WO2011138049A1 - Film muqueux contenant deux produits de substitution du sucre - Google Patents

Film muqueux contenant deux produits de substitution du sucre Download PDF

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Publication number
WO2011138049A1
WO2011138049A1 PCT/EP2011/002267 EP2011002267W WO2011138049A1 WO 2011138049 A1 WO2011138049 A1 WO 2011138049A1 EP 2011002267 W EP2011002267 W EP 2011002267W WO 2011138049 A1 WO2011138049 A1 WO 2011138049A1
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WO
WIPO (PCT)
Prior art keywords
weight
mucosal
film
film according
sugar substitute
Prior art date
Application number
PCT/EP2011/002267
Other languages
German (de)
English (en)
Inventor
Thomas Kohr
Petra Obermeier
Original Assignee
Hexal Aktiengesellschaft
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 Aktiengesellschaft filed Critical Hexal Aktiengesellschaft
Priority to EP11717971A priority Critical patent/EP2566467A1/fr
Publication of WO2011138049A1 publication Critical patent/WO2011138049A1/fr

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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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
    • A23L27/70—Fixation, conservation, or encapsulation of flavouring agents
    • A23L27/79—Fixation, conservation, or encapsulation of flavouring agents in the form of films
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P20/00—Coating of foodstuffs; Coatings therefor; Making laminated, multi-layered, stuffed or hollow foodstuffs
    • A23P20/20—Making of laminated, multi-layered, stuffed or hollow foodstuffs, e.g. by wrapping in preformed edible dough sheets or in edible food containers
    • 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
    • A61K9/0012—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
    • 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 invention relates to a mucosal film containing a drug and a combination of a first sugar substitute Zi and a second sugar substitute Z 2 , wherein and Z 2 are each 4- to 8-valent mutually different alcohols, as well as on its production and a A pharmaceutical product containing one or more such mucosal films.
  • Solid pharmaceutical dosage forms such as tablets or capsules can be used as carrier systems for the oral administration of pharmaceutical drugs.
  • successful administration of such dosage forms in normal use requires that the patient hold a liquid with which to take this dosage form.
  • this often turns out to be difficult.
  • dysphagia it is often a problem especially for elderly patients and children to take solid oral dosage forms with liquids as well. This often leads to low compliance (compliance) and can thus endanger the success of therapy.
  • 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.
  • WO 2007/009800 A2 describes oral films containing an antiemetic or antimigraine agent.
  • WO 2007/009801 A2 discloses oral films suitable for the administration of a neuroleptic such as olanzapine. Both films are characterized by the fact that they stick in the mouth after contact with liquid or saliva and quickly disintegrate there in the oral cavity, which is why they are not ausspuckbar.
  • One common method of preparation of such films involves formulating a drug-containing solution or suspension, applying the solution or suspension to a carrier, and then drying the supported solution or suspension to form a film. Finally, the resulting film is detached from the carrier, assembled with the example of a cutting machine in the single doses and then packaged.
  • Rigid and brittle films can result in the removal of the film from the package during administration to patients, a portion of the film is not removed and thus the patient does not receive the intended dose of the contained drug. Such an underdose can serious consequences for the patient. Furthermore, an unpleasant mouthfeel is associated with increased brittleness of the film, which can lead to reduced patient compliance. If necessary, it is already not possible from the outset to package and package the film, since the film already disintegrates during these working steps, so that the film produced must be discarded as a production committee.
  • the mucosal, preferably oral film should have a high dosing accuracy even after prolonged contact with air and lead to a low rejection during its production process.
  • the production of the mucosal film should also be inexpensive.
  • a further object of the invention was to provide a mucosal, preferably oral, film which, if appropriate, sticks in the mouth after contact with liquid or saliva and should disintegrate there quickly.
  • a mucosal, preferably oral film is intended to cause a pleasant mouthfeel.
  • the abovementioned objects could be achieved by a mucosal, preferably oral film containing a combination of a first sugar substitute ⁇ and a second sugar substitute Z 2 , wherein Zi is a 4- to 8-valent alcohol having preferably 5 to 12 carbon atoms, and Z 2 is a different from Zi 4 to 8-valent alcohol having preferably 5 to 12 carbon atoms, be solved unexpectedly.
  • the abovementioned objects were also able to achieve a water content of 2 to 12% by weight, preferably 2.5 to 8, by means of a mucosal, preferably oral film which, despite contact with air for 24 hours and a relative humidity of 50% at 25 ° C. , 0 wt .-%, are solved unexpectedly.
  • the invention therefore relates to a mucosal, preferably oral film containing a drug and a combination of a first sugar substitute Z and a second sugar substitute Z 2 , wherein ⁇ ⁇ is a 4- to 8-valent alcohol having preferably 5 to 12 carbon atoms, and Z 2 is a different from ⁇ ⁇ 4 to 8-valent alcohol having preferably 5 to 12 carbon atoms.
  • the weight ratio of ⁇ ⁇ to Z 2 in this case is preferably 10: 1 to 1:10.
