WO2012121461A1 - Stable fast-dissolving film formulation for oral dosage form - Google Patents
Stable fast-dissolving film formulation for oral dosage form Download PDFInfo
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- 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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- montelukast
- stable oral
- film
- film formulation
- hydrochloride
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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
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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
- A61K9/0012—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
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- 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
The present invention relates to a stable fast-dissolving film formulation for an oral dosage form, and more specifically to a stable fast-dissolving film formulation for an oral dosage form which reduces the content of impurities in storage by reducing the disintegration of montelukast as a medically-active ingredient included in the formulation or other various medically-active ingredients.
Description
본원은 안정한 경구용 속용 필름 제제에 관한 것으로서, 상기 제제에 포함된 의학적 활성 성분으로서 몬테루카스트 또는 그 외 다양한 의학적 활성 성분들의 분해를 감소시켜 보관시 불순물 함량을 감소시킨 안정한 경구용 속용 필름 제제에 관한 것이다.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. .
최근 수명 연장으로 고령 인구의 사회적 구성비율이 증가하고 있는데, 이들 고령자들은 약물 동태학적인 변화뿐만 아니라, 시력, 청력, 기억력 및 육체적 능력이 퇴보된 상태이기 때문에, 적절한 약물 치료가 필요하다. 특히, 일반 정제나 캅셀제를 복용하는 데에 어려움을 겪고 있으며, 이러한 관점에서 고령자들을 위한 경구투여제의 대체 제제가 요구된다.The recent increase in lifespan is increasing the social composition of the elderly population, which requires deterioration of vision, hearing, memory and physical ability as well as pharmacokinetic changes. In particular, there is a difficulty in taking general tablets or capsules, and in view of this, there is a need for an alternative preparation for oral administration for the elderly.
구강 내에서 쉽게 붕해 또는 용해되는 속용 필름은 물이 없이도 복용할 수 있으므로, 정제나 캅셀제를 복용하기에 어려움을 겪는 노인뿐만 아니라, 어린이, 장애자, 침대에 누워 있는 환자, 그리고 바쁜 현대인들에게도 매우 유용한 제제이다. 노인과 어린이에게 정제 또는 캅셀제의 대용으로 액상 제제 처방이 가능하지만, 액상 제제는 안정성이 떨어지고, 용량이 정확하지 않다는 단점이 있다.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.
특히, 약물이 구강점막으로 흡수될 경우 간초회통과도 회피할 수 있으므로, 속용 필름은 소화관으로부터 흡수되는 약물들 중에서, 간 대사를 많이 받는 약물들에 대해서도 적용할 수 있다. In particular, when the drug is absorbed into the oral mucosa can also avoid the hepatic hyperpass, the fast-release film can be applied to drugs that have a lot of liver metabolism among drugs absorbed from the digestive tract.
예를 들어, 몬테루카스트는 시스테인 류코트리엔(cysteinyl leukotriene) CysLT1 수용체를 억제하는, 선택적이고 경구 활성이 있는 류코트리엔 수용체 안타고니스트이다. 류코트리엔은 기도 근육의 수축과 염증 및 폐 내의 유체 축적에 연관이 있다. 몬테루카스트 나트륨은 천식 및 알레르기성 비염과 같은 호흡기 질환의 치료에 유용한 치료제이다.For example, 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.
몬테루카스트 나트륨의 화학명은 [R-(E)]-1-[[[1-[3-[2-(7-클로로-2-퀴놀리닐)에테닐]페닐]-3-[2-(1-히드록시메틸에틸)페닐]프로필]티오]메틸] 시클로프로판 아세트산 모노나트륨 염이다. 몬테루카스트 나트륨은 흡습성이 있고 광학 활성이 있는 백색 내지 미백색 분말이다. 몬테루카스트 나트륨은 메탄올, 에탄올, 및 물에 자유롭게 용해되고, 아세토니트릴에는 실질적으로 불용성이다. 몬테루카스트 나트륨 염의 구조는 하기와 같다:The chemical name of 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:
몬테루카스트는 많은 공급원에서 유래할 수 있는 외래 화합물 또는 불순물을 함유할 수 있으며 이는 미반응 출발 물질, 반응 부산물, 부반응 생성물, 또는 분해 생성물이다. 몬테루카스트 또는 임의 활성 약학 성분 (API)에서 불순물은 바람직하지 못하며, 심한 경우에는 그 API를 함유하는 제제로서 치료되는 환자에게 심지어 유해할 수도 있다.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.
또한, 활성 약학 성분 중 불순물이 활성 약학 성분 자체의 분해로부터 발생할 수 있고, 이는 보관, 및 화학적 합성을 비롯한 제조공정 동안 순수 활성 약학 성분의 안정성에 관련한 것임이 당업계에 공지되어 있다. 공정 불순물로는 미반응 출발 물질, 출발 물질에 함유된 불순물의 화학적 유도체, 합성 부산물, 및 분해 생성물이 포함된다.It is also known in the art that 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.
