Classifications

• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • 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
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
  • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
• • 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
  • A61K47/02—Inorganic compounds
• • 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
• • 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
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
• • 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
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • 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
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • 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
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• • 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
• • 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
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/38—Cellulose; Derivatives thereof
• • 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
  • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• • 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
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
  • A61K9/7007—Drug-containing films, membranes or sheets

Definitions

• the present invention relates to a pharmaceutical formulation that is based on a non-muco-adhesive, oral, rapidly disintegrating, preferably single-layer film, and contains one or more bitter tasting drugs or pharmaceutically acceptable salts thereof, together with appropriate excipients to mask the taste.
• oral films are characterized for example by the fact that they have a low layer thickness and a large surface area, and remain stuck to oral mucosa and disintegrate very quickly in the oral cavity. They can be taken always and everywhere discretely according to the patient's needs, without the need of additional, simultaneous intake of fluid.
• a particular problem with the administration of bitter tasting drugs in the form of an orally dispersible film poses their release in the oral cavity or on the tongue of the patient. Because of the bitter taste of the respective drugs, taking such formulations is often perceived as very unpleasant, leading to an impairment of compliance. The masking of the bitter taste of the drugs used, i. e. the flavor optimization of oral films is therefore of great importance in the development of this dosage form.
• Method for taste masking in pharmaceutical preparations generally include for example the use of coatings, the production of granules, the use of sweeteners, the microencapsulation, the use of taste suppressiva and taste enhancer, the preparation of solid dispersions, the use of ion exchange resins, the use of viscosity-increasing substances, the complex formation, the use of pH modifying agents, and the use of adsorbents (see for example Ayenew, Z. et al., Trends in Pharmaceutical Taste Masking Technologies: A Patent Review, Recent Patents on Drug Delivery and Formulation 2009, 3, 26-39).
• Non-mucoadhesive, orally disintegrating films as pharmaceutical dosage forms are described in WO 2008/040534.
• the drugs released therefrom are however not absorbed via the oral mucosa.
• the objective in the for development of these films was instead the provision of a generic dosage form, the pharmacokinetic properties of which are similar to those of orally administered dosage forms, after the administration of which there is an absorption of the released drugs in the gastrointestinal tract, such as tablets, capsules, liquid suspensions or orally disintegrating tablets.
• the films disclosed in WO 2008/040534 may also contain flavorings, sweeteners and taste-masking agents.
• amino alkyl methacrylate copolymers such as Eudragit E PO and cyclodextrin are described.
• the list of drugs that is described in WO 2008/040534 for administration with the film formulation disclosed therein contains i. a. the following bitter tasting drugs: risperidone, sildenafil, vardenafil, sumatriptan, zolmitriptan, naratriptan, cetirizine and dextromethorphan.
• sweetener for taste masking.
• suitable sweeteners natural and artificial sweeteners are described, such as monosaccharides, disaccharides and polysaccharides, saccharin salts, sweeteners based on dipeptide, such as sweeteners derived from L-aspartic acid, and protein based sweeteners.
• suitable sweeteners are sucralose, aspartame, acesulfame potassium, neotame, saccharin, xylitol, and mixtures thereof.
• Bitter tasting drugs which are mentioned in US 2003/0211136, are i. a. dextromethorphan, diphenhydramine, cetirizine and nicotine.
• WO 2006/013416 Another film formulation for oral administration of a bitter tasting drug is described in WO 2006/013416.
• a complex is used for taste masking, which consists of a taste receptor blocker, a taste receptor competitor and a sweetener as well as optionally of a flavoring agent.
• Hydrogenated ethoxylated glycerol esters are described as suitable taste receptor blockers.
• the taste receptor competitor generally include substances that give a salty or a sour taste, such as citric acid and phosphoric acid or their sodium and potassium salts as well as sodium chloride and hydroxy acids, such as glycolic acid, lactic acid and tartaric acid, etc., and their salts.
