of the aforesaid.
  • Synthetic sweeteners that can typically be used are sucralose, aspartame and saccharin.
  • a sweetener When a sweetener is used, its proportion is desirably from 0.1 % to 5% by weight, preferably 0.5 to 4% wt., more preferably 1 to 2 % wt. related to the dry weight of the film or suspension.
  • a filler may be present.
  • a filler is used when a low dose API (an API to be administered in a low dose, such as 2.5 to 20 mg API per single dosage form) is present in the film or suspension.
  • a low dose API an API to be administered in a low dose, such as 2.5 to 20 mg API per single dosage form
  • Microcrystalline cellulose, lactose, mannitol, calcium phosphate, calcium carbonate and mixtures thereof may be used as filler according to the present invention.
  • a dye may be present in the film and in the suspension of the invention. Titanium oxide may be used preferably.
  • the film forming suspension was prepared by stirring 227.6 g of a water/ethanol solvent system (30% wt. ethanol) with 0.15 g of Polysorbat 80 (Tween® 80) for 5 minutes. 30 g of olanzapine (olanzapine free base polymorphic form II) was added and stirred for another 5 minutes at 200 rotations per minute (rpm). 35 g of hydroxy propyl methyl cellulose (Methocel E5LV) were added and stirred for another 2 minutes. Whilst stirring, 17.85 g of Kollidon 25, 13.0 g of propylene glycol, 1 g sucralose, 0.5 g levomenthol, 0.5 g peppermint flavor and 2 g titanium dioxide were slowly added.
  • the stirring of the suspension was continued for 2 hours.
  • the viscosity of the suspension was measured to be 2318 mPa * s at RTP.
  • the suspension was cast on a polyethylene terephthalate (PET) foil.
  • PET polyethylene terephthalate
  • the resulting laminate was dried at 50°C for 15 minutes. After drying, the film was cut into squares of 2 cm 2 , the foil was removed and the film packaged into sachets. Aggregation was measured according to the procedure disclosed below. No aggregation was observed.
  • the film met the content uniformity requirement according to Ph. Eur. 7.4 chapter 2.9.40.
  • the pull-off properties of the obtained film were excellent and the film was readily removed from the foil without any damages. The flexibility was tested and was found to be good. No foam formation was observed during the production process. Ethanol and water are removed during the drying process. The results are summarized in Table 2.
  • the agglomerates formation in the orodispersible film made according to examples 1 to 12 was compared to the agglomerate formation of the standard orodispersible films comprising olanzapine of examples 13 and 14.
  • the agglomeration test was performed using an optical microscope. A 6 cm 2 sample of each orodispersible film was analyzed. The sample was divided into a 10x10 (100) squares matrix.
  • Presence of agglomerates means in the present context that more than 10% of the squares (e.g. at least 10 squares) show agglomerate formation.
  • the expression "free from agglomerates” means in the present context that 10% or less of the squares show agglomerate formation.
  • the disintegration time of the orodispersible films made according to examples 1 to 12 were compared to the disintegration time of the standard orodispersible films comprising olanzapine of examples 13 and 14.
  • the disintegration test was performed using the following test procedure: A Petri dish was filled with 4 ml of demineralized water having a temperature of 25°C and was placed on a dark surface. The orodispersible film was taken out of the sachet with a pair of tweezers and was placed centered and horizontally onto the water surface. Time measurement starts when the film gets into contact with the water. The disintegration of the film was observed visually. The disintegration time is the time at which the film starts disrupting in its central parts. .
  • Table 2 is a summary table of the properties of the films of the invention.
  • APIs of the present invention have a solubility of less than 10 mg/ml and hence are “slightly soluble”, “very slightly soluble” or “practically insoluble” APIs according to the above Table 3. Sometimes, APIs are generally indicated as “low soluble” or “insoluble” (the latter where appropriate) in the present context.
  • RTP means in the present context "room temperature and pressure”. Room temperature in this context is 25 °C and room pressure is 1 atm. Further preferred variants of the invention