  • Another object of the invention is a mucosal, preferably oral film containing a drug and excipients, which is characterized in that the water content of 2 to 12 wt .-%, preferably 2.5 to 8.0 wt .-% based on the total weight of the mucosal film, wherein the constituents are chosen so that the water content does not decrease on contact with air at 25 ° C. with a relative humidity of 50% after 24 h, ie furthermore in the range from 2 to 12% by weight. , preferably 2.5 to 8.0 wt .-%, based on the total weight of the mucosal film is.
  • the present invention describes a method for producing a mucosal, preferably oral, film comprising the steps:
  • the weight ratio of ⁇ to Z 2 is in this case preferably 10: 1 to 1: 10th
  • a further subject of the invention is a pharmaceutical product which comprises a sachet and a mucosal, preferably oral film according to the present invention or a multidose container containing 2 to 100, preferably 5 to 50 mucosal, preferably oral, films according to the present invention.
  • "Mucosal” film in the sense of this invention means a film which is suitable for application to the animal or human mucosa (tunica mucosa). suitable is. Typically, this is aptitude for a nasal, rectal, vaginal, glansal and / or oral application, preferably for oral administration.
  • “Oral” film in the sense of this invention means a film which is suitable for oral application.
  • a mucosal, preferably oral "film” is understood to mean a two-dimensional dosage form.
  • the planar dosage form can have various shapes. Examples of shapes are a round, rounded, oval, elliptical, triangular, quadrangular or polygonal shape.
  • the mucosal film according to the invention is of angular shape, more preferably of quadrangular shape.
  • the mucosal film of the present invention has an area of 0.1 to 15 cm 2 , preferably 0.5 to 10 cm 2, and particularly preferably 1 to 8 cm 2 . The area determination is generally carried out by known methods.
  • the mucosal, preferably oral film of the present invention has a layer thickness of 5 to 400 ⁇ , preferably 10 to 350 ⁇ and particularly preferably 20 to 220 ⁇ , in particular 30 to 190 ⁇ on.
  • the layer thickness may e.g. by means of scanning with a digital dial gauge from Mahr Model Extramess 2001.
  • the mucosal, preferably oral, film according to the invention usually has a weight of from 5 mg to 1000 mg, preferably from 10 mg to 250 mg, particularly preferably from 20 mg to 180 mg.
  • the mucosal, preferably oral, film according to the present invention may be monolayered or multi-layered.
  • the film is single-layered.
  • single-layered means that the film is present in the form of a single, substantially homogeneous layer.
  • the film of the invention is preferably flexible. It means flexible that the film bends at a certain external force, but does not break.
  • the flexibility of the film can be determined by a tensile test.
  • the test can be carried out with the material testing machine TMZ2.5 / TS1 S from Zwick / Roell as a 180 ° tensile test.
  • the settings on the material testing machine such as pre-load, pre-load speed, pre-load hold time mode, time to pre-load, force zeros after pre-load, measuring path, test speed and force shut-off threshold are made taking into account the explanations in the operating manual.
  • the test can be carried out with the material testing machine TMZ2.5 / TS1 S from Zwick / Roell as a 90 ° puncture test.
  • the settings on the material testing machine such as pre-load, pre-load speed, pre-load hold-time mode, time to pre-load, test speed and force shut-off threshold are made taking into account the explanations in the operating manual.
  • the in vitro disintegration time of the inventive mucosal, preferably oral, film in artificial saliva is usually 15 to 180 seconds, preferably 30 to 150 seconds, especially 50 to 130 seconds.
  • the in vitro disintegration time is determined by placing the film according to the invention in a Petri dish filled with artificial saliva (height of the liquid column 1. 0 cm) and determining the time after which the mucosal film has completely disintegrated without stirring , The end point of the decay is determined by visual inspection.
  • the in-vivo disintegration time in the oral cavity is usually less than 200 seconds, preferably 5 to 60 seconds, especially 10 to 30 seconds.
  • the time is determined after which a subject or patient perceives the film as being dissolved. An average of 10 subjects or patients is preferably formed.
  • the mucosal film according to the invention is non-mucoadhesive.
  • non-mucoadhesive is to be understood as meaning only brief adherence (shorter than 60 seconds, preferably shorter than 30 seconds, in particular shorter than 15 seconds) of the oral film to a mucous membrane, such as, for example, the oral mucosa.
  • the film remains adhered to the mucous membrane after contact with liquid or saliva in oral administration and decomposes rapidly, for example under the action of saliva.
  • “mucoadhesive” describes a deliberate, longer adherence to the mucosal surface, in order to achieve targeted systemic administration of the drug.
  • Drug reabsorption of the mucosal film can be both systemic and enteral.
  • drug resorption according to the invention will be predominantly enteral, preferably over 70% enteral drug absorption, more preferably over 90% enteral drug absorption.
  • the mucosal, preferably oral, film according to the invention is free of pores or voids. This is under pore or cavity an area understood, which is filled with a fluid (a gas and / or a liquid) and which is preferably produced in a controlled manner during production.