• sweeteners both substances are suitable whose sweetness effect occurs immediately, as well as substances whose sweetness effect occurs only delayed. Examples are saccharin, sucralose, neotame, alitame, aspartame and cyclamate, etc. for sweeteners with immediate effect as well as monoammonium glycyrrhizinate for sweeteners with delayed sweetness effect.
• sweeteners dextromethorphan, chlorhexidine, guaifenesin, pseudoephedrine, caffeine, peroxides, atorvastatin, aspirin, paracetamol, diphenhydramine, doxylamine, sildenafil citrate and loperamide are disclosed in WO 2006/013416.
• a polymer-based edible film formulation with sildenafil citrate, tadalafil, or vardenafil as drug contained therein is disclosed in US 2009/0047330.
• the film formulation may also contain flavoring agents, such as menthol and the like, as well as sweeteners, such as acesulfame potassium, sucralose, aspartame and glyrrhizin.
• a fundamental problem of these formulations is that the effective covering of taste of extremely bitter tasting drugs such as sildenafil, is difficult to achieve—if at all—by conventional methods, i.e. solely by the addition of sweeteners, flavoring agents, etc. This applies in particular, if drug concentrations of more than 50 or 60% by weight related to the total weight of the formulation are used. In such cases it is usually necessary to coat the particular drug in a complex method (see Section 4. Factors affecting selection of taste masking technology: A. Extend of bitter taste in Ayenew, Z. et al., Trends in Pharmaceutical Taste Masking Technologies: A Patent Review, Recent Patents on Drug Delivery and Formulation 2009, 3, 26-39).
• the object of the present invention is accordingly, to provide a film formulation for oral administration that after taking in the oral cavity disintegrates quickly and which enables effective taste masking of high concentrations of extremely bitter tasting drugs contained therein and which can at the same time be produce both simply and inexpensively.
• bitterness masker containing one or more inorganic and/or organic salt(s) and a plurality of monocyclic monoterpenes, and one or more sweetener(s) and optionally one or more flavoring agent(s) is suitable for effective taste masking even of extremely bitter tasting drugs in films suitable for oral administration.
• an acceptably tasting single-layer film or a single-layer preparation comprising one or more film formers and one or more extremely bitter tasting drug(s) can be formed.
• the bitter taste sensation induced by the one or more drug(s) formulated in a film is more intense and unpleasant, the longer the film remains in the oral cavity, i. e. the greater the retention time of the drug or the drugs is in the oral cavity.
• This criterion can in general be met in that the oral film is kept very thin, i.e. has a large surface to volume ratio.
• the film according to the invention or the preparation according to the invention disintegrates within a few seconds in the oral cavity.
• the film/the preparation is dissolved by saliva or decomposed, for example a water-soluble film is dissolved.
• the film or the preparation can no longer be spit out.
• the drug is predominantly swallowed and absorbed in the gastrointestinal tract.
• the drug may be partially absorbed transmucosally, this is however negligible.
• the film/the preparation is preferably substantially free of voids, surfactants and sherbets.
• the preparation of the oral films according to the invention or the preparations according to the invention further is much cheaper than the production of for example so-called melting tablets, for which a complex lyophilization process is required, or the preparation of orally dispersible formulations, in which a bitter tasting drug is taste masked in complex processes such as microencapsulation, covering or complexation.
• the film according to the invention is further characterized in that it also remains flexible over a long period of time in open storage under the conditions of climate zones II-IV and does not break when applied by the patient.
