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WO2012121461A1 - Formulation de film stable à dissolution rapide pour forme pharmaceutique orale - Google Patents

Formulation de film stable à dissolution rapide pour forme pharmaceutique orale Download PDF

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Publication number
WO2012121461A1
WO2012121461A1 PCT/KR2011/006860 KR2011006860W WO2012121461A1 WO 2012121461 A1 WO2012121461 A1 WO 2012121461A1 KR 2011006860 W KR2011006860 W KR 2011006860W WO 2012121461 A1 WO2012121461 A1 WO 2012121461A1
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Prior art keywords
montelukast
stable oral
film
film formulation
hydrochloride
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Ceased
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PCT/KR2011/006860
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English (en)
Korean (ko)
Inventor
정경태
전창욱
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Chabio and Diostech Co Ltd
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Chabio and Diostech Co Ltd
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Publication of WO2012121461A1 publication Critical patent/WO2012121461A1/fr
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    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to a stable oral rapid-release film formulation, and relates to a stable oral rapid-release film formulation which reduces the impurity content during storage by reducing degradation of montelukast or various other medically active ingredients as a medical active ingredient included in the formulation. .
  • the disintegrating film that disintegrates or dissolves easily in the oral cavity can be taken without water, so it is very useful not only for the elderly who have difficulty taking tablets or capsules, but also for children, people with disabilities, patients lying in bed, and busy modern people. Formulation. While it is possible to formulate liquid formulations in place of tablets or capsules for the elderly and children, liquid formulations have the disadvantages of poor stability and inaccurate dosage.
  • the fast-release film can be applied to drugs that have a lot of liver metabolism among drugs absorbed from the digestive tract.
  • montelukast is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT1 receptor.
  • Leukotriene is involved in contraction and inflammation of airway muscles and fluid accumulation in the lungs.
  • Montelukast sodium is a useful therapeutic agent for the treatment of respiratory diseases such as asthma and allergic rhinitis.
  • montelukast sodium is [R- (E)]-1-[[[1- [3- [2- (7-chloro-2-quinolinyl) ethenyl] phenyl] -3- [2- (1 -Hydroxymethylethyl) phenyl] propyl] thio] methyl] cyclopropane acetic acid monosodium salt.
  • Montelukast sodium is a hygroscopic, optically active white to off white powder.
  • Montelukast sodium is freely soluble in methanol, ethanol, and water and is substantially insoluble in acetonitrile.
  • the structure of the montelukast sodium salt is as follows:
  • Montelukast may contain foreign compounds or impurities that may be derived from many sources, which are unreacted starting materials, reaction byproducts, side reaction products, or decomposition products. Impurities in montelukast or any active pharmaceutical ingredient (API) are undesirable and, in severe cases, may even be harmful to the patient being treated as a formulation containing the API.
  • API active pharmaceutical ingredient
  • impurities in the active pharmaceutical ingredient can arise from the degradation of the active pharmaceutical ingredient itself, which relates to the stability of the pure active pharmaceutical ingredient during the manufacturing process, including storage, and chemical synthesis.
  • Process impurities include unreacted starting materials, chemical derivatives of impurities contained in the starting materials, synthetic byproducts, and degradation products.
  • WO 2007/092031 reported that some impurities such as [R- (E)]-1-[[[3- [2- ( 7-chloro-2-quinolinyl) ethenyl] phenyl] -3- [2- (1-hydroxy-1-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid S-monoxide "Monte S -oxide”) is reported to increase.
  • the montelukast sodium formulation was developed by Merck, USA, and is commercially available in adult 10 mg coated tablets and 4 mg and 5 mg chewable tablets for children.
  • the commercially available coated tablets it is difficult to take without water, and it is difficult to apply to elderly people who have insufficient swallowing ability and patients who are unable to take oral preparations.In the case of chewable tablets, the tablets have strong mechanical strength. It is difficult to chew. Accordingly, there is a need for the development of a montelukast sodium formulation in which the above problems are solved.
  • the present application relates to a stable oral rapid-release film formulation, and relates to a stable oral rapid-release film formulation which has reduced impurity content during storage by reducing degradation of montelukast or various other medically active ingredients as a medically active ingredient included in the formulation. will be.
  • One aspect of the present disclosure is to provide a stable oral rapid dissolution film formulation containing a pharmaceutically active ingredient, which contains an antioxidant and an antioxidant synergist simultaneously.
  • Such stable oral fast-acting film preparations according to the present application may improve the stability of the preparation by reducing the degradation of montelukast or various other medically active ingredients as a medically active ingredient included in the preparation to reduce the impurity content during storage.