  • a fluid a gas and / or a liquid
  • the mucosal, preferably oral, film of the present invention may have a smooth surface or a rough surface.
  • a rough surface is to be understood as meaning a surface which has elevations and / or depressions.
  • the rough surface may represent a regular pattern such as a wave pattern or lattice pattern or an irregular pattern.
  • a sugar substitute Zi or Z 2 is understood as meaning energetically utilizable sweeteners which comprise 4 to 8-hydric alcohols.
  • the sugar substitutes Zi and Z2 thus preferably exhibit a physiological calorific value in a mammal (in particular in a human).
  • the sugar substitutes Zi and Z 2 (4- to 8-hydric alcohols) according to this invention are usually monomolecular compounds having 4 to 8 hydroxyl groups.
  • the sugar substitutes ⁇ and Z 2 have 5 to 25 carbon atoms, more preferably 5 to 12 carbon atoms.
  • the sugar substitutes of the present invention generally have a molecular weight of 90 to 900 g / mol, preferably 100 to 400 g / mol, more preferably 1 10 to 300 g / mol.
  • the sugar substitutes 7 ⁇ and Z 2 can be selected independently of one another from glucose, sorbitol, lactose, fructose, maltose, isomaltose, leucrose, glucaric acid, xylose, sorbose, galactose, pentaerythritol and xylitol.
  • the sugar replacements are sugar alcohols (alditols).
  • Particularly preferred sugar substitutes are sorbitol and xylitol.
  • the first sugar substitute ⁇ is different here from the second sugar substitute Z 2 .
  • a preferred embodiment relates to a mucosal, preferably oral film comprising a combination of a first sugar substitute ⁇ and a second sugar substitute Z 2 , wherein the first sugar substitute Zi sorbitol and the second sugar substitute Z 2, for example, glucose, lactose, fructose, maltose, isomaltose, Leucrose, glucaric acid, xylose, sorbose, galactose, pentaerythritol and xylitol.
  • An alternative preferred embodiment relates to a mucosal, preferably oral film comprising a combination of a first sugar substitute Z1 and a second sugar substitute Z 2 , wherein the second sugar substitute Z 2 xylitol and the first sugar substitute Z ⁇ eg from glucose, lactose, fructose, Maltose, isomaltose, leucrose, glucaric acid, xylose, sorbose, galactose, pentaerythritol and sorbitol.
  • the mucosal, preferably oral, film contains a combination of a first sugar substitute ⁇ and a second sugar substitute Z 2 , wherein the first sugar substitute Zi is sorbitol and the second sugar substitute Z 2 is xylitol.
  • the mucosal, preferably oral, films according to the invention containing a combination of a first sugar substitute Zi and a second sugar substitute Z 2 , wherein ⁇ is a 4- to 8-valent alcohol having 5 to 12 carbon atoms and Z 2 is a 4-8 different from Zi -valent alcohol having 5 to 12 carbon atoms the weight ratio of the sugar substitutes Zi to Z 2 is usually 10: 1 to 1:10, preferably 5: 1 to 1: 5, particularly preferably 1: 1 to 1: 2.
  • films according to the invention comprising a combination of a first sugar substitute ⁇ and a second sugar substitute Z 2 , where ⁇ is a 4- to 8-valent alcohol having 5 to 12 carbon atoms and Z 2 is one of ⁇ ⁇ various 4- to 8-valent alcohol having 5 to 12 carbon atoms, the weight proportions of Zi and Z 2 in the sum of usually 0.1 to 50 wt .-%, preferably 0.5 to 20 wt .-%, particularly preferably 1 to 10% by weight, based on the dry weight of the mucosal, preferably oral, film.
  • dry weight is meant the total weight of the mucosal, preferably oral, film minus the weight of the water and / or the solvents contained therein.
  • the mucosal, preferably oral, film contains a combination of a first sugar substitute Zi and a second sugar substitute Z 2 , wherein the first sugar substitute Zi is sorbitol and the second sugar substitute Z 2 is xylitol and wherein the weight ratio of Z to Z 2 10: 1 to 1:10.
  • the mucosal, preferably oral, film contains a combination of a first sugar substitute Z and a second sugar substitute Z 2 , wherein the first sugar substitute Zi is sorbitol and the second sugar substitute Z 2 is xylitol and wherein the weight ratio of Zi to Z 2 5: 1 to 1: 5.
  • the mucosal, preferably oral film contains a combination of a first sugar substitute ⁇ and a second sugar substitute Z 2 , wherein the first sugar substitute Z ⁇ sorbitol and the second sugar substitute Z 2 xylitol and wherein the weight ratio of ⁇ to Z 2 is 1: 1 to 1: 2.
  • the mucosal, preferably oral, film of the present invention contains one or more drugs.
  • Drug is understood to mean a substance which produces a medicinal effect in a mammal, preferably in a human.