• the present invention relates to:
• a pharmaceutical film formulation comprising
• a pharmaceutical film formulation according to item 1 further comprising one or more humectants and/or one or more flavoring agent(s);
• bitter tasting drug is selected from cetirizine, sildenafil and sumatriptane;
• R 1 and R 2 are identical or different from each other and each represent an OH group or a linear or branched C 1-4 alkyl group, preferably wherein R 1 is an isopropyl group and an R 2 is a methyl group, and
• R 3 represents a linear or branched C 1-4 alkyl or C 1-4 alkoxy group, which may optionally be substituted with an OH group, and/or
• X represents O, NH or CH 2 ,
• R 1 and R 2 are identical or different from each other and each represents an OH group or a linear or branched C 1-4 alkyl group, preferably wherein R 1 is an isopropyl group and an R 2 is a methyl group, and
• R 3 represents a linear or branched C 1-4 alkyl group, which may optionally be substituted with an OH group, and/or
• R 1 and R 2 are identical and each represent a linear or branched C 1-4 alkyl group
• R 3 represents a linear or branched C 1-4 alkyl group
• R 4 represents a saturated or unsaturated, linear or branched C 1-4 alkyl group, preferably a 1-propenyl group or a 2-propanyl group and may optionally be substituted with an OH group;
• said one or said more inorganic and/or organic salt(s) is/are selected from sodium chloride, magnesium chloride, ammonium chloride, sodium ascorbate, calcium ascorbate and sodium citrate;
• bitterness masker contains sodium chloride and a mixture comprising
• humectant comprises sorbitol and/or xylitol
• humectant comprises a mixture of sorbitol and xylitol in a ratio of 1:1.5;
• a pharmaceutical film formulation according to any of the preceding items, wherein the sweetener(s) is/are selected from sucrose, sucralose, aspartame or acesulfame potassium;
• a pharmaceutical film formulation according to any of items 2-11, wherein the flavoring agent(s) is/are selected from grapefruit flavor, peppermint oil, peppermint flavor, levomenthol, menthol and/or low molecular weight organic acids such as citric acid, succinic acid, malic acid and adipic acid;
• a pharmaceutical film formulation according to any of the preceding items, wherein the content of the bitter tasting drug(s) is between 0.1 and 75% w/w, related to the dry weight of the film formulation;
• a pharmaceutical film formulation according to item 14 further comprising one or more humectants in an amount of 1-10% w/w and/or one or more flavoring agent(s) in an amount of 0.01-15% w/w, wherein the respective amounts are related to the dry weight of the film formulation;
• a pharmaceutical film formulation according to any of the preceding items, characterized in that the film formulation is a non-mucoadhesive film and that the non-mucoadhesive film is a single-layer;
• a pharmaceutical film formulation according to any of the preceding items, characterized in that it contains 50-75% w/w sildenafil citrate related to the dry weight of the film formulation as an active ingredient;
• the present invention relates to a pharmaceutical film formulation comprising
• the above pharmaceutical film formulation further contains one or more humectants, and/or one or more flavoring agent(s) capable of acting as for example taste receptor competitor(s).
• the film formulation contains one, two or three bitter tasting drugs or pharmaceutically acceptable salts thereof, more preferably one or two bitter tasting drugs or pharmaceutically acceptable salts thereof, most preferably a bitter tasting drug or a pharmaceutically acceptable salt thereof.
• a bitter tasting drug for the purpose of this invention is any drug that stimulates the bitter receptors of the human tongue by for example forming an association, in particular a bond, with the bitter receptors, such that a nerve impulse is triggered, which produces an (unpleasant) bitter taste sensation.
• bitter tasting drug(s) is/are selected from cetirizine, anti-migraine agents, such as sumatriptan, almotriptan, avitriptan, eletriptan, frovatriptan, naratriptan, rizatriptan and zolmitriptan, and PDE-V inhibitors such as sildenafil, tadalafil and vardenafil, or pharmaceutically acceptable salts thereof.
• anti-migraine agents such as sumatriptan, almotriptan, avitriptan, eletriptan, frovatriptan, naratriptan, rizatriptan and zolmitriptan
• PDE-V inhibitors such as sildenafil, tadalafil and vardenafil, or pharmaceutically acceptable salts thereof.
• bitter tasting drug(s) is/are cetirizine, sumatriptan, almotriptan, avitriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, zolmitriptan, sildenafil, tadalafil and/or vardenafil or pharmaceutically acceptable salts thereof.
• bitter tasting drug(s) is/are cetirizine, sumatriptan, sumatriptan succinate, sildenafil and sildenafil citrate.
• bitter tasting drug is sildenafil or sildenafil citrate.
