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 based on a non-mucoadhesive, oral, rapidly disintegrating, preferably monolayer film which contains one or more bitter-tasting drugs or pharmaceutically acceptable salts thereof and corresponding taste masking auxiliaries.
• Oral administration of drugs is still the most commonly used route of administration.
• oral films which can be taken without fluid intake and rapidly disintegrate in the oral cavity.
• Oral films are characterized by the fact that they have a small layer thickness and a large surface, stick to the oral mucosa and disintegrate in the oral cavity in no time. You can always and everywhere as needed be taken discreetly without the need for the additional, simultaneous intake of fluid.
• bitter-tasting drugs in the form of an orally dispersible film Due to the bitter taste of the respective drugs, the intake of such formulations is often perceived as very unpleasant, leading to impairment of compliance.
• the masking of the bitter taste of the drugs used, i. the flavor optimization of oral films, is therefore of great importance in the development of this dosage form.
• Methods for taste masking in pharmaceutical preparations include e.g. the use of coatings, the production of granules, the use of sweeteners, microencapsulation, the use of taste suppressants and enhancers, the preparation of solid dispersions, the use of ion exchange resins, the use of viscosity enhancing substances, complex formation, the use of pH modifying substances as well as the use of adsorbents (see eg Ayenew, Z. et al., Trends in Pharmaceutical Key Masking Technologies: A Patent Review, Recent Patents on Drug Delivery and Formulation 2009, 3, 26-39).
• Non-mucoadhesive, mouth-disintegrating films as a pharmaceutical dosage form are described in WO 2008/040534.
• the released drugs are not absorbed through the oral mucosa.
• the aim of the development of these films was instead to provide a generic dosage form, the pharmacokinetic properties of which correspond to those of orally administered dosage forms, after the administration of which there is an absorption of the drugs released therefrom 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 substances.
• Aminoalkylmethacrylat copolymers are described, such as Eudragit E PO and cyclodextrin.
• the list of drugs described in WO 2008/040534 for administration with the film formulation disclosed therein includes, among others, the following bitter-tasting drugs: risperidone, sildenafil, vardenafil, sumatriptan, zolmitriptan, naratriptan, cetirizine and dextromethorphan.
• US 2003/0211 136 discloses rapidly disintegrating films for oral administration characterized in particular by the presence of a sweetener for taste masking.
• Suitable sweeteners are described as natural and artificial sweeteners, e.g. Monosaccharides, disaccharides and polysaccharides, saccharin salts, dipeptide based sweeteners, e.g. L-aspartic acid-derived sweeteners and protein-based sweeteners.
• Other suitable sweeteners are sucralose, aspartame, acesulfame potassium, neotame, saccharin, xylitol, and mixtures thereof.
• Bitter-tasting drugs which are mentioned in US 2003/021 1136, 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. It employs a taste masking complex consisting of a taste receptor blocker, a taste receptor competitor and a sweetener, and optionally a flavoring agent.
• Suitable flavor receptor blockers are hydrogenated, ethoxylated glycerol esters.
• the taste receptor competing agents generally contain substances which impart a salty or acidic taste, for example citric acid and phosphoric acid or their sodium and calcium salts, and also sodium chloride and hydroxy acids such as glycolic acid, lactic acid and tartaric acid, etc., and salts thereof.
• Suitable sweeteners are both substances whose sweetening effect occurs immediately, as well as substances whose sweetness effect occurs only delayed.
• Examples are saccharin, sucralose, neotame, alitame, aspartame and cyclamate, etc., for immediate sweetening sweeteners, and monoammonium glycyrrhizinate for sweetener sweeteners.
• Dextromethorphan, chlorhexidine, guaifenesin, pseudoephedrine, caffeine, peroxides, atorvastatin, aspirin, paracetamol, diphenhydramine, doxylamine, sildenafil citrate and loperamide are disclosed in WO 2006/013416 as bitter-tasting drugs.
• a polymer-based edible film formulation with sildenafil citrate, tadalafil or vardenafil as the drug contained therein is disclosed in US 2009/0047330.
• the use of cyclodextrins or the encapsulation of the drugs is suggested.