Mahmoud M. Al Omari등의 문헌(Journal of Pharmaceutical and Biomedical Analysis 45,2007,465-471)에 의하면 액체 및 고체 상태에서 Monte cis-isomer, Monte S-oxide, Monte dehydro 등의 불순물이 발생하며 산성 또는 중성영역에서 빛에 의한 광분해가 심하고, 65℃ 산성영역에서 특히 불안정하다고 보고되었고, WO 2007/092031 에서는 보관 중에도 일부 불순물인 [R-(E)]-1-[[[3-[2-(7-클로로-2-퀴놀리닐)에테닐]페닐]-3-[2-(1-히드록시-1-메틸에틸)페닐]프로필]티오]메틸] 시클로프로판아세트산 S-모노옥시드(이하 "Monte S-oxide"라 칭함)가 증가하는 것으로 보고되고 있다. Mahmoud M. Al Omari et al. (Journal of Pharmaceutical and Biomedical Analysis 45,2007,465-471) show that impurities such as Monte cis- isomer, Monte S- oxide, and Monte dehydro occur in the liquid and solid state and are acidic or Photolysis by light in the neutral region was severe and reported particularly unstable in the acidic region at 65 ° C. 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.
몬테루카스트 나트륨 제제는 미국 머크 사에서 개발되어 성인용 10 mg 코팅정과 소아용 4 mg 및 5 mg 츄어블 정제로 제품화되어 시판 중이다. 시판품 중 코팅정의 경우 물 없이 복용하기에 어려운 단점이 있으며, 삼키는 능력이 부족한 노인 및 경구용 제제를 복용하기 힘든 환자의 경우 적용하기가 힘들며, 츄어블 정제의 경우 정제의 기계적 강도가 강하기 때문에 소아 환자가 씹어서 복용하기에는 어려운 단점을 갖고 있다. 이에, 상기한 문제점들이 해결된 몬테루카스트 나트륨 제제의 개발이 요구되고 있다.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. Among 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.
본원은, 안정한 경구용 속용 필름 제제에 관한 것으로서, 상기 제제에 포함된 의학적 활성 성분으로서 몬테루카스트 또는 그 외 다양한 의학적 활성 성분들의 분해를 감소시켜 보관시 불순물 함량을 감소시킨 안정한 경구용 속용 필름 제제에 관한 것이다.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.
그러나, 본원이 해결하고자 하는 과제는 이상에서 기술한 과제로 제한되지 않으며, 기술되지 않은 또 다른 과제들은 아래의 기재로부터 당업자에게 명확하게 이해될 수 있을 것이다.However, the problem to be solved by the present application is not limited to the problem described above, another problem that is not described will be clearly understood by those skilled in the art from the following description.
본원의 일 측면은, 의학적 활성 성분을 함유하는 안정한 경구용 속용 필름 제제로서, 산화방지제 및 항산화 상승제(synergist)를 동시에 함유하는, 안정한 경구용 속용 필름 제제를 제공할 수 있다. 이러한 본원에 따른 안정한 경구용 속용 필름 제제는, 상기 제제에 포함된 의학적 활성 성분으로서 몬테루카스트 또는 그 외 다양한 의학적 활성 성분들의 분해를 감소시켜 보관시 불순물 함량을 감소시킴으로써 제제의 안정성을 향상시킬 수 있다.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.
본원에 따른 의학적 활성 성분을 함유하는 안정한 경구용 속용 필름 제제는, 산화방지제 및 항산화 상승제(synergist)를 동시에 함유함으로써, 상기 제제에 포함된 의학적 활성 성분으로서 몬테루카스트 또는 그 외 다양한 의학적 활성 성분들의 분해를 감소시키고 보관시 불순물 함량을 감소시켜 제제의 안정성을 향상시킬 수 있다. 특히, 몬테루카스트 또는 그의 염을 의학적 활성 성분으로서 함유하는 경우, 상기 본원에 따른 필름 제제를 알카리 영역의 pH 및 적절한 온도 하에서 필름을 제조함으로써 몬테루카스트 또는 그의 염의 불순물 생성을 감소시켜, 안정한 몬테루카스트 구강 붕해 필름 제제를 용이하게 수득할 수 있어 그의 대량 생산이 가능하도록 하고, 불순물 없이 안정하게 장기간 보관할 수 있도록 한다.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. In particular, when containing montelukast or a salt thereof as a medically active ingredient, 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.
도 1은 본원의 일 실시예에 따른 몬테루카스트 구강붕해 필름 10 mg, Singulair 코팅정 10 mg 및 Singulair 츄어블 정제 5 mg의 용출시험 결과를 비교하여 나타낸 그래프이다. 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.
이하, 첨부한 도면을 참조하여 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있도록 본원의 구현예 및 실시예를 상세히 설명한다.Hereinafter, with reference to the accompanying drawings will be described in detail the embodiments and embodiments of the present application to be easily carried out by those of ordinary skill in the art.
그러나 본원은 여러 가지 상이한 형태로 구현될 수 있으며 여기에서 설명하는 구현예 및 실시예에 한정되지 않는다. 그리고 도면에서 본 발명을 명확하게 설명하기 위해서 설명과 관계없는 부분은 생략하였으며, 명세서 전체를 통하여 유사한 부분에 대해서는 유사한 도면 부호를 붙였다.As those skilled in the art would realize, the described embodiments may be modified in various different ways, all without departing from the spirit or scope of the present invention. In the drawings, parts irrelevant to the description are omitted in order to clearly describe the present invention, and like reference numerals designate like parts throughout the specification.