  • Stable oral fast-acting film preparations containing a medically active ingredient according to the present invention contain a antioxidant and a synergist simultaneously, thereby degrading montelukast or various other medically active ingredients as a medically active ingredient included in the preparation. It is possible to improve the stability of the formulation by reducing the content and reducing the impurity content during storage.
  • the film formulation according to the present application is prepared under a pH of the alkaline region and at a suitable temperature to reduce the impurity production of montelukast or its salts, thereby providing a stable montelukast orally disintegrating film formulation. It can be easily obtained to enable its mass production and to be stored for a long time stably without impurities.
  • 1 is a graph showing the dissolution test results of montelukast oral disintegrating film 10 mg, Singulair coated tablet 10 mg and Singulair chewable tablet 5 mg according to an embodiment of the present application.
  • One aspect of the present application provides a stable oral rapid dissolution film formulation containing a pharmaceutically active ingredient, wherein the stable oral dissolution film formulation simultaneously contains an antioxidant and an antioxidant synergist.
  • Such stable oral fast-acting film preparations according to the present application can improve the stability of the preparation by reducing the degradation of montelukast or various other medically active ingredients as a medically active ingredient included in the preparation and reducing the impurity content during storage.
  • the antioxidant is selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sesamol, gosipol, lecithin, tocopherols, propyl gallate, and combinations thereof It may be, but is not limited thereto.
  • the antioxidant synergist is in the group consisting of acidic compounds such as phosphate, ascorbic acid, isoascorbic acid, citric acid, tartaric acid, phosphoric acid, boric acid, hydrochloric acid, phytic acid, phospholipids and combinations thereof and salts thereof It may include, but not limited to being selected.
  • the phosphate salt may include potassium dihydrogen phosphate, dipotassium phosphate or a combination thereof, but is not limited thereto.
  • the film formulation may contain, but is not limited to, 0.015 wt% or more of the antioxidant and 0.1 wt% or more of the antioxidant synergist.
  • the film formulation may contain, but is not limited to, 0.015 wt% to 10 wt% of the antioxidant and 0.1 wt% to 10 wt% of the antioxidant synergist.
  • the pharmaceutically active ingredient is a pharmacologically active ingredient orally administered as the pharmacologically active ingredient used in the film for the present invention, but can be quickly exhibited the drug by showing a rapid dissolution, particularly This is preferable.
  • diabetes treatment Insomnia therapy; Urogenital therapy; Obesity treatment; Enzymes; Peptic ulcer solvents; Antitussive expectorants; Skin disease treatments; Antiemetic agent; Antidepressants; Antihistamines; Antipyretic analgesic agents; Hormonal preparations; Circulatory therapy; Treatments for the digestive system; Mental neurological agents; Erectile dysfunction treatment; Osteoporosis therapeutics; Arthritis agents; Epilepsy treatments; Muscle relaxants; Brain function improvers; Schizophrenic agents; Immunosuppressants; Antibiotic; Anticancer agents; Anticancer adjuvant; Vaccines; Mouthwashes; Anemia treatment agents; Constipation therapy; vitamin; Nutrients; Lactic acid bacteria;
  • the pharmaceutically active ingredient is, for example, triclosan, cetyl pyridium chloride, dominfen bromide, quaternary ammonium salt, zinc compound, acid guinarin, fluoride, alexidine, octonidine, EDTA, aspirin, acetaminophen Ibuprofen, ketoprofen, diflunisal, phenopropenecalcium, naproxen, tolmethine sodium, indomethacin, benzonatate, caramifen, edysylate, menthol, dextrose metropan hydrobromide, crofediol Hydrochloride, diphenhydramine, pseudoephedrine, phenylephrine, phenylpropanolamine, pseudoephedrine sulfate, bromfenyramine maleate, chlorpheniramine maleate, carbinoxamine maleate, clemastine fumarate, dexchlorphenir Am
  • the film formulation may include less than 2.7% by weight or less than 1.7% by weight of impurities derived from the medically active ingredient after 6 months storage at 75 ° C. under 75% relative humidity. It doesn't happen.
  • the medical active ingredient is montelukast sodium
  • the fast-acting film formulation including montelukast sodium as the medical active ingredient may be biologically equivalent, but is not limited thereto.
  • the stable oral fast-acting film formulation containing the montelukast sodium as a medical active ingredient may be prepared in an atmosphere that blocks light or reduces the amount of light to 50 Lux or less, but is not limited thereto. no.
  • the rapid-release film preparation according to the present application comprises a salt of montelukast as the medical active ingredient, by including phosphate as the antioxidant synergist, to suppress the generation of impurities due to the decomposition of the salt of montelukast It may be particularly effective, but is not limited thereto.