  • the present invention is directed to an orodispersible film comprising:
  • the orodispersible film is a orodispersible film wherein the amount of surfactant is from 0.01 % wt. to 0.5% wt., preferably from 0.1 % wt. to 0.2% wt. related to the dry weight of the film.
  • the orodispersible film is the orodispersible film according to the first aspect and any of the embodiments thereof, wherein the amount of the active pharmaceutical ingredient is from 20 to 70% wt., preferably from 20 to 50% wt., even more preferably from 20 to 40% wt. related to the dry weight of the film.
  • the orodispersible film is the orodispersible film according to the first aspect and any of the embodiments thereof, wherein the surfactant is Tween 80 and the active pharmaceutical ingredient is olanzapine, preferably olanzapine free base or olanzapine polymorph forms I and II.
  • the orodispersible film is the orodispersible film according to the first aspect and any of the embodiments thereof, wherein the solubility of the active ingredient is less than 5 mg/ml, preferably less than 1 mg/ml, more preferably less than 0.1 mg/ml in water at RTP.
  • the surfactant is an anionic or a non-ionic surfactant.
  • the orodispersible film is the orodispersible film according to the fifth embodiment of the first aspect, wherein the surfactant is selected from
  • alkoxylated fatty alcohols of formula RO(Ci-C 4 alkyl-0) n H wherein R is a (C 6 -Ci 8 )alkyl and n is 10 to 50, preferably R is (Ci 2 -Ci 8 )alkyl, Ci-C 4 alkyl-0 is ethoxy (EO) and n is 20;
  • the orodispersible film is the orodispersible film according to the sixth aspect, wherein the surfactant is selected from a (Ci 0 -Ci 4 )-alkyl sulfate or a polyoxyethylene sorbitan monooleat, preferably sodium lauryl sulfate and polysorbate 80, more preferably polysorbate 80.
  • the surfactant is selected from a (Ci 0 -Ci 4 )-alkyl sulfate or a polyoxyethylene sorbitan monooleat, preferably sodium lauryl sulfate and polysorbate 80, more preferably polysorbate 80.
  • the orodispersible film is the orodispersible film of the first aspect and any embodiments thereof, wherein the active pharmaceutical ingredient is a micronized active pharmaceutical ingredient.
  • the orodispersible film is the orodispersible film according to the eight embodiment wherein the mean particle size of the micronized active pharmaceutical ingredient is between 1 and 20 ⁇ , preferably between 1 and 10 ⁇ .
  • the orodispersible film is the orodispersible film according to the first aspect and any of the embodiments thereof, wherein the active pharmaceutical ingredient is olanzapine, preferably olanzapine free base, olanzapine polymorph form I and olanzapine polymorph form II.
  • the orodispersible film is the orodispersible film according to the first aspect and any of the embodiments thereof further comprising one of more components selected from a film forming polymer/agent, a plasticizer, a wetting agent, a flavoring, a taste masker, a preservative, a sweetener, a coloring agent and a filler.
  • the orodispersible film is the orodispersible film according to the first aspect and any of the embodiments thereof comprising:
  • plasticizer 5 to 35% wt. of plasticizer related to the dry weight of the film.
  • the orodispersible film is the orodispersible film according to the first aspect and any of the embodiments thereof comprising:
  • the surfactant is selected from polysorbate 80 and sodium lauryl sulfate.
  • the orodispersible film is the orodispersible film according to the first aspect and any of the embodiments thereof comprising:
  • the active pharmaceutical ingredient is olanzapine
  • the surfactant is polysorbate 80
  • the film forming agent is hydroxy propyl methyl cellulose and/or povidone
  • the plasticizer is glycerol and/or propylene glycol.
  • the orodispersible film is the orodispersible film according the first aspect and any of the above embodiments thereof comprising:
  • the active pharmaceutical ingredient is olanzapine
  • the surfactant is sodium lauryl sulfate
  • the film forming agent is hydroxy propyl methyl cellulose and/or povidone
  • the plasticizer is glycerol and/or propylene glycol.
  • the present invention is directed to a film forming suspension comprising:
  • an active pharmaceutical ingredient having a solubility of less than 10 mg/ml in water at RTP;