• the drug content in the inventive film formulations is at least 0.1 to 75% w/w, preferably at least 20 to 75% w/w, more preferably at least 60 to 75% w/w and preferably 60 or up to 60% w/w and particularly preferably 75% or up to 75 w/w, related to the dry weight of the film formulation.
• the inventive film formulation contains one or more film formers, preferably one film former.
• a film former within the meaning of this invention is a substance that is able to form the matrix of a film, in particular a substance, which confers the film formulation a certain degree of flexibility in the mechanical properties, such as restoring force, flexural modulus, tensile modulus, and the like.
• one or more film formers may be used, which are selected from:
• methyl cellulose MC
• HPC hydroxypropyl cellulose
• HPMC hydroxypropyl methyl cellulose
• carboxymethly cellullose, starch or modified starch, pullulan, pectin and/or gelatin may be used as film formers.
• MC and/or HPC and/or HPMC used as film formers.
• HPC is used as film former.
• this has preferably a weight-average molecular weight of 25.000 to 400.000 g/mol.
• the weight-average molecular weight is determined in the present application by means of gel permeation chromatography.
• this preferably has a weight-average molecular weight of 50.000 to 1.250.000 g/mol, more preferably of 70.000 to 500.000 g/mol.
• HPC with a softening temperature of 110 to 150° C. is used.
• the used HPC has a water content of 2 to 12% w/w.
• a particularly preferred HPC has all of these properties at the same time and has a weight-average molecular weight of 70.000 to 500.000 g/mol.
• HPMC this preferably has a weight-average molecular weight of 10.000 to 1.500.000 g/mol, more preferably of 50.000 to 500.000 g/mol.
• HPMC with a glass transition temperature (Tg) of 160 to 190° C. which preferably has a water content of 1 to 15% w/w and particularly preferably has a weight-average molecular weight of 50.000 to 500.000 g/mol.
• carboxymethyl cellulose this preferably has a weight-average molecular weight of 90.000 to 700.000 g/mol, more preferably of 110.000 to 450.000 g/mol.
• carboxymethyl cellulose having a water content of 0.1 to 10% w/w is used, which particularly preferably has a weight-average molecular weight of 110.000 to 450.000 g/mol.
• starch or modified starch this preferably has a weight-average molecular weight of 50.000 to 160.000 g/mol, more preferably of 55.000 to 150.000 g/mol.
• a starch or modified starch with a water content of 8 to 15% w/w is used, which particularly preferably has a weight-average molecular weight of 55.000 to 150.000 g/mol.
• pullulan (1,6-alpha-maltotriose) this preferably has a weight-average molecular weight of 8.000 to 2.000.000 g/mol, more preferably of 20.000 to 900.000 g/mol.
• a pullulan with a water content of 0.1 to 6% w/w is used, which particularly preferably has a weight-average molecular weight of 20.000 to 900.000 g/mol.
• pectin In the case of pectin this preferably has a weight average-molecular weight of 30.000 to 100.000 g/mol, more preferably of 35.000 to 90.000 g/mol.
• pectin with a melting point of 140-160° C. (in the dry state) is used, which particularly preferably has a weight-average molecular weight of 35.000 to 90.000 g/mol.
• this preferably has a weight-average molecular weight of 15.000 to 250.000 g/mol, more preferably of 25.000 to 150.000 g/mol.
• gelatin with a water content of 8 to 12% w/w is used, which particularly preferably has a weight-average molecular weight of 25.000 to 150.000 g/mol.
• polyvinylpyrrolidone this can be obtained, for example by polymerization of N-vinylpyrrolidone-2.
• the polyvinylpyrrolidone has a weight-average molecular weight of 5.000 to 100.000 g/mol, more preferably of 8.000 to 80.000 g/mol, particularly preferably of 10.000 g/mol to 40.000 g/mol.
• polyvinyl alcohol that is produced for example by hydrolytic cleavage of polyvinyl esters with alkalis.