• the film formulation and flavorings such.
• sweeteners such as acesulfame potassium, sucralose, aspartame and glyrrhizin included.
• a fundamental problem with these formulations is that the effective flavor masking of extremely bitter tasting drugs, such as e.g. Sildenafil, by conventional techniques, i. only by the addition of sweeteners, flavorings, etc., if at all - is difficult to achieve. This is especially true when drug concentrations greater than 50 or 60% based on the total weight of the formulation are used. In such cases, it is usually necessary to coat the respective drug in a complex process (see section 4. Factors affecting selection of taste masking technology: A. Extend of bitter taste in Ayenew, Z. et al., Trends in Pharmaceutical Key Masking Technologies: A Patent Review, Recent Patents on Drug Delivery and Formulation 2009, 3, 26-39).
• bitter mask containing one or more inorganic and / or organic salt (s) and several monocyclic monoterpenes, and one or more sweetener (s) and optionally one or more flavoring agents effective taste masking also extremely bitter-tasting drugs in films for oral administration is suitable.
• the film or the preparation according to the invention disintegrates within a few seconds in the oral cavity.
• the film / preparation is dissolved or decomposed by saliva, for example, a water-soluble film is dissolved.
• the film or the preparation is no longer ausspuckbar.
• the drug is predominantly swallowed and absorbed in the gastrointestinal tract.
• the drug may be partially transmucosal, but this is negligible.
• the film / preparation is preferably substantially free of voids, surfactants and effervescent additives.
• the preparation of the oral films or of the preparations according to the invention is also significantly more cost-effective than, for example, the production of so-called orodispersible tablets, for which a complicated lyophilization process is required, or the preparation of orally dispersible formulations in which a bitter-tasting drug is used in complex processes such as microencapsulation Taste-masking, coating or complexing.
• the film according to the invention is further characterized in that it remains flexible over a long period of time even in open storage under the conditions of climate zones II-IV and does not break when used by the patient.
• the present invention relates to:
• a pharmaceutical film formulation comprising
• bitter-tasting drug s
• pharmaceutically acceptable salts thereof s
• a pharmaceutical film formulation according to item 1 further comprising one or more humectants and / or one or more flavoring agents;
• bitter-tasting drug is selected from cetirizine, sildenafil and sumatriptan;
• Ri and R 2 are the same or different and each represents an OH group or a linear or branched Ci_ 4 alkyl group, wherein preferably R ⁇ is a
• Isopropyl group and R 2 is a methyl group
• R 3 is a linear or branched Ci -4 alkoxy group represents 4 alkyl or CI_, which may optionally be substituted with an OH group; and / or a compound of the formula (B)
• X represents O, NH or CH 2 ,
• R 2 are the same or different and each represents an OH group or a linear or branched d.
• 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; and / or a compound of the formula (C)
• R 2 are the same and each represents a linear or branched Ci_ 4 alkyl group
• R 3 is an OH group or a linear or branched d. Represents 4- alkyl group and
• R 4 is a saturated or unsaturated, linear or branched CI_ 4 alkyl group, preferably a 1-propenyl group or a 2-propenyl group, and may be optionally substituted with an OH group;
• Ammonium chloride sodium ascorbate, calcium ascorbate and sodium citrate
• bitter mask comprises sodium chloride and a mixture
• sweetener (s) is / are selected from sucrose, sucralose, aspartame or acesulfame potassium;
• a pharmaceutical film formulation according to any preceding item wherein the content of the bitter-tasting drug (s) is between 0.1 and 75% w / w, preferably between 10 and 75%, 20 and 75% or 50 and 75% G / G, based on the dry weight of the film formulation;
• bitter-tasting drug s
• pharmaceutically acceptable salts thereof in an amount of at least 0, 1-75% w / w
• one or more film formers in an amount of 1-90% w / w,
• 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 agents in an amount of 0.01-15% w / w, wherein the respective amounts are based on the dry weight of the film formulation;
• bitter-tasting drug selected from cetirizine, sildenafil and sumatriptan, or pharmaceutically acceptable salts thereof in an amount of up to 75% w / w,
• one or more film formers selected from methyl cellulose,
• Hydroxypropylcellulose and / or hydroxypropylmethylcellulose in an amount of 9-20% w / w, a mixture of sorbitol and xylitol in a ratio of 1: 1, 5 in an amount of 2.5-5% w / w,
• Sucralose in an amount of 2-6% w / w and
• a pharmaceutical film formulation according to any one of the preceding points characterized in that the film formulation is a non-mucoadhesive film and that the non-mucoadhesive film is single layered;
• a pharmaceutical film formulation according to one of the preceding points characterized in that it contains as active ingredient 50-75% w / w sildenafil citrate based on the dry weight of the film formulation;
• the present invention relates to a pharmaceutical film formulation comprising
• bitter-tasting drug s
• pharmaceutically acceptable salts thereof s
• sweetener one or more sweetener (s).