  • the film forming suspension is the film forming suspension according to the second aspect, wherein the amount of the solvent is from 0% wt. to 65% wt. of the water/solvent mixture, preferably from 20% wt. to 40% wt. of the water/solvent mixture, more preferably from 25% wt. to 35% wt. of the water/solvent mixture.
  • the film forming suspension is the film forming suspension according to the second aspect and any of the embodiments thereof, wherein the solvent is ethanol or isopropanol, preferably ethanol.
  • the film forming suspension is the film forming suspension according to the second aspect and any of the embodiments thereof, wherein the amount of surfactant is from 0.01 % wt. to 0.5% wt., preferably from 0.1 % wt. to 0.2% wt., related to the dry weight of the suspension.
  • the film forming suspension is the film forming suspension according to the second aspect and any of the embodiments thereof, wherein the amount of the active pharmaceutical ingredient is from 20 to 70% wt., preferably from 20 to 50% wt., even more preferably from 20 to 40% wt. related to the dry weight of the film or suspension.
  • the film forming suspension is the film forming suspension according to the second aspect and any embodiments thereof, wherein the suspension has a viscosity at RTP of from 1000 to 5000 mPa * s, preferably 2000 to 4000 mPa * s, more preferably 2000 to 2500 mPa * s.
  • the film forming suspension is the film forming suspension according to the second aspect and any of the first to fifth embodiments thereof, wherein the solubility of the active ingredient is less than 5 mg/ml, preferably less than 1 mg/ml, more preferably less than 0.1 mg/ml in water at RTP.
  • the film forming suspension is the film forming suspension according to the second aspect and any of the first to sixth embodiments thereof, wherein the surfactant is an anionic or a non-ionic surfactant.
  • the film forming suspension is the film forming suspension according to the seventh embodiment, wherein the surfactant is selected from
  • alkoxylated fatty alcohols of formula RO(CrC 4 alkyl-0) n H wherein R is a (C 6 -Ci 8 )alkyl and n is 10 to 50, preferably R is (Ci 2 -Ci 8 )alkyl, Ci-C 4 alkyl-0 is ethoxy (EO) and n is 20;
  • the film forming suspension is the film forming suspension according to the eighth embodiment, wherein the surfactant is selected from a (Ci 0 -Ci 4 )-alkyl sulfate or a polyoxyethylene sorbitan monooleat, preferably sodium lauryl sulfate and polysorbate 80, more preferably polysorbate 80.
  • the surfactant is selected from a (Ci 0 -Ci 4 )-alkyl sulfate or a polyoxyethylene sorbitan monooleat, preferably sodium lauryl sulfate and polysorbate 80, more preferably polysorbate 80.
  • the film forming suspension is the film forming suspension according to the second aspect and to any of the embodiments thereof, wherein the active pharmaceutical ingredient is a micronized active pharmaceutical ingredient.
  • the film forming suspension is the film forming suspension according to the tenth embodiment, wherein the mean particle size of the micronized active pharmaceutical ingredient is between 1 and 20 ⁇ , preferably between 1 and 10 ⁇ .
  • the film forming suspension is the film forming suspension according to the second aspect and any of the embodiments thereof, wherein the active pharmaceutical ingredient is olanzapine, preferably olanzapine free base, olanzapine polymorph form I and olanzapine polymorph form II.
  • the film forming suspension is the film forming suspension according to the second aspect and any of the embodiments thereof, further comprising one of more components selected from a film forming polymer/agent, a plasticizer, a wetting agent, a flavoring, a taste masker, a preservative, a sweetener, a coloring agent and a filler.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne des compositions pharmaceutiques, en particulier des films orodispersibles comprenant un ingrédient pharmaceutique actif ayant une solubilité inférieure à 10 mg/mL dans l'eau à température et pression ambiantes et un surfactant 1) ayant une solubilité supérieure à 30 mg/mL dans l'eau à température et pression ambiantes et 2) ayant une solubilité supérieure à 5 mg/mL dans l'éthanol à température et pression ambiantes. La présente invention concerne en outre des suspensions filmogènes et des procédés de préparations des films orodispersibles et des suspensions filmogènes.
PCT/EP2014/079475 2013-12-31 2014-12-30 Film orodispersible WO2015101639A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP13199917.9 2013-12-31
EP13199917 2013-12-31