본원 명세서 전체에서, 어떤 부분이 어떤 구성요소를 "포함"한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성 요소를 더 포함할 수 있는 것을 의미한다.Throughout this specification, when a part is said to "include" a certain component, it means that it can further include other components, without excluding the other components unless specifically stated otherwise.
본 명세서에서 사용되는 정도의 용어 "약", "실질적으로" 등은 언급된 의미에 고유한 제조 및 물질 허용오차가 제시될 때 그 수치에서 또는 그 수치에 근접한 의미로 사용되고, 본원의 이해를 돕기 위해 정확하거나 절대적인 수치가 언급된 개시 내용을 비양심적인 침해자가 부당하게 이용하는 것을 방지하기 위해 사용된다. 또한, 본원 명세서 전체에서, "~ 하는 단계" 또는 "~의 단계"는 "~를 위한 단계"를 의미하지 않는다.As used herein, the terms "about", "substantially", and the like, are used at, or in close proximity to, numerical values when manufacturing and material tolerances inherent in the meanings indicated are provided to aid the understanding herein. In order to prevent the unfair use of unscrupulous infringers. In addition, throughout this specification, "step to" or "step of" does not mean "step for."
본원의 일 측면은, 의학적 활성 성분을 함유하는 안정한 경구용 속용 필름 제제로서, 산화방지제 및 항산화 상승제(synergist)를 동시에 함유하는, 안정한 경구용 속용 필름 제제를 제공한다. 이러한 본원에 따른 안정한 경구용 속용 필름 제제는, 상기 제제에 포함된 의학적 활성 성분으로서 몬테루카스트 또는 그 외 다양한 의학적 활성 성분들의 분해를 감소시키고 보관시 불순물 함량을 감소시켜 제제의 안정성을 향상시킬 수 있다.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.
일 구현예에 있어서, 상기 산화방지제는 BHA(butylated hydroxyanisole), BHT(butylated hydroxytoluene), 세사몰, 고시폴, 레시틴, 토코페롤류, 프로필갈레이트, 및 이들의 조합으로 이루어진 군에서 선택되는 것을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.In one embodiment, 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.
일 구현예에 있어서, 상기 항산화 상승제는 인산염, 아스코빈산, 이소아스코빈산, 구연산, 주석산, 인산, 붕산, 염산, 피틴산, 인지방질 및 이들의 조합 등과 같은 산성 화합물 및 이들의 염으로 이루어진 군에서 선택되는 것을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.In one embodiment, 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.
일 구현예에 있어서, 상기 인산염은 포타슘디하이드로겐포스페이트, 디포타슘포스페이트 또는 이들의 조합을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다. In one embodiment, the phosphate salt may include potassium dihydrogen phosphate, dipotassium phosphate or a combination thereof, but is not limited thereto.
일 구현예에 있어서, 상기 필름 제제는, 0.015 중량% 이상의 상기 산화방지제 및 0.1 중량% 이상의 상기 항산화 상승제를 함유할 수 있으나, 이에 제한되는 것은 아니다.In one embodiment, 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.
일 구현예에 있어서, 상기 필름 제제는, 0.015 중량% 내지 10 중량%의 상기 산화방지제 및 0.1 중량% 내지 10 중량%의 상기 항산화 상승제를 함유할 수 있으나, 이에 제한되는 것은 아니다.In one embodiment, 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.
일 구현예에 있어서, 상기 의학적 활성성분은, 본 발명의 속용 필름에 사용되는 의약적 활성성분은 경구투여되는 약리학적 활성성분이면 가능하나, 특히 빠른 용해를 나타냄으로써, 약효를 신속히 나타낼 수 있는 약물이 바람직하다. 예를 들어, 당뇨병치료제; 불면증치료제; 비뇨생식기치료제; 비만치료제; 효소제; 소화성궤양용제; 진해거담제; 피부질환치료제; 항구토제; 항우울제; 항히스타민제; 해열진통소염제; 호르몬제제; 순환기용치료제; 소화기관용치료제; 정신신경용제; 발기부전치료제; 골다공증치료제; 관절염치료제; 간질치료제; 근육이완제; 뇌기능개선제; 정신분열증치료제; 면역억제제; 항생제; 항암제; 항암치료보조제; 백신제; 구강청결제; 빈혈치료제; 변비치료제; 비타민; 영양제; 유산균제제; 종합감기약; 및 건강기능식품으로 이루어진 군으로부터 선택되는 하나 이상을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다. In one embodiment, 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. For example, 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; Comprehensive cold medicine; And it may include one or more selected from the group consisting of health functional food, but is not limited thereto.