• the above pharmaceutical film formulation further contains one or more humectants and / or one or more flavorants, which may act as a taste receptor competitor (s), for example.
• 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 in the sense of this invention is any drug which stimulates the bitter receptors of the human tongue, in which e.g. an association, in particular a binding, with which bitter receptors enter, so that a nerve impulse is triggered, which produces an (unpleasant) bitter taste sensation.
• bitter-tasting drug are selected from cetirizine, antimigraine agents, e.g. Sumatriptan, almotriptan, avitriptan, eletriptan, frovatriptan, naratriptan, rizatriptan and zolmitriptan, and PDE-V inhibitors, e.g. Sildenafil, tadalafil and vardenafil, or pharmaceutically acceptable salts thereof.
• cetirizine e.g. Sumatriptan, almotriptan, avitriptan, eletriptan, frovatriptan, naratriptan, rizatriptan and zolmitriptan
• PDE-V inhibitors e.g. Sildenafil, tadalafil and vardenafil, or pharmaceutically acceptable salts thereof.
• bitter-tasting drug cetirizine, sumatriptan, almotriptan, avitriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, Zolmitriptan, sildenafil, tadalafil and / or vardenafil or pharmaceutically acceptable salts thereof.
• bitter-tasting drug cetirizine, sumatriptan, sumatriptan succinate, sildenafil and 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 G / G, in each case based on the dry weight of the film formulations.
• a film-forming agent is a substance capable of forming the matrix of a film, in particular a substance which imparts to the film formulation a certain flexibility of the mechanical properties, such as restoring force, flexural modulus, expansion modulus and the like.
• one or more film formers can be used, which are selected from:
• polymeric carbohydrates such as, for example, cellulose and its derivatives, starch and its derivatives, agar-agar, alginic acid, arabinogalactan, galactomannan, carrageenan, dextran, tragacanth and gums of plant origin,
• synthetic polymers which are preferably soluble or swellable in water, such as polyvinyl pyrrolidone, polyvinyl alcohol, polyacrylic acid or polyacrylamide, and
• Polypeptides such as gelatin, albumin or collagen, or
• MC methylcellulose
• HPC hydroxypropylcellulose
• HPMC hydroxypropylmethylcellulose
• carboxymethlycellullose starch or modified Starch
• pullulan pullulan
• pectin pectin and / or gelatin
• MC and / or HPC and / or HPMC are particularly preferable to use as the film former.
• HPC is used as a film former.
• MC preferably has a weight-average molecular weight of 25,000 to 400,000 g / mol.
• the weight average molecular weight in this application is determined by gel permeation chromatography.
• HPC it preferably has a weight-average molecular weight of 50,000 to 1,250,000 g / mol, more preferably 70,000 to 500,000 g / mol.
• an HPC having a softening temperature of 110 to 150 ° C is used.
• HPMC preferably has a weight-average molecular weight of 10,000 to 1,500,000 g / mol, more preferably 50,000 to 500,000 g / mol.
• HPMC having a glass transition temperature (Tg) of 160 to 190 ° C, more preferably having a water content of 1 to 15% w / w, and more preferably having a weight average molecular weight of 50,000 to 500,000 g / mol ,
• carboxymethyl cellulose In the case of carboxymethyl cellulose, it preferably has a weight-average molecular weight of from 90,000 to 700,000 g / mol, more preferably from 1 10,000 to 450,000 g / mol.