  • the phosphate salt may include potassium dihydrogen phosphate, dipotassium phosphate, or a combination thereof.
  • the present invention is not limited thereto.
  • the stable oral fast-acting film preparation containing sodium montelukast as a medical active ingredient by containing butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) or a combination thereof as the antioxidant, It may be particularly effective at inhibiting the generation of impurities due to the decomposition of salts, but is not limited thereto.
  • the stable oral fast-acting film preparation comprising montelukast sodium as a medically active ingredient is particularly effective in suppressing the generation of impurities due to the decomposition of the salt of montelukast by simultaneously comprising the phosphate and the antioxidant. It may be, but is not limited thereto.
  • the stable oral fast-acting film formulation comprising sodium montelukast as a medically active ingredient has an impurity derived from the montelukast of 2.7% by weight or less after storage for 6 months at 75% relative humidity.
  • the weight percentage may be less than, but is not limited thereto.
  • the impurities derived from montelukast may include, but are not limited to, sulfoxide of montelukast, cis-isomers of montelukast, ketocarbinol of montelukast, or a combination thereof.
  • the stable oral fast-acting film formulation comprising sodium montelukast as a medically active ingredient has a sulfoxide of montelukast of 2.5% by weight or less or 1.5% by weight after storage for 6 months at 75% relative humidity. It may be, but is not limited thereto.
  • the stable oral fast-acting film formulation containing sodium montelukast as a medical active ingredient may be 0.1 wt% or less of cis-isomer of montelukast after 6 months storage at 75% relative humidity.
  • the present invention is not limited thereto.
  • the stable oral fast-acting film formulation containing sodium montelukast as a medical active ingredient may be 0.1 wt% or less of ketocarbinol of montelukast after 6 months at 75 ° C. under 75% relative humidity. It is not limited to this.
  • the use of montelukast sodium, which is unstable to light, heat and pH, to produce a montelukast orally disintegrating film formulation with an impurity content of less than 2.7%, requires control of temperature, pH and light blockage.
  • the stable oral fast-acting film formulation containing the montelukast sodium as a medical active ingredient can be prepared as follows. That is, in a light-blocked reactor, an antioxidant synergist such as phosphate is dissolved or dispersed in water or a mixture of water and ethanol, the pH is adjusted to 8 to 10, and then the temperature is controlled to 30 ° C. or lower, and an emulsifier, a fragrance, and a sweetener , Thickeners, moisturizers, pigments, mold release agents and antioxidants are added sequentially, and then montelukast sodium is added and stirred for a sufficient time to ensure good dispersion.
  • an antioxidant synergist such as phosphate is dissolved or dispersed in water or a mixture of water and ethanol, the pH is adjusted to 8 to 10, and then the temperature is controlled to 30 ° C. or lower, and an emulsifier, a fragrance, and a sweetener , Thickeners, moisturizers, pigments, mold release agents and
  • a suitable solution for preparing a water-soluble polymer which is a film-forming agent, is prepared.
  • the viscosity is preferably 4,000-12,000 CPS, but is not limited thereto.
  • the solution is prepared by preparing and molding in the condition that the pH is in the alkaline region and the temperature is 30 °C or lower, and then storing it in a package that blocks light and air.
  • the content of the montelukast oral disintegrating film can be prepared with a content of less than 2.7%.
  • the sulphoxide of montelukast can be reduced to 2.5% by weight or less by using phosphate as the antioxidant synergist, and in the case of cis-isomer, the irradiation dose of light, that is, Lux By adjustment it can be reduced to 0.1% by weight or less.
  • ketocarbinol in the case of the montelukast-derived another impurity ketocarbinol can be reduced to 0.1% by weight or less by the addition of antioxidants such as BHA, BHT.
  • antioxidants such as BHA, BHT.
  • ketocarbinol it is possible to make a stable film preparation by using 0.015% to 0.02% by weight of the antioxidant relative to the total raw material input amount. Accordingly, the content of the montelukast-derived impurities may be reduced to below the regulation value upon 6 months of accelerated storage (under 40 ° C., 75% RH).
  • the ondansetron salt comprising as a medically active ingredient contained in the stable oral rapid dissolution film preparation is ondansetron hydrochloride, and the rapid dissolution film preparation comprising the ondansetron hydrochloride as a medical active ingredient It may be to have.
  • the sildenafil salt comprising the stable active oral fast-acting film preparation as a medically active ingredient is sildenafil citrate
  • the rapid-release film preparation comprising the sildenafil citrate as a medically active ingredient is biocompatible. It may be to have.