구체적으로, 상기 의학적 활성성분은, 예를 들어, 트리클로산, 세틸 피리듐클로라이드, 도미펜 브로마이드, 4차암모늄염, 아연화합물, 산귀나린, 플루오라이드, 알렉시딘, 옥토니딘, EDTA, 아스피린, 아세트아미노펜, 이부프로펜, 케토프로펜, 디플루니살, 페노프로펜칼슘, 나프록센, 톨메틴나트륨, 인도메타신, 벤조나테이트, 카라미펜, 에디실레이트, 멘톨, 덱스트로메트로판 히드로브로마이드, 크로페디아놀 히드로클로라이드, 디펜히드라민, 슈도에페드린, 페닐에페린, 페닐프로판올아민, 슈도에페드린설페이트, 브롬페니르아민말레이트, 클로르페니르아민말레이트, 카르비녹사민말레이트, 클레마스틴푸마레이트, 덱스클로르페니르아민말레이트, 디펜히드라민히드로클로라이드, 디펜히드라민시트레이트, 디페닐피랄린히드로클로라이드, 독실아민숙시네이트, 프로메타진히드로클로라이드, 피릴아민말레이트, 트리펠렌아민시트레이트, 트리프롤리딘히드로클로라이드, 아크리바스틴, 로라타딘, 브롬페니르아민, 덱스브롬페니르아민, 구아이페네신, 이페칵, 칼슘아이오다이드, 테르핀히드레이트, 로페르아미드, 파모티딘, 라니티딘, 오메프라졸, 란소프라졸, 지방족알콜, 니코틴, 카페인, 스트리키닌, 피크로톡신, 펜틸렌테트라졸, 페니히단토인, 페노바르비탈, 프리미돈, 카르밤아제핀, 에토숙시미드, 메토숙시미드, 펜숙시미드, 트림메타디온, 디아제팜, 벤조디아제핀, 펜아세미드, 펜에투리드, 아세타졸아미드, 술티암, 브로마이드, 레보도파, 아만타딘, 몰핀, 헤로인, 히드로모르틴, 메토폰, 옥시모르폰, 레보르판올, 코데인, 히드로코돈, 자이코돈, 날노르핀, 날록손, 날트렉손, 살리실레이트, 페닐부타존, 인도메타신, 펜아세틴, 클로르프로마진, 메토트리메프라진, 할로페리돌, 클로자핀, 레세르핀, 이미프라민, 트라닐시프로민, 페넬진, 리듐, 아포모르핀, 실데나필, 타다라필, 바데나필, 온단세트론, 도네피질, 졸피뎀타르타레이트, 그라니세트론, 몬테루카스트, 폴코딘, 부틸스코폴아민, 펜타닐시트레이트, 염산옥시코돈, 염산부프레놀핀, 에시탈로프램옥살레이트, 리바스티그민타르타레이트, 에소메프라졸 마그네슘, 아리피프라졸, 졸미트립탄, 리자트립탄 벤조에이트, 텔미사르탄, 리스페리돈, 벤조카인, 세트리진히드로클로라이드, 밤부테롤 히드로클로라이드, 갈란타민 히드로브로마이드, 니카르디핀 히드로클로라이드, 파록세틴 히드로클로라이드, 멜록시캄, 톨테리딘타르타레이트, 독사조신 메실레이트 및 이들의 약제학적으로 허용가능한 염으로 이루어진 군에서 선택되는 1종 이상을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다. Specifically, 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 Amine Maleate, Diphenhydramine Hydrochloride, Diphenhydramine Citrate, Diphenylpyraline Hydrochloride, Doxylamine Suk Sinate, promethazine hydrochloride, pyrylamine maleate, tripyleneamine citrate, triprolidine hydrochloride, acribastin, loratadine, bromfenyramine, dexbromfenyramine, guapenesine, Ipecac, calcium iodide, terpinhydrate, loperamide, pamotidine, ranitidine, omeprazole, lansoprazole, aliphatic alcohol, nicotine, caffeine, strikinin, picrotoxin, pentylenetetrazole, phenihidantoin , Phenobarbital, primidone, carbamazepine, etosuccimid, metosuccimid, pensuccimid, trimmedadione, diazepam, benzodiazepines, phenacemid, peneturide, acetazolamide, sultiam, bromide, levodopa, Amantadine, morphine, heroin, hydromortin, methopone, oxymorphone, levorpanol, codeine, hydrocodone, gycodone, nalnorphine, naloxone, naltrexone, salicylate, phenylbu John, indomethacin, phenacetin, chlorpromazine, methotreeprazine, haloperidol, clozapine, reserpin, imipramine, tranilciprofin, phenelzin, iridium, apomorphine, sildenafil, tadalafil, vardenafil, Ondansetron, donepezil, zolpidem tartrate, granitone, montelukast, polcodine, butylscopolamine, fentanyl citrate, oxycodone hydrochloride, buprenoline hydrochloride, ecithalopram oxalate, rivastigmine tartarate , Esomeprazole Magnesium, Aripiprazole, Zolmitriptan, Rizatriptan Benzoate, Telmisartan, Risperidone, Benzocaine, Cetrizine Hydrochloride, Bambuterol Hydrochloride, Galantamine Hydrobromide, Nicardipine Hydrochloride, Paroxetine Hydrochloride, meloxycamp, tolteridine tartarate, doxazosin mesylate and their pharmaceutically acceptable It is one containing at least one element selected from the group consisting of, but not limited thereto.
일 구현예에 있어서, 상기 필름 제제는 4O℃에서 상대습도 75% 하에서 6 개월 동안 저장 후에 상기 의학적 활성 성분으로부터 유래된 불순물이 2.7 중량% 이하 또는 1.7 중량% 이하로 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.In one embodiment, 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.
일 구현예에 있어서, 상기 의학적 활성 성분이 몬테루카스트 나트륨이고, 상기 몬테루카스트 나트륨을 의학적 활성성분으로 포함하는 상기 속용 필름 제제가 생물학적 동등성을 갖는 것일 수 있으나, 이에 제한되는 것은 아니다.In one embodiment, the medical active ingredient is montelukast sodium, and the fast-acting film formulation including montelukast sodium as the medical active ingredient may be biologically equivalent, but is not limited thereto.