• carboxymethyl cellulose having a water content of 0.1 to 10% w / w, more preferably having a weight average molecular weight of 110,000 to 450,000 g / mol.
• starch or modified starch it preferably has a weight-average molecular weight of 50,000 to 160,000 g / mol, more preferably 55,000 to 150,000 g / mol.
• a starch or modified starch having a water content of 8 to 15% w / w, more preferably having a weight average molecular weight of 55,000 to 150,000 g / mol.
• pullulan (1,6-alpha-maltotriose)
• it preferably has a weight-average molecular weight of 8,000 to 2,000,000 g / mol, more preferably 20,000 to 900,000 g / mol.
• a pullulan having a water content of 0.1 to 6% w / w, more preferably having a weight average molecular weight of 20,000 to 900,000 g / mol.
• pectin In the case of pectin, it preferably has a weight-average molecular weight of from 30,000 to 100,000 g / mol, more preferably from 35,000 to 90,000 g / mol.
• pectin having a melting temperature of 140 to 160 ° C in the dry state
• a weight average molecular weight of 35,000 to 90,000 g / mol is also preferable to use.
• gelatin In the case of gelatin, it preferably has a weight-average molecular weight of 15,000 to 250,000 g / mol, more preferably 25,000 to 150,000 g / mol.
• gelatin having a water content of 8 to 12% w / w, which more 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 8,000 to 80,000 g / mol, particularly preferably 10,000 g / mol to 40,000 g / mol.
• polyvinyl alcohol this is prepared, for example, by hydrolytic cleavage of polyvinyl esters with alkalis.
• the polyvinyl alcohol has a weight-average molecular weight of from 20,000 to 220,000 g / mol, more preferably from 25,000 to 100,000 g / mol, particularly preferably from 28,000 g / mol to 40,000 g / mol.
• the content of film formers in the film formulations according to the invention is 1 to 90% w / w, preferably 5 to 60% w / w, more preferably 8 to 40% w / w, particularly preferably 9 to 20% w / w, in each case based on the Dry weight of the film formulations.
• the film formulation according to the invention contains one or more humectants.
• the humectants provide a certain moisture content in the final film formulations of the present invention. A certain amount of moisture is necessary to ensure that the film does not break during manufacture, packaging, transportation and use, but instead remains flexible.
• the humectant (s) for use in the film formulations of the invention is / are selected from sugar alcohols, e.g. Sorbitol and xylitol.
• a combination of sorbitol and xylitol is used as a humectant.
• the weight ratio of sorbitol and xylitol is preferably 1: 1, 5.
• the total amount of humectant in the film formulations according to the invention is 1-10% w / w, preferably 2.5-5% w / w, in each case based on the dry weight of the film formulations.
• the film formulation according to the invention contains a special combination of
• sweetener (s) optionally one or more sweetener (s) and / or one or more flavoring agents
• taste masking is understood to mean the covering of the unpleasant and, in particular, the bitter taste of a substance, for example a medicinal substance.
• Suitable inorganic salts for use in the film formulations according to the invention 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 film formulations according to the invention are the salts of ascorbic acid and citric acid, preferably sodium ascorbate, calcium ascorbate and sodium citrate.
• the film formulations according to the invention comprise sodium chloride.
• the total amount of inorganic / s and / or organic salt (s) in the film formulations of the present invention is 0.5-10% w / w, preferably 1-5% w / w, and more preferably 1-2% w / w, in each case based on the dry weight of the film formulations.
• Suitable monocyclic monoterpenes for use in the film formulations according to the invention are selected from a compound of the formula (A)
• F and R 2 are the same or different and each represents an OH group or a linear or branched Ci_ 4 alkyl group, preferably a
• Isopropyl group and R 2 is a methyl group
• R 3 is a linear or branched Ci -4 alkoxy group represents 4 alkyl or CI_, which may optionally be substituted with an OH group; and / or a compound of the formula (B)
• X represents O, NH or CH 2
• F and R 2 are the same or different and each represents an OH group or a linear or branched Ci_ 4 alkyl group, preferably a
• Isopropyl group and R 2 is a methyl group
• R 3 is a linear or branched CI_ 4 alkyl group which may be optionally substituted with an OH group; and / or a compound of the formula (C)
• R 4 is a saturated or unsaturated, linear or branched d. 4- alkyl group, preferably a 1-propenyl group or a 2-propenyl group, and may be optionally substituted with an OH group; wherein the compounds of formulas (A), (B) and (C) comprise both the pure enantiomers and / or cis-trans isomers and the respective mixtures thereof.