Publications (1)

Publication Number Publication Date
WO2015101639A1 true WO2015101639A1 (fr) 2015-07-09

Family

ID=49880637

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2014/079475 WO2015101639A1 (fr) 2013-12-31 2014-12-30 Film orodispersible

Country Status (1)

Country Link
WO (1) WO2015101639A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2736822C1 (ru) * 2017-02-17 2020-11-20 Лтс Ломанн Терапи-Системе Аг Структурированные ородиспергируемые пленки
WO2022069952A1 (fr) * 2020-11-24 2022-04-07 Lulla Geeta Procédé de préparation d'un film orodispersible convenant à divers principes actifs

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008098195A2 (fr) * 2007-02-09 2008-08-14 Todd Maibach Film comprenant de la nitroglycérine
US20090004254A1 (en) * 2007-06-19 2009-01-01 Todd Maibach Film comprising active drugs
US20110237563A1 (en) * 2010-03-23 2011-09-29 Dominique Costantini Fast dissolving drug delivery systems

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008098195A2 (fr) * 2007-02-09 2008-08-14 Todd Maibach Film comprenant de la nitroglycérine
US20090004254A1 (en) * 2007-06-19 2009-01-01 Todd Maibach Film comprising active drugs
US20110237563A1 (en) * 2010-03-23 2011-09-29 Dominique Costantini Fast dissolving drug delivery systems

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2736822C1 (ru) * 2017-02-17 2020-11-20 Лтс Ломанн Терапи-Системе Аг Структурированные ородиспергируемые пленки
WO2022069952A1 (fr) * 2020-11-24 2022-04-07 Lulla Geeta Procédé de préparation d'un film orodispersible convenant à divers principes actifs

Similar Documents

Publication Publication Date Title
JP6294479B2 (ja) 経口分散性フィルム
JP2022058678A (ja) ブプレノルフィンの乱用抵抗性粘膜付着性送達デバイス
US20090047330A1 (en) Oral fast dissolving films for erectile dysfunction bioactive agents
JP2012072166A (ja) 粘膜分配用組成物と方法
BRPI0714514B1 (pt) Grânulo compreendendo núcleo revestido por oxicodona, bem como comprimido para desintegração oral e seu processo de fabricação
WO2010068789A1 (fr) Carbonate de sodium enrobé de polyéthylèneglycol utilisé comme excipient pharmaceutique et compositions contenant ce composé
CN103025321A (zh) 快速溶解的药物释放系统
Singh et al. Fast dissolving drug delivery systems: formulation, preparation techniques and evaluation
ES2961850T3 (es) Minimización de la aireación de suspensiones durante la mezcla en línea
JP2013515782A (ja) オンダンセトロンを含む経口投与可能なフィルム製剤
BRPI0407116B1 (pt) Partícula revestida baseada em princípio ativo, composição farmacêutica ou cosmética, e, método para produção de partícula revestida baseada em princípio ativo
US10335443B2 (en) Orodispersible film
JP7359764B2 (ja) ジアミン誘導体を含む顆粒剤
US11179331B1 (en) Oral soluble film containing sildenafil citrate
WO2015101639A1 (fr) Film orodispersible
WO2008048018A1 (fr) Suspension d'un matériau à base de megestrol pharmaceutiquement stable
EP4021405A1 (fr) Formulation pharmaceutique
Garg et al. Development and evaluation of a buccal bioadhesive system for smoking cessation therapy
Gupta et al. An overview of novel techniques employed in mouth dissolving drug delivery system
EP1652514A1 (fr) Preparation dispersee sur place
JP5433295B2 (ja) キサンタンガム被覆水溶性糖類及び圧縮成形製剤
JP5811404B2 (ja) セトロンを頬側経粘膜投与するための処方物（ｆｏｒｍｕｌａｔｉｏｎ）
JP2012031164A (ja) フィルム状製剤
ES2939889T3 (es) Formulación microgranular novedosa
TWI835118B (zh) 布瑞哌唑口溶膜組合物、其製備方法及用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14830398

Country of ref document: EP

Kind code of ref document: A1

REEP Request for entry into the european phase

Ref document number: 2014830398

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14830398

Country of ref document: EP

Kind code of ref document: A1