  • the drugs are selected from Analgesics, neuroleptics, PDE-5 inhibitors, antipsychotics, H antihistamines, H 2 antihistamines, anti-dementia drugs, antidiabetics, anti-inflammatory agents, antimicrobials, muscle relaxants, opioids, proton pump inhibitors, smoking cessation agents, vasodilators, phytopharmaceuticals, 5-alpha reductase inhibitors, anti-adiposity, Antiasthmatics such as Leukotrienantagonisten, Antidiarrhoica, antiemetics, antihypertensive agents such as Sartane or ACE inhibitors, antiparkinsonian drugs, antitussives, expectorants, hypnotics such as benzodiazepines, lipid-
  • a mucosal, preferably oral, film containing a combination of a first sugar substitute and a second Sugar substitute Z 2 , wherein ⁇ is a 4- to 8-valent alcohol having 5 to 12 carbon atoms and Z 2 is a 4 to 8-valent alcohol having 5 to 12 carbon atoms of Z 1 , and a drug selected from olanzapine, sildenafil , Sumatriptan and their pharmaceutically acceptable salts, wherein the weight ratio of Z 1 to Z 2 is 10: 1 to 1:10.
  • the mucosal, preferably oral, film contains a combination of a first sugar substitute Zi and a second sugar substitute Z2, wherein the first sugar substitute Zi is sorbitol and the second sugar substitute Z 2 is xylitol, and a drug selected from olanzapine, Sildenafil, sumatriptan and their pharmaceutically acceptable salts, wherein the weight ratio of ⁇ to Z 2 is 5: 1 to 1: 5.
  • the mucosal, preferably oral film contains a combination of a first sugar substitute Zi and a second sugar substitute Z 2 , wherein the first sugar substitute Zi is sorbitol and the second sugar substitute Z 2 xylitol, and a drug selected from olanzapine, sildenafil , Sumatriptan and their pharmaceutically acceptable salts, wherein the weight ratio of ⁇ ⁇ to Z 2 is 1: 1 to 1: 2.
  • the drug content in the film according to the invention may be from 0.1 to 80% by weight and in particular from 1 to 70% by weight, based on the dry weight of the film.
  • the indications of the amount of the drug usually refer to the drug in "free form", i. not in the form of a salt.
  • the mucosal film according to the invention contains the sugar substitutes and Z 2 as pharmaceutical excipients.
  • the mucosal film according to the invention can still further pharmaceutical excipients such as film images, plasticizers, fillers and sweeteners.
  • the mucosal, preferably oral, film of the present invention preferably contains one or more film formers.
  • a film former (b) in the sense of this invention is usually a substance capable of forming the matrix of a film.
  • the film formers according to the present invention are preferably selected from the group consisting of polymeric carbohydrates such as cellulose and its derivatives, starch and its derivatives, agar-agar, alginic acid, arabinogalactan, galactomannan, carrageenan, dextran, traganth and gums of plant origin, synthetic polymers which are preferably soluble or swellable in water, such as polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid or polyacrylamide, polypeptides such as gelatin, albumin or collagen, or mixtures of such substances.
  • HPC Hydroxypropylcellulose
  • HPMC hydroxypropylmethylcellulose
  • starch modified starch
  • pullulan pullulan
  • pectin gelatin and / or carboxymethlycellullose
  • HPC and / or HPMC are preferably used as film formers.
  • HPC and / or HPMC is used, in particular HPMC is used.
  • HPMC it 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.
  • the weight average molecular weight is determined by gel permeation chromatography.
  • T g glass transition temperature
  • HPMC is used with a water content of 1 to 15 wt .-%.
  • 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. Also preferred is HPC having a softening temperature used from 110 to 150 ° C. Preferably, HPC with a water content of 2 to 12 wt .-% is used.
  • starch or modified starch it preferably has a weight-average molecular weight of from 50,000 to 160,000 g / mol, more preferably from 55,000 to 150,000 g / mol. It is further preferable to use starch or modified starch having a water content of 8 to 15% by weight.
  • 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. It is also preferable to use pullulan having a water content of 0.1 to 6% by weight.
  • pectin In the case of pectin, this 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. It is also preferred to use pectin having a melting temperature of 140 to 160 ° C (in the dry state).
  • this preferably has a weight-average molecular weight of from 15,000 to 250,000 g / mol, more preferably from 25,000 to 150,000 g / mol. Preference is further given to using gelatin having a water content of 8 to 12% by weight.
  • 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 110,000 to 450,000 g / mol. Preference is furthermore given to using carboxymethyl cellulose having a water content of from 0.1 to 10% by weight.
  • polyvinylpyrrolidone this can be obtained, for example, by polymerization of N-vinylpyrrolidone-2.
  • Polyvinylpyrrolidone a weight average molecular weight of 5,000 to 100,000 g / mol, more preferably from 8,000 to 80,000 g / mol, in particular from 10,000 g / mol to 40,000 g / mol.
  • polyvinyl alcohol this is prepared, for example, by hydrolytic cleavage of polyvinyl esters with alkalis.
  • polyvinyl alcohol has a weight-average molecular weight of from 20,000 to 220,000 g / mol, particularly preferably from 25,000 to 100,000 g / mol, in particular from 28,000 g / mol to 40,000 g / mol.