일 구현예에 있어서, 상기 몬테루카스트 나트륨을 의학적 활성성분으로 포함하는 안정한 경구용 속용 필름 제제는, 빛을 차단 또는 빛의 양을 50 Lux 이하로 감소시킨 분위기에서 제조된 것일 수 있으나, 이에 제한되는 것은 아니다.In one embodiment, 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.
일 구현예에 있어서, 본원에 따른 상기 속용 필름 제제가 상기 의학적 활성성분으로서 몬테루카스트의 염을 포함하는 경우, 상기 항산화 상승제로서 인산염을 포함함으로써, 상기 몬테루카스트의 염의 분해에 기인된 불순물 생성을 억제하는데 특히 효과적일 수 있으나, 이에 제한되는 것은 아니다. 일 구현예에 있어서, 본원에 따른 상기 속용 필름 제제가 상기 의학적 활성성분이 몬테루카스트의 염을 포함하는 경우, 상기 인산염은 포타슘디하이드로겐포스페이트, 디포타슘포스페이트, 또는 이들의 조합을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.In one embodiment, when 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. In one embodiment, when the fast-acting film preparation according to the present application includes the salt of montelukast, the phosphate salt may include potassium dihydrogen phosphate, dipotassium phosphate, or a combination thereof. However, the present invention is not limited thereto.
일 구현예에 있어서, 상기 몬테루카스트 나트륨을 의학적 활성성분으로 포함하는 안정한 경구용 속용 필름 제제는, 상기 항산화제로서 BHA (butylated hydroxyanisole), BHT(butylated hydroxytoluene) 또는 이들의 조합을 포함함으로써, 상기 몬테루카스트의 염의 분해에 기인된 불순물 생성을 억제하는데 특히 효과적일 수 있으나, 이에 제한되는 것은 아니다. In one embodiment, 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.
일 구현예에 있어서, 상기 몬테루카스트 나트륨을 의학적 활성성분으로 포함하는 안정한 경구용 속용 필름 제제는, 상기 인산염 및 상기 항산화제를 동시에 포함함으로써, 상기 몬테루카스트의 염의 분해에 기인된 불순물 생성을 억제하는데 특히 효과적일 수 있으나, 이에 제한되는 것은 아니다. In one embodiment, 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.
일 구현예에 있어서, 상기 몬테루카스트 나트륨을 의학적 활성성분으로 포함하는 안정한 경구용 속용 필름 제제는, 4O℃에서 상대습도 75% 하에서 6 개월 동안 저장 후에 상기 몬테루카스트로부터 유래된 불순물이 2.7 중량% 이하 또는 1.7 중량% 이하일 수 있으나, 이에 제한되는 것은 아니다. In one embodiment, 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.
일 구현예에 있어서, 상기 몬테루카스트로부터 유래된 불순물이 몬테루카스트의 설폭사이드, 몬테루카스트의 cis-이성질체, 몬테루카스트의 케토카비놀 또는 이들의 조합을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.In one embodiment, 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.
일 구현예에 있어서, 상기 몬테루카스트 나트륨을 의학적 활성성분으로 포함하는 안정한 경구용 속용 필름 제제는, 4O℃에서 상대습도 75% 하에서 6 개월 동안 저장 후에 몬테루카스트의 설폭사이드가 2.5 중량% 이하 또는 1.5 중량% 이하일 수 있으나, 이에 제한되는 것은 아니다.In one embodiment, 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.
일 구현예에 있어서, 상기 몬테루카스트 나트륨을 의학적 활성성분으로 포함하는 안정한 경구용 속용 필름 제제는, 4O℃에서 상대습도 75% 하에서 6 개월 동안 저장 후에 상기 몬테루카스트의 cis-이성질체가 0.1 중량% 이하일 수 있으나, 이에 제한되는 것은 아니다. In one embodiment, 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. However, the present invention is not limited thereto.
일 구현예에 있어서, 상기 몬테루카스트 나트륨을 의학적 활성성분으로 포함하는 안정한 경구용 속용 필름 제제는, 4O℃에서 상대습도 75% 하에서 6 개월 동안 저장 후에 상기 몬테루카스트의 케토카비놀이 0.1 중량% 이하일 수 있으나, 이에 제한되는 것은 아니다.In one embodiment, 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.
일 구현예에 있어서, 빛, 열 및 pH에 불안정한 몬테루카스트 나트륨을 사용해 불순물의 함량이 2.7% 미만인 몬테루카스트 구강붕해 필름 제제를 만들기 위해서는 온도, pH의 조절과 빛의 차단이 필요하다.In one embodiment, 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.