  • the pharmaceutically active ingredient may be 1% to 20% by weight based on the total weight of the generic film formulation, but is not limited thereto.
  • the medical active ingredient is montelukast sodium
  • its content may be 10 wt% to 20 wt% based on the total weight of the flux film formulation, but is not limited thereto.
  • the stable oral fast-acting film formulation containing the medically active ingredient comprises at least one medically active ingredient, the antioxidant, the antioxidant synergist, the at least one water soluble polymer, an aftertaste improver, and a taste blocker. It may be molded in the form of a film including at least one first sweetener, but is not limited thereto.
  • the after-improving agent may be to include a stevioside-based sweetener, but is not limited thereto.
  • the stable oral fast-acting film formulation containing the pharmaceutically active ingredient based on the total weight of the fast-acting film formulation, 0.1 to 10% by weight of the first sweetener, respectively, as the stevioside-based sweetener and high sweetener
  • the stevioside-based sweetener and the first sweetener may be included in a ratio (w / w) of 1: 3 to 3: 1, but are not limited thereto.
  • the rapid-release film formulations of the present application may include, but are not limited to, a high sweetener.
  • the first sweetener is dissolved in water or oil, emulsified as a drug having high unpleasant taste and a high sweetener, and then mixed with a water-soluble polymer and other additives to form a fast film.
  • the first sweetening agent as a high sweetening sweetener in the group consisting of aspartame, acesulfame salt, sucralose, saccharin salt, neotime, cyclate salt, taumatin, nagaraceae extract, and licorice extract It may include, but is not limited to, one or more high sweetening sweeteners selected. More preferably, it may include, but is not limited to, one or more high sweetening sweeteners selected from aspartame, sucralose, neotime, and acesulfame salts.
  • the maximum sweetness over time of the first sweetener, acesulfame potassium is expressed first, the maximum sweetness is expressed in the order of aspartame, sucralose, stevioside. Therefore, steviosides that express sweetness late in the control of the unpleasant taste felt when the drug is absorbed and left in the oral are preferred, but are not limited thereto.
  • a drug with a strong unpleasant taste is particularly strong and unpleasant taste in the aftertaste, for example, 0.1 to 10% by weight (w / w) of the stevioside-based sweetener, that is,
  • w / w 0.1 to 10% by weight
  • stevioside and / or its derivatives as a aftertaste enhancer with the first sweetener as the high sweetener may mask the taste and unpleasant taste, but is not limited thereto.
  • stevioside examples include, but is not limited to, Stevietenlite (Stevioside 98% or more), Stevietenrich (100% enzymatically treated Stevia) produced in Daepyeong, Stevia extract REB-A 73% ( Rebaudioside A 73% or more) and rebate 97% (rebaudioside A 97% or more) and the like, but are not limited thereto.
  • the enzyme-treated stevia is a product in which glucose is added to the stevia extract by using a sugar transfer enzyme, and is a micro-improved product that reduces the intrinsic bitter taste of stevioside and enhances solubility.
  • 97% of lebaten is the sweetest and the best sweetness of the seven sweet components of stevia is produced through a separate separation operation in stevia.
  • the water-soluble polymer is used as a film forming agent, pullulan, gelatin, pectin, low viscosity pectin, hydroxypropyl methyl cellulose, low viscosity hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose , Carboxymethyl cellulose, polyvinyl alcohol, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl polymer, polyethylene glycol, alginic acid, low viscosity alginic acid, sodium alginate, carrageenan, modified starch, casein, whey protein isolate, soy protein isolate It may include one or more water-soluble polymers selected from the group consisting of water, zein, levane, elcinan, gluten, acacia gum, carrageenan, arabian gum, guar gum, locust bean gum, xanthan gum, gellan gum and agar, It is not limited to this.
  • the water-soluble polymer may include one or more water-soluble polymers selected from the group consisting of pullulan, gelatin, pectin, low viscosity pectin, low viscosity alginic acid, hydroxypropylmethylcellulose, and modified starch, but is not limited thereto. It doesn't happen.
  • the water-soluble polymer is 50 to 90% by weight (w / w), preferably 60 to 80% by weight (w / w), more preferably 60 to 70% by weight (w) based on the total weight of the rapid film / w), but is not limited thereto.
  • the stable oral fast-acting film preparation containing the medically active ingredient is a filler, saliva stimulant, thickener, plasticizer, acidulant, flavoring, emulsifier, surfactant, binder, preservative, colorant, second sweetener. It may further include, but is not limited to, one or more pharmaceutically acceptable additives selected from the group consisting of moisturizers, pigments, coolants and release agents.