• the polyvinyl alcohol has a weight-average molecular weight of 20.000 to 220.000 g/mol, more preferably of 25.000 to 100.000 g/mol, particularly preferably of 28.000 g/mol to 40.000 g/mol.
• the content of film formers in the inventive film formulations is from 1 to 90% w/w, preferably 5 to 60% w/w, more preferably 8 to 40% w/w, more preferably 9 to 20% w/w, related to the dry weight of the film formulation.
• the inventive film formulation contains one or more humectants.
• the humectants ensure a certain moisture content in the final film formulations of the present invention.
• a certain moisture content is necessary in order to ensure that the film does not break during the manufacture, packaging, transport and application, but instead remains flexible.
• the moisture content is 0.5-10% w/w, more preferably 1-15% w/w and most preferably 2-10% w/w, related to the dry weight of the inventive film formulations.
• the humectant(s) for use in the inventive film formulations is/are selected from sugar alcohols such as sorbitol and xylitol.
• a combination of sorbitol and xylitol is used as humectant.
• the weight ratio of sorbitol and xylitol is preferably 1:1.5.
• the total amount of humectant in the inventive film formulations is 1-10% w/w, preferably 2.5-5% w/w, each related to the dry weight of the film formulations.
• the inventive film formulation contains a special combination
• Suitable inorganic salts for use in the inventive film formulations are halide salts of sodium, potassium, calcium, magnesium and ammonium, preferably sodium chloride, magnesium chloride and ammonium chloride.
• Suitable organic salts for use in the inventive film formulations are the salts of ascorbic acid and citric acid, preferably sodium ascorbate, calcium ascorbate, and sodium citrate.
• the inventive film formulations contain sodium chloride.
• the total amount of inorganic and/or organic salt(s) in the inventive film formulations is 0.5-10% w/w, preferably 1-5% w/w, and more preferably 1-2% w/w, each related to the dry weight of the film formulations.
• Suitable monocyclic monoterpenes for use in the inventive film formulations are selected from
• R 1 and R 2 are identical or different from each other and each represent an OH group or a linear or branched C 1-4 alkyl group, in which preferably R 1 is a isopropyl group and R 2 is a methyl group, and
• R 3 represents a linear or branched C 1-4 alkyl or C 1-4 alkoxy group, which may optionally be substituted with an OH group;
• X represents O, NH or CH 2
• R 1 and R 2 are identical or different from each other and each represents an OH group or a linear or branched C 1-4 alkyl group, in which preferably R 1 is an isopropyl group and R 2 is a methyl group, and
• R 3 represents a linear or branched C 1-4 alkyl group, which may optionally be substituted with an OH group;
• R 1 and R 2 are identical and each represents a linear or branched C 1-4 alkyl group
• R 3 represents an OH group or a linear or branched C 1-4 alkyl group
• R 4 is a saturated or unsaturated, linear or branched C 1-4 alkyl group, preferably represents a 1-propenyl or a 2-propenyl group, and may optionally be substituted with an OH group;
• the bitterness masker of the inventive film formulations contains several monocyclic monoterpenes.
• “several” monocyclic monoterpenes means at least two, in particular three, four, and preferably five monocyclic monoterpenes.
• the bitterness masker of the inventive film formulations contains a mixture of monocyclic monoterpenes of
• the total amount of the monocyclic monoterpenes in the inventive film formulations is 0.01-10% w/w, preferably 0.01-5% w/w and more preferably 0.01-2% w/w, each related to the dry weight of the film formulations.
• the weight ratio of the inorganic and or organic salt(s) to the monocyclic monoterpenes in the bitterness masker of the inventive film formulations is 1/10-10/1, preferably 1/3-3/1, more preferably 1/1, and most preferably 1/0,2-0,2/1.
• both substances are suitable whose sweetness effect occurs immediately, as well as substances whose sweetness effect occurs after a delay.
• Suitable sweeteners are natural and synthetic sweeteners.
• Suitable natural sweeteners are monosaccharides, disaccharides and polysaccharides, especially sucrose, as well as natural protein-based sweeteners such as thaumatin and monellin.