  • the content of film former (b) may be from 1 to 90% by weight, preferably from 5 to 60% by weight, more preferably from 8 to 40% by weight, in particular from 10 to 30% by weight, based on the dry weight of the film film according to the invention.
  • the mucosal, preferably oral, film of the present invention contains a combination of a first sugar substitute Zi and a second sugar substitute Z 2 , wherein Zi is a 4- to 8-valent alcohol of 5 to 12 carbon atoms and Z 2 is one of Zi is a different 4- to 8-valent alcohol having 5 to 12 carbon atoms and the weight ratio of Z to Z 2 is 10: 1 to 1:10, a drug and a film former.
  • the mucosal, preferably oral, film of the present invention contains a combination of a first sugar substitute ⁇ ⁇ and a second sugar substitute Z 2 , wherein ⁇ is a 4- to 8-valent alcohol of 5 to 12 carbon atoms and Z 2 is one Z is a different 4- to 8-valent alcohol having 5 to 12 carbon atoms and the weight ratio of ⁇ to Z 2 is 10: 1 to 1:10, a film former and a drug selected from olanzapine, sildenafil, sumatriptan and their pharmaceutically acceptable salts.
  • the mucosal, preferably oral, film of the present invention contains a combination of a first sugar substitute ⁇ .
  • ⁇ and a second sugar substitute Z 2) wherein ⁇ is a 4- to 8-valent alcohol having 5 to 12 carbon atoms and Z 2 is a 4 to 8-valent alcohol of 5 to 12 carbon atoms other than Zi and the weight ratio of Zi to Z 2 is 5: 1 to 1: 5, a film former and a drug selected from olanzapine, sildenafil, sumatriptan and their pharmaceutically acceptable salts.
  • the mucosal, preferably oral film of the present invention includes a combination of a first sugar substitute 7 ⁇ and a second sugar substitute Z 2, where Z is a 4- to 8-valent alcohol having 5 to 12 carbon atoms, and Z 2 Zi is a 4- to 8-valent alcohol having 5 to 12 carbon atoms and the Zi to Z 2 weight ratio is 1: 1 to 1: 2, a film former and a drug selected from olanzapine, sildenafil, sumatriptan and their pharmaceutically acceptable salts.
  • the mucosal, preferably oral film contains a combination of a first sugar substitute Zi and a second sugar substitute Z 2 , wherein the first sugar substitute ⁇ sorbitol and the second sugar substitute Z 2 xylitol, a film former and a drug selected from olanzapine , Sildenafil, sumatriptan and their pharmaceutically acceptable salts, wherein the weight ratio of Zi to Z 2 is 10: 1 to 1:10.
  • the mucosal, preferably oral film contains a combination of a first sugar substitute Zi and a second sugar substitute Z 2 , wherein the first sugar substitute Zi is sorbitol and the second sugar substitute Z 2 xylitol, a film former and a drug selected from Olanzapine, sildenafil, Sumatriptan and its pharmaceutically acceptable salts, wherein the weight ratio of Zi to Z 2 is 5: 1 to 1: 5.
  • the mucosal, preferably oral, film contains a combination of a first sugar substitute Zi and a second sugar substitute Z 2 , wherein the first sugar substitute is sorbitol and the second sugar substitute is Z 2 xylitol, a film former and a drug selected from Olanzapine, sildenafil, sumatriptan and their pharmaceutically acceptable salts, wherein the weight ratio of Zi to Z 2 is 1: 1 to 1: 2.
  • the mucosal, preferably oral, film of the present invention may further contain one or more plasticizers.
  • a plasticizer (d) is usually understood as meaning a substance which makes a formulation smoother and / or more elastic in use or further processing.
  • plasticizers are odorless and tasteless, physiologically harmless liquids that are capable of attenuating the intermolecular forces of the film former molecules.
  • plasticizers (d) usually allow a lowering of the glass transition temperature by mixing with film former (b), ie the glass transition temperature of the film former (b) is higher than the glass transition temperature of the mixture of plasticizer (d) and film former (b).
  • Plasticizers (d) may be, for example, esters, oils and / or resins.
  • plasticizers are selected from alkylene glycols such as ethylene glycol, propylene glycol, butylene glycol (1,4-butanediol), isopropyl palmitate, polyalkylene glycols such as polyethylene glycol, glycerol (also referred to as glycerin), triacetin, citrates such as triethyl citrate, tri-butyrate, acetyl citrate, phthalates such as dibutyl phthalate , Diethyl phthalate, dimethyl phthalate, sebacates such as dibutyl sebacate and / or diethyl sebacate, oils such as paraffin oil and / or Castor oil.
  • alkylene glycols such as ethylene glycol, propylene glycol, butylene glycol (1,4-butanediol), isopropyl palmitate
  • polyalkylene glycols such as polyethylene glycol, glycerol (also referred to as gly
  • the weight-average molecular weight is typically 200 to 6000 g / mol, preferably 250 to 2000 g / mol, in particular 300 to 800 g / mol.
  • the plasticizer (d) used is preferably dibutyl sebacate, isopropyl palmitate and / or polyethylene glycol.