  • the filler serves to reduce the slippery properties of the film in the oral cavity and to impart a backbone to the film. It also reduces the sticking properties of the films, and can control the sticking and dissolution rate of the film in the oral cavity and the dissolution rate of the drug.
  • the filler may be added to 1 to 15% by weight (w / w) relative to the total weight of the flux film.
  • Non-limiting examples of such fillers may include one or more components selected from the group consisting of microcrystalline cellulose, cellulose polymers, magnesium carbonate, calcium carbonate, limestone powder, silicates, clays, talc, titanium dioxide and calcium phosphate.
  • the plasticizer can be used to adjust the flexibility of the film.
  • the plasticizer may be added in an amount of 0.1 to 15 wt% (w / w) based on the total weight of the flux film.
  • Non-limiting examples of the plasticizer at least one selected from the group consisting of sorbitol, maltitol, xylitol, glycerin, polyethylene glycol, propylene glycol, hydrogenated syrup, starch syrup, glycerin, triacetin, glycerol oleate, sucrose fatty acid ester and medium chain fatty acid It may include ingredients.
  • the second sweetener may be added 0.1 to 10% by weight (w / w) based on the total weight of the film formulation.
  • the second sweetening agent aspartame, acesulfame salt, sucralose, saccharin salt, neotime, cyclate salt, taumartin, naphtha extract, licorice extract, stevitenite (over 98% stevioside) ), Stanbitenrich (100% enzymatically treated stevia), Stevia extract REB-A 73% (greater than Rebaudioside A 73%) and lebaten 97% (greater than Rebaudioside A 97%), sugar, glucose, Maltose, oligosaccharides, dextrins, alpha cyclodextrins, beta cyclodextrins, gamma cyclodextrins, methyl beta cyclodextrins, hydroxypropyl beta cyclodextrins
  • the emulsifier may be one or more components selected from the group consisting of glycerin fatty acid ester, sucrose fatty acid ester, lecithin, enzyme-treated lecithin, polysorbate, sorbitan fatty acid ester and propylene glycol fatty acid ester, but is not limited thereto. It doesn't happen.
  • the stable oral rapid-release film formulation according to the present application may also further comprise an acidulant.
  • the acidulant may adjust the taste together with the sweetener, and may serve to stimulate the generation of saliva so that the edible film may be dissolved well.
  • the acidulant may be added 0.1 to 10% by weight (w / w) based on the total weight of the film formulation.
  • Non-limiting examples of the acidulant may include one or more components selected from the group consisting of citric acid, malic acid, fumaric acid, tartaric acid, ascorbic acid, succinic acid, adipic acid and lactic acid.
  • the stable oral rapid-release film formulation according to the present application may also include a fragrance. Since the film formulation is a product that is dissolved and absorbed in the oral cavity, it is necessary to add an appropriate aroma.
  • the flavor may be natural flavors, artificial flavors or mixtures thereof.
  • the natural fragrance may be extracts from leaves, flowers, fruits, etc. of plants, oils of plants, and the like.
  • Plant oils include spearmint oil, cinnamon oil, peppermint oil, lemon oil, clove oil, bay oil, thyme oil, cedar leaf oil, nutmeg oil and sage ( sage) oil, almond oil, and the like.
  • artificial flavors of fruits such as lemons, oranges, grapes, limes, strawberries and artificial synthetic flavors such as vanilla, chocolate, coffee, cocoa, pine needles, ginseng, red ginseng, citrus may be used.
  • the amount of the perfume used depends on a number of factors such as the type, type, and desired strength of the perfume used in general, and may generally include 0.1 to 15% by weight (w / w) based on the total weight of the generic film.
  • the perfume in oil form may be used together with an emulsifier to make it compatible with water-soluble substances.
  • the amount of the emulsifier may be adjusted according to the type and amount of the fragrance, and generally, 0.1 to 10% by weight (w / w) may be added to the total weight of the generic film.
  • the emulsifier may be one or more components selected from the group consisting of glycerin fatty acid esters, sucrose fatty acid esters, lecithin, enzyme-treated lecithin, polysorbates, sorbitan fatty acid esters and propylene glycol fatty acid esters.
  • the stable oral rapid-release film formulation according to the present application may include a pigment suitable for the product.
  • the pigment may be appropriately adjusted as necessary, and may be added in an amount of 0.01 to 10 wt% (w / w) based on the total weight of the edible film.
  • the pigment may be a natural or synthetic pigment.
  • the stable oral rapid dissolution film formulation according to the present application may further comprise a refreshing agent.