• Suitable synthetic sweeteners are saccharin, cyclamate, sucralose, acesulfame potassium as well as synthetic protein-based sweeteners, such as aspartame.
• the inventive film formulations contains sucralose, aspartame or acesulfame potassium, preferably sucralose.
• the total amount of the sweetener(s) in the inventive film formulations is 1-15% w/w, preferably 1-10% w/w, and more preferably 2-6% w/w, each related to the dry weight of the film formulations.
• the inventive film formulation contains one or more flavoring agent(s).
• Suitable flavoring agents for use in the inventive film formulations are natural and artificial flavoring agents suitable for consumption, especially orange, strawberry, vanilla, grapefruit flavor, peppermint oil, peppermint flavor, and cinnamyl acetate, citral, citronella, eugenyle format, methyl anisole, levomenthol and menthol as well as low molecular weight organic acids such as citric acid, succinic acid, malic acid and adipic acid.
• the total amount of the flavoring agent(s) in the inventive film formulations is 0.01-15% w/w, preferably 0.05-10% w/w, and more preferably 0.5-7% w/w, each related to the dry weight of the film formulations.
• the total amount of the combination of a bitterness masker comprising a) one or more inorganic and/or organic salt(s) and b) at least two monocyclic monoterpenes, and one or more sweetener(s) and optionally one or more flavoring agent(s) in the inventive film formulations is 2-20% w/w, preferably 2-15% w/w, and more preferably 2-7% w/w, each related to the dry weight of the film formulations.
• the inventive film formulation comprises:
• the above inventive film formulation also contains one or more humectants in an amount of 1-10% w/w and/or one or more flavoring agent(s) in an amount of 0.01-15% w/w each related to the dry weight of the film formulation.
• the inventive film formulation comprises:
• inventive film formulation also contains one or more preservatives, dye(s) and/or filler(s).
• Suitable preservatives for use in the inventive film formulations are, for example sorbic acid and salts thereof.
• dyes in the inventive film formulations conventional pharmaceutical dyes and pigments may be used, in particular FD & C Blue No.1 Brilliant Blue (“Blaulack”) and FD & C Blue No. 2 Indigo Carmine (“Blaulack”) or any mixture thereof as well as TiO 2 , Fe x O x , ⁇ -carotene, carmoisine, indigo carmine, riboflavin and the like.
• Suitable fillers for use in the inventive film formulations are salts such as, carbonates and phosphates, oxides, such as, for example SiO 2 , in particular in the form of Aerosil, or the like and/or cellulose and its derivatives, as well as poorly soluble sugars or sugar derivatives, such as lactose or starch derivatives, such as, for example cyclodextrins, if those are available in the final inventive film formulation essentially undissolved and thus fulfill the mechanical properties of a filler.
• Preferably microcrystalline cellulose is used as filler.
• the total amount of preservatives, dyes and/or fillers in the inventive film formulations is from 0.1 to 60% w/w, preferably from 0.5 to 50% w/w and more preferably from 4 to 50% w/w, each related to the dry weight of the film formulations.
• the inventive film formulation is a monolayer, and preferably substantially free of voids, surfactants, and sherbets.
• the inventive film formulation is a film, in particular a solid film.
• the inventive film formulation is characterized by a very advantageous combination of mechanical stability of the film and rapid release of the drug.
• the inventive film formulation rapidly disintegrates in saliva.
• monolayer film formulation means a solid preparation which is in the form of a single film.
• monolayer means, that the film is in the form of a single layer, wherein the layer is preferably homogeneous.
• the film can be flexible or non-flexible. Preferably, the film is flexible.
• the inventive mono-layer film formulation is substantially free of voids.
• a void is understood as an area which is filled with a fluid such as gas and/or liquid.
• a cavity has a diameter of typically less than 100 micrometer.
• surfactants are disadvantageous due to the possible irritant effect on skin or mucosa. In addition, many of the common surfactants are tasting very bitter. Disadvantageous is also a possible interaction with the drug absorption in the gastrointestinal tract.