일 구현예에 있어서, 상기 몬테루카스트 나트륨을 의학적 활성성분으로 포함하는 안정한 경구용 속용 필름 제제는, 하기와 같이 제조될 수 있다. 즉, 빛이 차단된 반응기에서 물 또는 물과 에탄올의 혼합액에 인산염과 같은 항산화 상승제를 용해 또는 분산시키고, pH를 8 내지 10으로 조절한 다음 온도를 30℃ 이하로 조절하고 유화제, 향료, 감미제, 증점제, 보습제, 색소, 이형제 및 항산화제를 순차적으로 첨가한 뒤 몬테루카스트 나트륨을 투입하고 분산이 잘 되도록 충분한 시간 동안 교반시킨다. 몬테루카스트 나트륨이 잘 용해된 후 필름형성제인 수용성 고분자를 넣고 성형하기에 적당한 용액을 제조하며, 이때의 점도는 4,000 - 12,000 CPS인 것이 바람직하나, 이에 제한되는 것은 아니다. 이때 pH가 중성 또는 산성 영역이고 온도가 70℃ 이상에서는 불순물이 다량 발생하므로, pH가 알카리 영역이고 온도가 30℃이하인 조건에서 조액하고 성형한 뒤 빛과 공기가 차단되는 포장을 실시해 보관하면 유연물질의 함량이 2.7% 미만인 몬테루카스트 구강붕해 필름을 제조할 수 있다.In one embodiment, 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. After montelukast sodium is well dissolved, 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. At this time, since the impurities are generated in the neutral or acidic region and the temperature is 70 ℃ or higher, the solution is prepared by preparing and molding in the condition that the pH is in the alkaline region and the temperature is 30 ℃ 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%.
예를 들어, 특히 몬테루카스트-함유 제제의 경우 몬테루카스트로부터 유래된 불순물로서 설폭사이드(sulfoxide), cis-이성질체(cis-isomer), 및 케토카르비놀(ketocarbinol)을 불순물로서 각각 2.5%, 0.1%, 및 0.1% 이하로 규제하고 있다. 본원의 일 구현예에 있어서, 상기 몬테루카스트의 설폭사이드는, 상기 항산화 상승제로서 인산염을 포함하여 사용함으로써 2.5 중량% 이하로 감소시킬 수 있으며, cis-이성질체의 경우 제조시 빛의 조사량, 즉 Lux의 조절에 의해 0.1 중량% 이하로 감소시킬 수 있다. 본원의 일 구현예에 있어서, 상기 몬테루카스트-유래의 또 다른 불순물인 케토카르비놀의 경우에는 BHA, BHT과 같은 산화방지제의 첨가에 의해 0.1 중량% 이하로 감소시킬 수 있다. 특히, 케토카르비놀의 경우 전체 원료 투입량 대비 상기 산화방지제 0.015 중량% 내지 0.02 중량% 사용으로 안정한 속용 필름 제제를 만들 수 있다. 이에 따라, 가속 6개월 보관시 (40℃,RH 75% 조건 하) 상기 몬테루카스트-유래 불순물들의 함량이 규제치 이하로 감소될 수 있다.For example, especially for montelukast-containing preparations, sulfoxide, cis-isomer, and ketocarbinol as impurities derived from montelukast are 2.5%, 0.1%, and Regulated below 0.1%. In one embodiment of the present application, 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. In one embodiment of the present application, 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. In particular, in the case of 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).
본원의 다른 구현예에 있어서, 상기 안정한 경구용 속용 필름 제제가 함유하는 의학적 활성 성분으로서 포함하는 온단세트론 염이 온단세트론 히드로클로라이드이고, 상기 온단세트론 히드로클로라이드를 의학적 활성성분으로 포함하는 속용 필름 제제가 생물학적 동등성을 갖는 것일 수 있다.In another embodiment of the present application, 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.
본원의 다른 구현예에 있어서, 상기 안정한 경구용 속용 필름 제제가 함유하는 의학적 활성 성분으로서 포함하는 상기 실데나필 염이 실데나필 시트레이트이고, 상기 실데나필 시트레이트를 의학적 활성성분으로 포함하는 속용 필름 제제가 생물학적 동등성을 갖는 것일 수 있다.In another embodiment of the present application, the sildenafil salt comprising the stable active oral fast-acting film preparation as a medically active ingredient is sildenafil citrate, and the rapid-release film preparation comprising the sildenafil citrate as a medically active ingredient is biocompatible. It may be to have.
일 구현예에 있어서, 상기 의학적 활성성분은 상기 속용 필름 제제의 총중량 기준으로 1 중량% 내지 20 중량%일 수 있으나 이에 제한되는 것은 아니다. 예를 들어, 상기 의학적 활성성분이 몬테루카스트 나트륨인 경우, 그의 함량은 상기 속용 필름 제제의 총 중량 기준으로 10 중량% 내지 20 중량%일 수 있으나, 이에 제한되는 것은 아니다.In one embodiment, 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. For example, when 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.
일 구현예에 있어서, 상기 의학적 활성 성분을 함유하는 안정한 경구용 속용 필름 제제는, 1종 이상의 의학적 활성성분, 상기 산화방지제, 상기 항산화 상승제, 1종 이상의 수용성 고분자, 후미 개선제, 및 맛 차단제로서 1종 이상의 제 1 감미제를 포함하여 필름 형태로 성형된 것일 수 있으나, 이에 제한되는 것은 아니다.In one embodiment, 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.
일 구현예에 있어서, 상기 후미 개선제는 스테비오사이드계 감미제를 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다. 예를 들어, 상기 의학적 활성 성분을 함유하는 안정한 경구용 속용 필름 제제는, 상기 속용 필름 제제의 전체 중량 기준으로, 상기 스테비오사이드계 감미제 및 고감미 감미제로서 상기 제 1 감미제를 각각 0.1 내지 10 중량% 함유하고, 상기 스테비오사이드계 감미제 및 제 1 감미제는 1:3 내지 3:1의 비율(w/w)로 함유되는 것일 수 있으나, 이에 제한되는 것은 아니다.In one embodiment, the after-improving agent may be to include a stevioside-based sweetener, but is not limited thereto. For example, 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 And 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.