  • Cooling agent is not limited to this.
  • the refreshing agent may be WS3, WS23 or Questais-L.
  • the freshener may be appropriately adjusted in amount as necessary, and may be generally added in an amount of 0.01 to 5 wt% (w / w) based on the total weight of the soft film.
  • the stable oral fast dissolving film preparation according to the present application would be desirable to form a thin film that maintains an appropriate range of tensile strength and toughness in a very thin film state.
  • the thickness of the stable oral rapid dissolution film preparation according to the present application is from about 20 ⁇ m to about 200 ⁇ m, preferably from about 40 ⁇ m to about 100 ⁇ m.
  • Potassium dihydrogen phosphate and dipotassium phosphate were dissolved in 256 cc of water in a light-blocked reactor, and the temperature was adjusted to 30 ° C., followed by emulsifiers, flavors, sweeteners, pigments, mold release agents, thickeners, and antioxidants. It was added sequentially as described. BHT and BHA as antioxidants were dissolved beforehand in ethanol and added. 18.2 g of montelukast sodium was added and stirred for 1 hour to ensure good dispersion. After dissolving the montelukast sodium well, a suitable solution (viscosity about 7,000 cps) was prepared for addition and molding of pullulan, a film former.
  • the film was formed in a molding machine at about 80 ° C., cut into 2.2 cm x 3.7 cm in width, placed in an aluminum pouch, and subjected to a six month accelerated experiment at 40 ° C. and RH 75. It was.
  • the analysis results are described in Table 3 below.
  • Potassium dihydrogen phosphate and dipotassium phosphate were dissolved in 256 cc of water in a light-blocked reactor, and the temperature was adjusted to 30 ° C., followed by emulsifiers, flavors, sweeteners, pigments, mold release agents, thickeners, and antioxidants. It was added sequentially as content. BHT and BHA were added after dissolving in ethanol in advance. 15 g of montelukast sodium was added and stirred for 1 hour to ensure good dispersion. After dissolving the montelukast sodium well, a suitable solution (viscosity about 7,000 cps) was prepared for addition and molding of pullulan, a film former.
  • the film was molded in a molding machine at about 80 ° C., cut into a size of 2.2 cm ⁇ 3.7 cm, placed in an aluminum pouch, and subjected to a 6 month accelerated experiment at 40 ° C. and RH 75, followed by analysis of content and lead substance.
  • the analysis results are described in Table 3 below.
  • Polyvinyl alcohol was added to 256 cc of water in a light-blocked reactor and heated to 85 ° C. for 1 hour. After cooling to 30 ° C., potassium dihydrogen phosphate and dipotassium phosphate were dissolved, and emulsifiers, flavors, sweeteners, pigments, thickeners, mold release agents, and antioxidants were added sequentially as shown in Table 2 below. BHT and BHA were added after dissolving in ethanol in advance. 16 g of montelukast sodium was added and stirred for 0.5 hour to ensure good dispersion.
  • a suitable solution (viscosity about 7,000 cps) was prepared for addition and molding of pullulan, a film former.
  • the film was molded in a molding machine at about 80 ° C., cut into a size of 2.2 cm ⁇ 3.7 cm, placed in an aluminum pouch, and subjected to a 6 month accelerated experiment at 40 ° C. and RH 75, followed by analysis of content and lead substance.
  • the analysis results are described in Table 3 below.
  • polyvinyl alcohol was added to 300 cc of water and heated at 85 ° C. for 1 hour. After cooling to 30 ° C, potassium dihydrogen phosphate and dipotassium phosphate were dissolved, and emulsifiers, flavors, sweeteners, pigments, thickeners, mold release agents, and antioxidants were added sequentially as shown in Table 2 below.
  • BHT and BHA were added after dissolving in ethanol in advance. 16 g of montelukast sodium was added thereto, followed by stirring for 0.5 hours to ensure good dispersion. After dissolving montelukast sodium well, a suitable solution (viscosity about 7,000 cps) was prepared by adding the film forming agent HPMC.
  • the film was molded in a molding machine at about 80 ° C., cut into a size of 2.2 cm ⁇ 3.7 cm, placed in an aluminum pouch, and subjected to a 6 month accelerated experiment at 40 ° C. and RH 75, followed by analysis of content and lead substance.
  • the analysis results are described in Table 3 below.
  • phosphoric acid was dissolved in 256 cc of water, the pH was adjusted to 9, and then the temperature was adjusted to 70 ° C., and an emulsifier, a flavor, a sweetener, a moisturizer, a pigment, a filler, and a mold release agent were used in the contents shown in Table 2 below.