• the bitter mask of the film formulations according to the invention contains several monocyclic monoterpenes.
• "several" monocyclic monoterpenes means at least two, in particular three, four and preferably five monocyclic monoterpenes.
• the bitter mask of the film formulations according to the invention particularly preferably comprises a mixture of monocyclic monoterpenes
• the total amount of monocyclic monoterpenes in the film formulations of the present invention is 0.01-10% w / w, preferably 0.01-5% w / w, and more preferably 0.01-2% w / w, each based on the dry weight of the film formulations ,
• the weight ratio of the inorganic and / or organic salts (s) to the monocyclic monoterpenes in the Bitter Mask of the film formulations according to the invention is 1/10 -10 / 1, preferably 1 / 3-3 / 1, more preferably 1/1 and on most preferably 1 / 0.2-0.2 / 1.
• 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 or acesulfame potassium and synthetic protein-based sweeteners such as aspartame.
• the film formulations according to the invention preferably contain sucralose, aspartame or acesulfame potassium, particularly preferably sucralose.
• the total amount of sweetener (s) in the film formulations of this invention is 1-15% w / w, preferably 1-10% w / w, and more preferably 2-6% w / w, each based on the dry weight of the film formulations.
• the film formulation according to the invention contains one or more flavoring agents.
• Suitable flavoring agents for use in the film formulations of the invention are natural and artificial flavorings suitable for consumption, especially orange, strawberry, vanilla, grapefruit, peppermint, peppermint, cinnamyl, citral, citronella, eugenyl, methylanisole, levomenthol and menthol, and low molecular weight organic acids such as citric acid, succinic acid, malic acid and adipic acid.
• the total amount of the combination of a bitter mask containing 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 agents in the Film formulations according to the invention is 2-20% w / w, preferably 2-15% w / w and more preferably 2-7% w / w, in each case based on the dry weight of the film formulations.
• the film formulation according to the invention comprises: one or more bitter-tasting drug (s) or pharmaceutically-acceptable salts thereof in an amount of at least 0, 1-75% w / w,
• the above film formulation according to the invention further comprises one or more humectants in an amount of 1-10% w / w and / or one or more flavoring agents in an amount of 0.01-15% w / w each based on the dry weight the film formulation.
• the film formulation according to the invention particularly preferably comprises:
• bitter-tasting drug selected from cetirizine, sildenafil and sumatriptan, or pharmaceutically acceptable salts thereof in an amount of up to 75% w / w,
• one or more film formers selected from methyl cellulose,
• Sucralose in an amount of 2-6% w / w and
• Peppermint flavor and menthol in a total amount of 0.5-7% w / w wherein the respective quantities are based on the dry weight of the film formulation.
• the film formulation according to the invention further contains in each case one or more preservatives, dye (s) and / or filler (s).
• Suitable preservatives for use in the film formulations of the present invention are e.g. Sorbic acid and its salts.
• dyes pharmaceutically customary dyes and pigments can be used in the film formulations according to the invention, in particular FD & C Blue No. 2. 1 Brilliant Blue (“Blue Lacquer”) or FD & C Blue No. 2 Indigo Carmine (“Blue Lacquer”) or any mixture thereof, and TiO 2 , Fe x O x , ⁇ -Carotene, Azorubin, Indigotin, Riboflavin and the like.
• Suitable fillers for use in the film formulations of the invention are salts, such as carbonates and phosphates, oxides, such as Si0 2 , in particular in the form of Aerosil, or the like and / or cellulose and its derivatives, but also sparingly soluble sugars or sugar derivatives, such as Lactose or starch derivatives, such as cyclodextrins, provided that they are substantially undissolved in the finished film preparation according to the invention and thus meet the mechanical properties of a filler.