• the inventive monolayer film formulation is therefore substantially free of surfactants.
• substantially free of surfactants means that the film formulations contains less than 1% w/w, preferably less than 0.1% w/w and most preferably less than 0.01% w/w of surfactant, each related to the dry weight of the film formulations.
• no surfactants are added as ingredient.
• a surfactant in the context of this invention is any conventional surfactant or wetting agent or any surfactant substance.
• the inventive monolayer film formulation is also substantially free of effervescent additives.
• substantially free of effervescent additives means that the film formulations contains less than 1% w/w, preferably less than 0.1% w/w and most preferably less than 0.01% w/w effervescent additives, each related to the dry weight of the film formulations.
• no effervescent additive is added as an ingredient.
• An effervescent additive within the scope of this invention is a compound which upon addition of water, during storage, at elevated temperature or the like, releases a gaseous compound.
• an effervescent additive is a compound which, in the mouth, for example by the action of saliva, releases a gaseous compound, such as a carbon dioxide former.
• a gaseous compound such as a carbon dioxide former.
• the film formulations contain thus no or almost no effervescent additive, such as a carbon dioxide former.
• the film thickness of the inventive film formulation is from 5 to 500 micrometer, preferably from 5 to 400 micrometer, and more preferably from 5 to 300 micrometer.
• the inventive film formulation can be available as round, any rounded, oval, elliptical, triangular, square, for example square or rectangular, or polygonal film.
• the inventive film formulation is square or rectangular.
• the inventive film formulation may have a smooth surface or a surface with elevations and/or depressions.
• the surface of the inventive film formulation has a regular pattern of projections and depressions, such as a wave pattern or a grid pattern.
• the disintegration time of the inventive film formulation in the oral cavity is 1-100 seconds, preferably 1-50 seconds, more preferably 1-10 seconds.
• the inventive film formulation can be present on a carrier sheet.
• the support film on which the film according to the invention formulation is present is a carrier film made from polyethylene paper (PE paper), polypropylene foil (PP foil) and polyethylene terephthalate film (PET film).
• PE paper polyethylene paper
• PP foil polypropylene foil
• PET film polyethylene terephthalate film
• the inventive film formulation is intended for oral administration.
• the inventive film formulation for oral administration is a non-mucoadhesive film.
• the inventive film formulation is packed in a sachet bag.
• the present invention therefore also relates to sachet bags with one or more of the inventive film formulations.
• the inventive film formulation is packaged in multidose containers.
• the present invention therefore also relates to multi-dose containers with a plurality of the inventive film formulations.
• the bitter tasting drug(s) is (are) dissolved or suspended in a solvent.
• a solvent organic solvents such as alcohols, ketones, etc., or water or mixtures thereof can be used.
• Suitable solvents are, for example, ethanol, acetone and ethanol/water mixtures or acetone/water mixtures.
• the mixture is homogenized.
• the mixture is coated with a suitable coating method onto a support material.
• support material for example, PE paper, PP or PET film can be used.
• the coated substrate is dried at 30 to 120° C., preferably at 30 to 70° C.
• the coated carrier material is further processed into divided films with defined area. This can be done by punching, cutting or stamping.
• the films are packed individually with or without support foil in sachet bags or multidose containers. Before the intake of the inventive drug-containing film formulation it is possibly peeled off from the support material.
• the inventive film formulation is used for the administration of cetirizine for allergic symptoms, for the administration of anti-migraine drugs in the (acute) treatment of migraine attacks with or without aura and the like, or for administration of PDE-V inhibitors in the treatment of erectile dysfunction.
• the inventive film formulation is used for preparing a medicament for the alleviation of allergic symptoms, for the treatment of migraine with and without aura and the like, and for the treatment of erectile dysfunction.
• the present invention also relates to the use of the above described particular combination of a bitterness masker containing one or more inorganic and/or organic salt(s) as well as several monocyclic monoterpenes, and one or more sweetener(s) and optionally one or more flavoring agent(s) to mask the taste of bitter tasting substances, and in particular to mask the taste of one or more bitter tasting drug(s) or pharmaceutically acceptable salts thereof.