  • emulsifier, a flavor, a sweetener, a moisturizer, a pigment, a filler, and a mold release agent were used in the contents shown in Table 2 below.
  • 11.44 g of montelukast sodium was added, followed by stirring for 1 hour so that the dispersion was good.
  • a solution suitable for shaping pullulan, a film forming agent was prepared. The viscosity at this time was 7,000 cps.
  • the film was molded in a molding machine at about 80 ° C., cut into a size of 2.2 cm ⁇ 3.7 cm, placed in an aluminum pouch, and subjected to a 6 month accelerated experiment at 40 ° C. and RH 75, followed by analysis of content and lead substance.
  • the analysis results are described in Table 3.
  • Potassium dihydrogen phosphate and dipotassium phosphate were dissolved in 256 cc of water in a light-blocked reactor.
  • the temperature was adjusted to 30 ° C and emulsifiers, flavors, sweeteners, moisturizers, pigments, thickeners, mold release agents were added sequentially as shown in Table 2, and then 18.2 g of montelukast sodium were added and stirred for 1 hour to ensure good dispersion. After dissolving montelukast sodium well, pullulan, a film forming agent, was added to prepare a suitable solution (viscosity about 7,000 cps).
  • the film was molded in a molding machine at about 80 ° C., cut into a size of 2.2 cm ⁇ 3.7 cm, placed in an aluminum pouch, and subjected to a 6 month accelerated experiment at 40 ° C. and RH 75, followed by analysis of content and lead substance.
  • the analysis results are described in Table 3 below.
  • Potassium dihydrogen phosphate and dipotassium phosphate were dissolved in 256 cc of water in a light-blocked reactor, and the temperature was adjusted to 30 ° C., followed by emulsifiers, flavors, sweeteners, humectants, pigments, thickeners, and release agents. It was added sequentially as content. 18.2 g of montelukast sodium was added, followed by stirring for 1 hour to ensure good dispersion. After dissolving the montelukast sodium well, a suitable solution (viscosity about 7,000 cps) was prepared for addition and molding of pullulan, a film former.
  • the film was molded in a molding machine at about 80 ° C., cut into a size of 2.2 cm ⁇ 3.7 cm, placed in an aluminum pouch, and subjected to a 6 month accelerated experiment at 40 ° C. and RH 75, followed by analysis of content and lead substance.
  • the analysis results are described in Table 3 below.
  • Dissolve potassium dihydrogen phosphate and dipotassium phosphate in 256 cc of water in a light-blocked reactor adjust the temperature to 30 ° C, and then emulsify, flavor, sweetener, moisturizer, colorant, mold release agent, thickener, and antioxidant. It was added sequentially as described in Table 2.
  • BHT and BHA as antioxidants were dissolved in ethanol beforehand. 18.2 g of montelukast sodium was added, followed by stirring for 1 hour to ensure good dispersion. After dissolving the montelukast sodium well, a suitable solution (viscosity about 7,000 cps) was prepared for addition and molding of pullulan, a film former.
  • the film was molded in a molding machine at about 80 ° C., cut into a size of 2.2 cm ⁇ 3.7 cm, placed in an aluminum pouch, and subjected to an accelerated experiment at 40 ° C. and RH 75 for 6 months, and then analyzed for contents and soft substances.
  • the analysis results are described in Table 3 below .

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Abstract

La présente invention concerne une formulation de film stable à dissolution rapide pour une forme pharmaceutique orale, et plus spécifiquement une formulation de film stable à dissolution rapide pour une forme pharmaceutique orale qui réduit la teneur en impuretés dans le stockage en réduisant la désintégration de montélukast en tant que composants médicalement actifs compris dans la formulation ou d'autres composants médicalement actifs divers.