• microcrystalline cellulose is used as the filler.
• the total amount of preservatives, dyes and / or fillers in the film formulations of this invention 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, respectively based on the dry weight of the film formulations.
• the film formulation according to the invention is a single-layered and preferably substantially free of voids, surfactants and effervescent additives.
• the film formulation according to the invention is preferably a film, in particular a solid film.
• the film formulation according to the invention is characterized by a very advantageous combination of mechanical stability of the film and rapid release of the drug.
• the film formulation according to the invention disintegrates rapidly in saliva.
• monolayer film formulation means a solid formulation which is in the form of a monolayer film, wherein monolayer means that the film is in the form of a single layer, the layer being preferably homogeneous the movie is flexible.
• the single-layer film formulation according to the invention is substantially free of voids.
• a cavity is understood to mean a region which is filled with a fluid, for. As a gas and / or a liquid is filled. Such a cavity usually has a diameter of less than 100 ⁇ .
• surfactants are disadvantageous because of their potential skin or mucous membrane irritant effect. In addition, many of the usual surfactants taste very bitter. A disadvantage is also a possible interaction in the drug intake in the gastrointestinal tract.
• the single-layer film formulation according to the invention is therefore preferably substantially free of surfactants.
• the film formulations means less than 1% w / w, preferably less than 0.1% w / w, and most preferably less than 0.01% w / w surfactant, each based on the dry weight of the film formulations , contain.
• no surfactants are added as a constituent in the preparation of the film formulation according to the invention.
• a surfactant for the purposes of this invention is any conventional surfactant or wetting agent or surfactant.
• the single-layer film formulation according to the invention is also essentially free of effervescent additives.
• the film formulations means less than 1% w / w, preferably less than 0.1% w / w and particularly preferably less than 0.01% w / w effervescent additives, in each case based on the dry weight of the film formulations , contain.
• effervescent additive in the context of this invention is a compound which liberates a gaseous compound on addition of water, on storage, under elevated temperature or the like.
• An effervescent additive is preferably a compound which releases a gaseous compound in the mouth, for example by the action of saliva, such as, for example, a carbon dioxide generator.
• the film formulations thus contain no or almost no effervescent additive, such as a carbon dioxide generator.
• the film thickness of the film formulation according to the invention is 5 to 500 ⁇ , preferably 5 to 400 ⁇ and particularly preferably 5 to 300 ⁇ .
• the film formulation of the invention may be in the form of round, randomly rounded, oval, elliptical, triangular, quadrangular, e.g. square or rectangular or polygonal film.
• the film formulation according to the invention is square or rectangular.
• the film formulation according to the invention may have a smooth surface or a surface with elevations and / or depressions.
• the surface of the film formulation of the invention has a regular pattern of protrusions and depressions, such as a wave pattern or a grid pattern.
• the disintegration time of the film formulation according to the invention in the oral cavity is 1-100 seconds, preferably 1-50 seconds, more preferably 1-10 seconds.
• the film formulation according to the invention may be present on a carrier film.
• the carrier film on which the film formulation according to the invention is present is preferably a carrier film of polyethylene paper (PE paper), polypropylene film (PP film) or polyethylene terephthalate film (PET film).
• PE paper polyethylene paper
• PP film polypropylene film
• PET film polyethylene terephthalate film
• the film formulation according to the invention is intended for oral administration.
• the oral formulation film formulation of the present invention is a non-mucoadhesive film.
• the film formulation of the invention is packaged in sachet bags.
• the present invention therefore also relates to sachet bags with one or more of the film formulations according to the invention.
• the film formulation according to the invention is packaged in multidose containers.
• the present invention therefore also relates to multi-dose containers with several of the film formulations according to the invention.
• the bitter-tasting drug (s) are suspended or dissolved in a solvent.
• a solvent organic solvents such as alcohols, ketones, etc. or water or mixtures thereof can be used.
• Suitable solvents are e.g. Ethanol, acetone and ethanol / water mixtures or acetone / water mixtures.