  • a mucosal, preferably oral film containing a combination of a first sugar substitute and a second sugar substitute Z 2 wherein ⁇ is a 4- to 8-valent alcohol having 5 to 12 carbon atoms and Z 2 a Z is a different 4- to 8-valent alcohol having 5 to 12 carbon atoms and the weight ratio of Zi to Z 2 is 10: 1 to 1:10, a cellulose derivative as a film former (with HPMC or HPC being particularly preferred as cellulose derivatives) and one or more plasticizers selected from dibutyl sebacate, isopropyl palmitate and polyethylene glycol, is unexpectedly advantageous.
  • films with good physical properties can be produced despite high drug content (drug load).
  • the content of plasticizer (d) may be 0 to 20 wt .-%, preferably 0.1 to 10 wt .-% and particularly preferably 0.5 to 5 wt .-%, based on the dry weight of the film according to the invention.
  • the mucosal, preferably oral, film according to the invention may furthermore contain one or more fillers.
  • Fillers (e) according to this invention are all substances which are described in the prior art as pharmaceutical fillers. Fillers of the present invention are typically materials required to form the film body in small drug film sizes to obtain a sufficient amount of film mass for a suitable film size.
  • fillers typically salts such as carbonates, phosphates, oxides such as Si0 2 , in particular disperse Si0 2 (eg Aerosil ® ), but also Sugar derivatives, such as lactose or starch derivatives such as cyclodextrins and / or maltodextrins are used.
  • dispersed Si0 2 is used.
  • the content of fillers (e) may be from 0 to 20% by weight, preferably from 0.1 to 15% by weight and preferably from 0.5 to 5% by weight, based on the dry weight of the film according to the invention.
  • the mucosal, preferably oral, film according to the invention may furthermore contain one or more flavorings.
  • Flavorings (f) are understood to mean substances which provide for a flavor or taste of the mucosal, preferably oral, film.
  • flavorings typically natural or artificial flavorings, for example, lemon, orange, strawberry, vanilla, peppermint flavor, cinnamyl acetate, citral, citronella, eugenyl, menthol and / or methylanisole can be used.
  • the content of flavorings may be 0 to 15 wt .-%, 0.1 to 10 wt .-% and preferably 0.5 to 8 wt .-%, based on the dry weight of the film according to the invention.
  • the mucosal, preferably oral, film of the invention may further contain one or more sweeteners.
  • sweetener (g) according to the invention are meant all substances used for sweetening food. Preferably, the sweeteners do not substantially affect the insulin and blood sugar levels in the human organism.
  • the sweetener includes natural or synthetically produced sweeteners. Synthesized sweeteners are preferred. It is further preferred that the sweetener used is 2 to 3000 times sweeter than sucrose, more preferably 20 to 1500 times sweeter than sucrose, most preferably 50 to 800 sweeter than sucrose.
  • the sweetening agent may be, for example, sucralose (E955), aspartame, cyclamate, Saccharin, thaumatin, neohesperidin and / or acesulfame are selected. Sucralose is particularly preferred.
  • the content of sweetener may be 0 to 15% by weight and preferably 1 to 10% by weight, based on the dry weight of the film according to the invention.
  • the film of the present invention may contain dyes (i), bitter maskers (j), pH adjusters (k) and solvents (I).
  • dyes (i) it is possible to use pharmaceutically customary dyes and pigments, for example T1O.sub.2, iron oxides, .beta.-carotene, azorubin, indigotin and / or riboflavin.
  • Bitter mashers (j) in the sense of this invention are substances which weaken or mask the bitter taste of a substance or a group of substances.
  • component (k) substances for adjusting the pH of the film composition can be used.
  • component (k) low molecular weight organic acids such as citric acid, succinic acid, malic acid, adipic acid or basic compounds such as sodium bicarbonate used.
  • buffer systems as component (k), in particular an acetate buffer or a citrate buffer.
  • the type and amount of component (k) is particularly preferably chosen so that the resulting film of the invention, when dissolved in distilled water, produces a pH of from 4 to 7, in particular from 4.5 to 6.8.
  • Solvents (I) usually include organic solvents. Preference is given to using solvents of class 3 according to ICH guideline Q3C as organic solvents. For example, acetone, ethanol, ethyl acetate, isopropanol, propan-2-ol, preferably ethanol are used. Due to scientific principles, a substance may possibly fulfill several of the aforementioned properties (eg filler, plasticizer, sweetener). However, in the present invention, it is preferable that a substance is used only as one of the components (a) to (I). For example, if xylitol is used as sugar substitute Z 2 (c), xylitol is not also used as sweetener (g).
  • the nature and amount of the remaining components (b) and (d) to (I) may depend on the choice of the drug (a).