일 구현예에 있어서, 본원의 상기 속용 필름 제제는 고감미 감미제를 포함할 수 있으나, 이에 제한되는 것은 아니다. 불쾌한 맛을 나타내는 약물과 고감미 감미제로서 상기 제 1 감미제를 물이나 오일에 용해시키고 유화시켜 수용성 고분자 및 기타 첨가제와 혼합하여 속용 필름을 성형한다. In one embodiment, 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.
일 구현예에 있어서, 고감미 감미제로서 상기 제 1 감미제는 아스파탐, 아세설팜염, 슈크랄로스, 사카린염, 네오타임, 사이클라메이트염, 타우마틴, 나한과 추출물, 및 감초 추출물로 이루어진 군에서 선택되는 하나 이상의 고감미 감미제를 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다. 더욱 바람직하게는 아스파탐, 슈크랄로스, 네오타임, 및 아세설팜 염에서 선택되는 하나 이상의 고감미 감미제를 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다. 일 구현예에 있어서, 상기 제 1 감미제의 경시 최대 감미는, 아세설팜 칼륨이 제일 먼저 발현이 되고, 아스파탐, 슈크랄로스, 스테비오사이드의 순으로 최대 감미가 발현된다. 따라서 약물이 구강에서 흡수되고 남았을 때 느껴지는 불쾌한 맛의 제어에는 감미가 늦게 발현되는 스테비오사이드가 바람직하나, 이에 제한되는 것은 아니다.In one embodiment, 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. In one embodiment, 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.
일 구현예에 있어서, 불쾌한 맛이 강한 약품의 경우에는 후미에서 특히 고미 및 불쾌한 맛이 강하게 느껴지므로, 예를 들어, 전체중량 대비 0.1 내지 10 중량%(w/w)의 스테비오사이드계 감미제 즉, 스테비오사이드 및/또는 이의 유도체를 후미 개선제로서 상기 고감미 감미제로서 제 1 감미제와 병용하면 고미 및 불쾌한 맛을 차폐할 수 있으나, 이에 제한되는 것은 아니다.In one embodiment, in the case of 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, The use of 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.
일 구현예에 있어서, 스테비오사이드의 구체적인 예로는, (주)대평에서 생산되는 스텐비텐라이트(스테비오사이드 98% 이상), 스텐비텐리치 (효소처리 스테비아 100%), 스테비아추출물 REB-A 73%(레바우디오사이드 A 73% 이상) 및 레바텐 97% (레바우디오사이드 A 97% 이상) 등을 들 수 있으나, 이에 제한되는 것은 아니다.In one embodiment, specific examples of stevioside 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.
상기에서, 효소 처리 스테비아는 당전이 효소를 사용하여, 스테비아 추출물에 글루코스를 부가한 제품으로, 스테비오사이드의 고유한 쓴맛을 줄이고, 용해성을 높인 미질 개선품이다. 또한, 레바텐 97%는 스테비아의 감미성분 7가지 중 가장 감미도가 높고, 감미질이 우수한 성분으로서, 스테비아에서 별도의 분리조작을 통해 생산된다.In the above, 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. In addition, 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.
예를 들어, 상기 수용성 고분자는 필름형성제로서 사용되는 것으로서, 풀루란, 젤라틴, 펙틴, 저점도 펙틴, 하이드록시프로필메틸셀룰로오스, 저점도 하이드록시프로필메틸셀룰로오스, 하이드록시에틸셀룰로오스, 하이드록시프로필 셀룰로오스, 카르복시메틸셀룰로오스, 폴리비닐알콜, 폴리아크릴산, 메틸메타아크릴레이트 공중합체, 카르복시비닐 중합체, 폴리에틸렌글리콜, 알긴산, 저점도 알긴산, 알긴산 나트륨, 카라기난, 변성 전분, 카제인, 유장단백분리물, 콩단백분리물, 제인, 레반, 엘시난, 글루텐, 아카시아검, 카라기난, 아라비아 검, 구아 검, 로커스트빈 검, 잔탄 검, 겔란 검 및 아가로 이루어진 군으로부터 선택되는 하나 이상의 수용성 고분자를 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다. 바람직하게는, 상기 수용성 고분자는 풀루란, 젤라틴, 펙틴, 저점도 펙틴, 저점도 알긴산, 하이드록시프로필메틸셀룰로오스 및 변성 전분으로 이루어진 군으로부터 선택되는 하나 이상의 수용성 고분자를 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.For example, 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. Preferably, 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.
예를 들어, 상기 수용성 고분자는 속용 필름 전체중량 대비, 50~90 중량%(w/w), 바람직하게는 60~80 중량%(w/w), 보다 바람직하게는 60~70 중량%(w/w)를 함유할 수 있으나, 이에 제한되는 것은 아니다.For example, 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.
일 구현예에 있어서, 상기 의학적 활성 성분을 함유하는 안정한 경구용 속용 필름 제제는, 충전제, 타액 자극제, 증점제, 가소제, 산미제, 향료, 유화제, 계면활성제, 결합제, 보전제, 착색제, 제 2 감미제, 보습제, 색소, 청량제 및 이형제로 이루어진 군 중에서 선택된 1종 이상의 약학적으로 허용가능한 첨가제를 추가로 포함할 수 있으나, 이에 제한되는 것은 아니다.In one embodiment, 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.