• the mixture is homogenized.
• the mixture is spread on a substrate by means of a suitable brushing method.
• support material for example, PE paper, PP or PET film can be used.
• the coated support material is dried at 30 to 120 ° C, preferably at 30 to 70 ° C. Subsequently, the coated carrier material is further processed into areal divided, divided films.
• the films are individually packed in Sachet bags or multi-dose containers with or without carrier foil.
• the drug-containing film formulation according to the invention is optionally stripped off from the carrier material.
• the film formulation of the invention is used for the administration of cetirizine in allergic conditions, the administration of antimigraine agents in the (acute) treatment of migraine attacks with and without aura and the like, or for the administration of PDE-V inhibitors in the treatment of erectile dysfunction.
• the film formulation according to the invention is used for the production of a medicament for the alleviation of allergic complaints, for the treatment of migraine attacks 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 specific combination of a bitter mask 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 agents ( en) for taste masking bitter tasting substances and in particular for taste masking one or more bitter tasting drug (s) or pharmaceutically acceptable salts thereof.
• the present invention relates to the use of the special combination described above of a bitter mask 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 a plurality of flavoring agent (s) for the preparation of a flavor acceptable pharmaceutical film formulation of bitter tasting substances, in particular one or more bitter-tasting drug (s) or pharmaceutically acceptable salts thereof.
• a bitter mask 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 a plurality of flavoring agent (s) for the preparation of a flavor acceptable pharmaceutical film formulation of bitter tasting substances, in particular 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 of (Z) -1- (2,6,6-trimethyl-1-cyclohexen-1-yl) - 2-butene-1-one, N-ethyl-2- (isopropyl) -5-methylcyclohexanecarboxamide, menthyl lactate, menthol ethylene glycol carbonate and menthol propylene glycol carbonate, for the preparation of a flavor acceptable pharmaceutical film formulation of at least one bitter-tasting drug or a pharmaceutically acceptable salt thereof.
• the disclosure of the present application also includes any combinations of the embodiments respectively described for the individual features of the film formulation according to the invention and all preferred embodiments with one another, ie the present application also discloses, for example, a film formulation according to the invention
• a bitter-tasting drug in an amount of 60% w / w or 75% w / w, one or more film-forming agents in an amount of 1-90% w / w,
• a sweetener in an amount of 2-6% w / w
• Peppermint flavor and menthol in a total amount of 0.01-15% w / w and one or more flavoring agents, preservatives, colorants and / or fillers in a total amount of 4 to 50% G /G,
• the present application also discloses any combinations of individual features of the examples of the inventive film formulation described below with specific embodiments of the individual features of the film formulation according to the invention as described above.
• the disclosure of the present application includes not only the respective numerical ranges and their end values as such, but also all numerical values within the disclosed numerical ranges, ie all intermediate values of such numerical ranges, as well as all combinations of the intermediate values of different numerical ranges.
• the term "comprising 7" comprising "in connection with the pharmaceutical film formulation according to the invention means both formulations which, in addition to the listed constituents, may contain further constituents, as well as formulations which contain only the listed components.
• 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.
• the solution 2 is then added to the solution 1 and stirred until further processing (at least about 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 set Stirring was added to the resulting solution. Subsequently, the sildenafil citrate is weighed and added to the resulting solution.
• Solution 2 Sodium chloride, sorbitol, xylitol, blue lake and water are weighed into a second vessel and dissolved with stirring.
• the solution 2 is then added to the solution 1 and stirred until further processing (at least about 6 hours).
• Solution 1 Menthol, peppermint flavor and ethanol are weighed in and stirred until the 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, glycerol and water are weighed in and dissolved with stirring (about 15 min). The resulting solution remains milky cloudy.
• Solution 2 is added to solution 1 with stirring.
• sildenafil citrate is weighed and added to the resulting solution and it is stirred overnight (at least about 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 the solution 1 and stirred until further processing (at least about 6 hours).
• All the films prepared according to Examples 1-4 are characterized by excellent handleability, rapid disintegration in the mouth and a pleasant taste and a very good masking of the bitter taste of the drug contained in each case.

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• 2010
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