  • the film according to the invention contains from 5.0 to 40% by weight, particularly preferably from 15 to 30% by weight, of olanzapine (a), in particular in the form of the free base;
  • the film according to the invention contains
  • sildenafil (a), in particular in the form of sildenafil citrate; 2.0 to 40 wt .-%, particularly preferably 5.0 to 20 wt .-% film former (b); 0.5 to 20 wt .-%, more preferably 1, 0 to 3.0 wt .-% sugar substitutes Z ⁇ and Z2 (c);
  • plasticizer (d) From 0.5 to 25% by weight, more preferably from 2.0 to 10% by weight, of plasticizer (d); 0 to 20 wt .-%, particularly preferably 0, 1 to 10 wt .-% filler (s); and 0.1 to 10% by weight, more preferably 0.5 to 8.0% by weight of sweetener (g), based on the dry weight of the film according to the invention.
  • the film according to the invention contains
  • sumatriptan (a) in particular in the form of sumatriptan succinate
  • plasticizer (d) From 0.5 to 25% by weight, more preferably from 2.0 to 10% by weight, of plasticizer (d); 0 to 20 wt .-%, particularly preferably 0.5 to 10 wt .-% filler (s); and from 0.1 to 10% by weight, particularly preferably from 1.0 to 5.0% by weight of sweetener (g), based on the dry weight of the film according to the invention.
  • the mucosal, preferably oral, film of the present invention comprises water (h) in a weight fraction of from 2 to 12% by weight, more preferably from 2.5 to 8.0% by weight, based on the total weight of the oral film, on.
  • the weight fraction of water in the mucosal, preferably oral, film is determined using a Mitsubishi Moisture Meter Model CA-06 combined with a Model VA-06 furnace according to the Karl Fischer method (KF method).
  • KF method Karl Fischer method
  • the sample preparation takes place in said KF oven.
  • the liberated water is then transferred by means of a dry carrier gas stream in the KF titration cell and determined there.
  • the mucosal, preferably oral film according to the invention may additionally contain organic solvents (I).
  • the amount of solvents is low. This is preferably 0.1 to 50,000 ppm, particularly preferably 1, 0 to 5000 ppm.
  • the stated range of organic solvents can lead to an improvement in the flexibility of the resulting film compared to films that are completely free of organic solvents.
  • Another object of the invention relates to a mucosal, preferably oral film in which the water content is 2 to 12 wt .-%, preferably 2.5 to 8.0 wt .-% based on the total weight of the mucosal film, wherein the ingredients so are chosen so that the water content does not decrease when in contact with air at 25 ° C with a relative humidity of 50% after 24 h, ie further in the range of 2 to 12 wt .-%, preferably 2.5 to 8.0 wt .-% based on the total weight of the mucosal film.
  • suitable ingredients reference is made to the above explanations concerning the constituents (a) to (I).
  • the invention further provides a process for the preparation of the mucosal, preferably oral, film described above, comprising the steps:
  • the method according to the invention preferably comprises the steps:
  • water and / or organic solvents are usually used according to the invention.
  • organic solvents the solvents described above under the component (I) can be used. Preference is given to using solvents of class 3 according to ICH guideline Q3C as organic solvents. For example, acetone, ethanol, ethyl acetate, isopropanol, propan-2-ol, preferably ethanol are used.
  • Water can also be used to prepare the emulsion, suspension or solution.
  • pharmaceutically customary water can be used as the water.
  • pharmaceutically customary water is typically meant Aqua Purificata Ph. Eur.
  • the formulation of the solution, emulsion or suspension according to the above-mentioned process step I it is also possible to use mixtures of water and organic solvent, in particular alcohol / water mixtures. Preference is given to water or water / ethanol (Weight ratio 3: 1 to 1: 3) used. In the case of an emulsion or suspension, these are preferably homogenized.
  • step II the mixture is then preferably applied to a substrate by means of a coating process (e.g., a doctoring or doctoring process).
  • a coating process e.g., a doctoring or doctoring process
  • the order can be done for example by means of doctor blade, roller blade, slot dies or Schlitzg cashmaschinen.
  • a constant application of the coating composition to the support material is preferably achieved in that the coating composition is present in excess, but is reduced to the required amount at the job site on the substrate by the application process.
  • paper, coated papers or a film containing polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET) or polymethyl methacrylate (PMMA), preferably PET, can be used as the carrier material.
  • PE polyethylene
  • PP polypropylene
  • PET polyethylene terephthalate
  • PMMA polymethyl methacrylate
  • step III drying of the resulting from step II supported solution, emulsion or suspension, so that forms a film according to the invention.
  • the drying is usually carried out at 20 to 80 ° C, preferably at 30 to 65 ° C, in particular at 40 to 55 ° C.
  • the drying time is preferably 5 to 100 minutes, particularly preferably 10 to 80 minutes, in particular 20 to 40 minutes.
  • the dryers used may be, for example, hot air dryers, electron beam dryers, UV radiation dryers, infrared dryers or contact dryers.
  • step IV if appropriate, the support material coated with the film according to the invention is further processed into areally divided, divided films, that is, assembled. This can be done for example by cutting, punching or embossing. Cutting is preferred.
  • the carrier film can be removed before or after the assembly.
  • Another object of the invention relates to a pharmaceutical product comprising a sachet and a mucosal film according to the present invention or a multidose container containing 2 to 50, preferably 5 to 50 mucosal films according to the present invention.