• the present invention provides the use of the above described particular combination of a bitterness masker containing one or more inorganic and/or organic salt(s) as well as several monocyclic monoterpenes, and one or more sweetener(s) and optionally one or more flavoring agent(s) to prepare a pharmaceutical film formulation having an acceptable taste of bitter tasting substances, in particular of one or more bitter tasting drug(s) or pharmaceutically acceptable salts thereof.
• the present invention relates to the use of a combination of pharmaceutically acceptable excipients, comprising NaCl, sucralose, menthol, and a mixture of monocyclic monoterpenes from (Z)-1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-buten-1-one, N-ethyl-2-(isopropyl)-5-methyl cyclohexane carboxamide, menthyl lactate, menthol ethylene glycol carbonate and menthol propylene glycol carbonate for the preparation of a pharmaceutical film formulation having acceptable taste of at least one bitter tasting drug, or a pharmaceutically acceptable salt thereof.
• a combination of pharmaceutically acceptable excipients comprising NaCl, sucralose, menthol, and a mixture of monocyclic monoterpenes from (Z)-1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-buten-1-one, N-ethyl-2-(isopropyl)
• inventive film formulation also includes in particular any combinations of each of the described embodiments of the individual features of the inventive film formulation and of all preferred embodiments with each other, i.e. the present application discloses, for example also an inventive film formulation comprising
• peppermint flavor and menthol in a total amount of 0.01-15% w/w, and
• the disclosure of the present application comprises not only the respective number ranges and their final values as such, but all numerical values lying within the disclosed number ranges, i. e., all intermediate values of such number ranges and all combinations of the intermediate values of various number ranges.
• Solution 1 Aerosil, peppermint, menthol, sucralose, contramarum forte, glycerol and ethanol are weighed and stirred for 10 minutes. HPC is weighed and added with stirring to the resulting solution. Subsequently, the sildenafil citrate is weighed and added to the resulting solution.
• Solution 2 sodium chloride, sorbitol, xylitol, “blaulack” and water are weighed into a second vessel, and dissolved with stirring.
• Solution 2 is then added to solution 1 and stirred until further processing continues (at least approximately 6 hours).
• Solution 1 Aerosil, peppermint, menthol, sucralose, contramarum forte, glycerol 87% and ethanol are weighed and stirred for 10 minutes. HPMC is weighed and added with stirring to the resulting solution. Subsequently, the sildenafil citrate is weighed and added to the resulting solution.
• Solution 2 sodium chloride, sorbitol, xylitol, “Blaulack” and water are weighed into a second vessel, and dissolved with stirring.
• the solution 2 is then added to solution 1 and stirred until further processing continues (at least approximately 6 hours).
• Solution 1 menthol, peppermint flavor, and ethanol are weighed and stirred until menthol is dissolved (about 3 minutes). Metolose 60SH 50 is weighed and added with stirring to the resulting solution.
• Solution 2 sucralose, sorbitol, NaCl, contramarum forte, Aerosil, glycerin and water are weighed and dissolved with stirring (15 min). The resulting solution remains cloudy milky.
• Solution 2 is added with stirring to solution 1.
• sildenafil citrate is weighed and added to the resulting solution and the mixture is stirred overnight (at least approximately 6 hours).
• Solution 1 MCC, peppermint, menthol, sucralose, contramarum forte, dibutyl sebacate and acetone are weighed and stirred for 10 minutes. HPC is weighed and added with stirring to the resulting solution. Subsequently, the sildenafil citrate is weighed and added to the resulting solution.
• Solution 2 sodium chloride, blue dye and water are weighed into a second vessel, and dissolved with stirring.
• the solution 2 is then added to solution 1 and stirred until further processing continues (at least approximately 6 hours).

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• 2010
  • 2010-10-28 DE DE102010049708A patent/DE102010049708A1/de not_active Withdrawn
• 2011
  • 2011-10-27 US US13/881,613 patent/US20130217697A1/en not_active Abandoned
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