PCT/KR2011/006860 2011-03-04 2011-09-16 Formulation de film stable à dissolution rapide pour forme pharmaceutique orale Ceased WO2012121461A1 (fr)

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CN104784157A (zh) * 2015-04-04 2015-07-22 齐鲁制药有限公司 一种稳定的孟鲁司特口腔薄膜剂
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
WO2018176149A1 (fr) * 2017-03-30 2018-10-04 Intelgenx Corp. Méthode de traitement et dispositif pour la biodisponibilité améliorée d'antagonistes des récepteurs des leucotriènes
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10195153B2 (en) 2013-08-12 2019-02-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
WO2019224323A1 (fr) * 2018-05-23 2019-11-28 Klaria Pharma Holding Ab Préparation pharmaceutique
EP3528796A4 (fr) * 2016-10-20 2020-04-29 Intelgenx Corp. Dispositif et procédé de traitement d'états associés à une neuro-inflammation
US10959958B2 (en) 2014-10-20 2021-03-30 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form
US11007144B2 (en) 2016-11-15 2021-05-18 Klaria Pharma Holding Ab Pharmaceutical formulation
US11179331B1 (en) 2020-04-21 2021-11-23 Cure Pharmaceutcai Holding Corp Oral soluble film containing sildenafil citrate
US11219600B2 (en) 2017-06-08 2022-01-11 Klaria Pharma Holding Ab Pharmaceutical formulation
US12156937B2 (en) 2018-09-28 2024-12-03 Intelgenx Corp. Oral film formulation for modulating absorption profile
US12303501B2 (en) 2018-11-05 2025-05-20 Intelgenx Corp. Lipophilic active oral film formulation and method of making the same
US12440472B2 (en) 2021-06-16 2025-10-14 Intelgenx Corp. Stable tryptamine oral films

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WO2013100564A1 (fr) * 2011-12-26 2013-07-04 에스케이케미칼 주식회사 Film pour administration orale contenant du montélukast ou un sel pharmaceutiquement acceptable de celui-ci
KR101546667B1 (ko) 2012-05-03 2015-08-25 주식회사 씨엠지제약 물성 및 쓴맛 차폐효과가 향상된 실데나필 경구용 속용 필름
KR101538985B1 (ko) * 2014-09-02 2015-07-24 주식회사 서울제약 타다라필 구강붕해필름 및 이의 제조방법
CN105769825A (zh) * 2014-12-24 2016-07-20 广州朗圣药业有限公司 一种孟鲁司特钠的口腔膜剂及其制备方法

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KR20050048056A (ko) * 2003-11-18 2005-05-24 (주)케이비피 경구용 소모 필름 조성물
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KR20100086140A (ko) * 2009-01-22 2010-07-30 일동제약주식회사 몬테루카스트를 활성성분으로 함유하는 구강 내 속붕해정 조성물 및 그 제조방법
KR20100138768A (ko) * 2009-06-25 2010-12-31 (주)차바이오앤디오스텍 불쾌한 맛을 효과적으로 은폐한 경구용 속용 필름

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US10639281B2 (en) 2013-08-12 2020-05-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US10195153B2 (en) 2013-08-12 2019-02-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10792254B2 (en) 2013-12-17 2020-10-06 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
US10959958B2 (en) 2014-10-20 2021-03-30 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form
CN104784157A (zh) * 2015-04-04 2015-07-22 齐鲁制药有限公司 一种稳定的孟鲁司特口腔薄膜剂
EP3528796A4 (fr) * 2016-10-20 2020-04-29 Intelgenx Corp. Dispositif et procédé de traitement d'états associés à une neuro-inflammation
US12285521B2 (en) 2016-11-15 2025-04-29 Klaria Pharma Holding Ab Pharmaceutical formulation
US11007144B2 (en) 2016-11-15 2021-05-18 Klaria Pharma Holding Ab Pharmaceutical formulation
WO2018176149A1 (fr) * 2017-03-30 2018-10-04 Intelgenx Corp. Méthode de traitement et dispositif pour la biodisponibilité améliorée d'antagonistes des récepteurs des leucotriènes
US11219600B2 (en) 2017-06-08 2022-01-11 Klaria Pharma Holding Ab Pharmaceutical formulation
US11904049B2 (en) 2017-06-08 2024-02-20 Klaria Pharma Holding Ab Pharmaceutical formulation
US12005140B2 (en) 2018-05-23 2024-06-11 Klaria Pharma Holding Ab Pharmaceutical formulation
IL278927B1 (en) * 2018-05-23 2024-09-01 Klaria Pharma Holding Ab Pharmaceutical formulation
IL278927B2 (en) * 2018-05-23 2025-01-01 Klaria Pharma Holding Ab Pharmaceutical preparation
WO2019224323A1 (fr) * 2018-05-23 2019-11-28 Klaria Pharma Holding Ab Préparation pharmaceutique
US12156937B2 (en) 2018-09-28 2024-12-03 Intelgenx Corp. Oral film formulation for modulating absorption profile
US12303501B2 (en) 2018-11-05 2025-05-20 Intelgenx Corp. Lipophilic active oral film formulation and method of making the same
US11179331B1 (en) 2020-04-21 2021-11-23 Cure Pharmaceutcai Holding Corp Oral soluble film containing sildenafil citrate
US12440472B2 (en) 2021-06-16 2025-10-14 Intelgenx Corp. Stable tryptamine oral films

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AR085610A1 (es) 2013-10-16
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