  • a sachet is to be understood as packaging in the form of a bag, bag or bag.
  • the sachet of the invention may typically be made of one or more sachet forming materials.
  • the Sachet forming material may, for.
  • polymeric packaging selected from polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC), polystyrene (PS), polyamide (PA), polycarbonate (PC), polyethylene vinyl acetate (EVA) or polyethylene terephthalate (PET), preferably PET include ,
  • the mucosal, preferably oral film according to the invention has the advantage that a cost-effective polymeric packaging can be used, since the film has a high stability to running oxygen and humidity and thus the oxygen and water vapor permeability of the packaging material is not a limiting factor.
  • the soluble adjuvants were first dissolved in the solvent mixture.
  • the insoluble excipients and the drug were then suspended in this solution.
  • the suspension was then homogenized for 6 hours with a Viscojet type stirrer.
  • the coating composition was then applied by means of a doctor blade application in the required amount to the carrier film and dried at 50 ° C for 30 minutes with a hot air dryer. In this case, a film was obtained with a thickness of 150 ⁇ .
  • the resulting film was then cut to the required size and packaged in sachets.
  • the kink test shows that the films of the invention containing a combination of sugar substitutes Zi and Z2 have advantageous flexibility, both directly after their removal from the protective package and after prolonged contact with air compared to films containing only one or no sugar substitute exhibit.
  • the brittleness of the comparison films leads to an unpleasant mouthfeel and is associated with the risk of underdosing of the contained drug, since it is difficult to remove the films from a packaging without destruction.
  • the penetration test shows that the flexibility (extensibility) of the film according to the invention does not change even during prolonged storage under air contact.
  • films containing only a sugar substitute after initially increased flexibility, a large decrease in extensibility after prolonged air contact is observed.
  • the films were each placed in a Petri dish filled with artificial saliva (height of the liquid column 1.0 cm) and the time was determined after which the films were completely disintegrated without stirring. The end point of the decay is determined by visual inspection.
  • the product "TMP Tüshaus Ptyalin” manufactured by TMP Tüshaus Medical GmbH was used as artificial saliva.
  • the film according to the invention already has an advantageously short disintegration time of 121 s after removal from the packaging, which even shortens to 100 s after prolonged storage under contact with air.
  • the disintegration time of the comparative film increases from an initial 140 s after 7 days storage under air contact to 190 s.

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  • Nutrition Science (AREA)
  • Food Science & Technology (AREA)
  • General Health & Medical Sciences (AREA)
  • Polymers & Plastics (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
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  • Mycology (AREA)
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  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un film muqueux qui contient un médicament et une association d'un premier produit de substitution du sucre Z1 et d'un second produit de substitution du sucre Z2, Z1 et Z2 étant respectivement des alcools tétra- à octavalents différents l'un de l'autre, ainsi que la préparation dudit film muqueux, et un médicament qui contient un ou plusieurs films muqueux de la sorte.
PCT/EP2011/002267 2010-05-07 2011-05-06 Film muqueux contenant deux produits de substitution du sucre WO2011138049A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP11717971A EP2566467A1 (fr) 2010-05-07 2011-05-06 Film muqueux contenant deux produits de substitution du sucre

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP10004873 2010-05-07
EP10004873.5 2010-05-07

Publications (1)

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WO2011138049A1 true WO2011138049A1 (fr) 2011-11-10

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WO (1) WO2011138049A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11179331B1 (en) 2020-04-21 2021-11-23 Cure Pharmaceutcai Holding Corp Oral soluble film containing sildenafil citrate

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040096569A1 (en) * 2002-11-15 2004-05-20 Barkalow David G. Edible film products and methods of making same
WO2007009800A2 (fr) 2005-07-20 2007-01-25 Hexal Ag Film oral a decomposition rapide ne pouvant pas etre recrache utilise pour des antiemetiques ou antimigraineux
WO2007009801A2 (fr) 2005-07-20 2007-01-25 Hexal Ag Film a decomposition rapide, qui est oral et ne degorge pas destine a un neuroleptique
US20080063779A1 (en) * 2002-10-30 2008-03-13 Reg Macquarrie Edible dissolving gelatin strips

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080063779A1 (en) * 2002-10-30 2008-03-13 Reg Macquarrie Edible dissolving gelatin strips
US20040096569A1 (en) * 2002-11-15 2004-05-20 Barkalow David G. Edible film products and methods of making same
WO2007009800A2 (fr) 2005-07-20 2007-01-25 Hexal Ag Film oral a decomposition rapide ne pouvant pas etre recrache utilise pour des antiemetiques ou antimigraineux
WO2007009801A2 (fr) 2005-07-20 2007-01-25 Hexal Ag Film a decomposition rapide, qui est oral et ne degorge pas destine a un neuroleptique

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11179331B1 (en) 2020-04-21 2021-11-23 Cure Pharmaceutcai Holding Corp Oral soluble film containing sildenafil citrate

Also Published As

Publication number Publication date
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