상기 추가 첨가제 성분들을 자세히 설명하면 다음과 같다. The additional additive components are described in detail as follows.
예를 들어, 상기 충전제는 구강에서 필름이 미끈거리는 특성을 감소시키고, 필름에 골격을 부여하는 역할을 한다. 또한 필름끼리 점착되는 성질도 감소시키며, 끈적거림과 구강에서의 필름의 분해속도와 약물의 용출속도를 조절할 수 있다. 상기 충전제는 속용 필름 전체중량 대비, 1 내지 15 중량%(w/w) 첨가될 수 있다. 상기 충전제의 비제한적 예로서, 미세결정 셀룰로오스, 셀룰로스 중합체, 탄산마그네슘, 탄산칼슘, 석회석 가루, 실리케이트, 점토, 활석, 이산화티타늄 및 인산칼슘으로 이루어진 군으로부터 선택되는 하나 이상의 성분을 포함할 수 있다.For example, 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.
예를 들어, 상기 가소제는 필름의 유연성을 조절할 때 사용될 수 있다. 가소제는 속용 필름 전체중량 대비, 0.1 내지 15 중량%(w/w) 첨가될 수 있다. 상기 가소제의 비제한적 예로서, 솔비톨, 말티톨, 자일리톨, 글리세린, 폴리에틸렌글리콜, 프로필렌글리콜, 수첨물엿, 물엿, 글리세린, 트리아세틴, 글리세롤올레이트, 자당 지방산에스테르 및 중쇄 지방산으로 이루어진 군으로부터 선택되는 하나 이상의 성분을 포함할 수 있다.For example, 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.
예를 들어, 상기 제 2 감미제는 상기 필름 제제의 전체중량 기준으로 0.1 내지 10 중량%(w/w) 첨가될 수 있다. 상기 제 2 감미제의 비제한적 예로서, 아스파탐, 아세설팜염, 슈크랄로스, 사카린염, 네오타임, 사이클라메이트염, 타우마틴, 나한과 추출물, 감초 추출물, 스텐비텐라이트(스테비오사이드 98% 이상), 스텐비텐리치 (효소처리 스테비아 100%), 스테비아추출물 REB-A 73%(레바우디오사이드 A 73% 이상) 및 레바텐 97%(레바우디오사이드 A 97% 이상), 설탕, 포도당, 말토스, 올리고당, 덱스트린, 알파 사이크로덱스트린, 베타 사이크로덱스트린, 감마 사이크로덱스트린, 메틸 베타 사이크로덱스트린, 하이드록시프로필 베타 사이크로덱스트린, 클러스터 덱스트린, 난소화성덱스트린, 수첨 난소화성덱스트린, 전화당, 과당, 락토스, 갈락토스, 물엿, 솔비톨, 말티톨, 자일리톨, 에리스리톨, 수첨물엿, 만니톨, 및 트레할로스에서 선택되는 하나 이상을 포함할 수 있다. For example, the second sweetener may be added 0.1 to 10% by weight (w / w) based on the total weight of the film formulation. As a non-limiting example of 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, cluster dextrins, indigestible dextrins, hydrogenated indigestible dextrins, invert sugar , Fructose, lactose, galactose, syrup, sorbitol, maltitol, xylitol, erythritol, hydrogenated syrup, mannitol, and trehalose.
예를 들어, 상기 유화제는 글리세린지방산에스테르, 슈크로스지방산에스테르, 레시틴, 효소처리레시틴, 폴리솔르베이트, 솔비탄지방산에스테르 및 프로필렌글리콜지방산에스테르로 이루어진 군으로부터 선택되는 하나 이상의 성분일 수 있으나, 이에 제한되는 것은 아니다.For example, 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.
본원에 따른 상기 안정한 경구용 속용 필름 제제는 또한 산미제를 추가로 포함할 수 있다. 상기 산미제는 감미제와 함께 맛을 조절하며, 식용 필름이 잘 용해될 수 있도록 침의 발생을 자극하는 역할을 할 수 있다. 상기 산미제는 상기 필름 제제 전체중량 대비, 0.1 내지 10 중량%(w/w) 첨가될 수 있다. 상기 산미제의 비제한적 예로서, 구연산, 사과산, 푸말산, 타르타르산, 아스코르브산, 숙신산, 아디핀산 및 락트산으로 이루어진 군으로부터 선택되는 하나 이상의 성분을 포함할 수 있다.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.
본원에 따른 상기 안정한 경구용 속용 필름 제제는 또한 향료를 포함할 수 있다. 상기 필름 제제는 구강 내에서 용해시켜 흡수 되는 제품이므로 적절한 향을 추가할 필요가 있다. 상기 향료는 천연 향료, 인공향료 또는 이들의 혼합물일 수 있다.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.
상기 천연 향료는 식물의 잎, 꽃, 열매 등으로부터의 추출물, 식물의 오일 등일 수 있다. 식물의 오일은 스피어민트오일, 계피오일, 페퍼민트 오일, 레몬 오일, 정향(clove) 오일, 베이(bay) 오일, 백리향(thyme) 오일, 삼나무잎(cedar leaf) 오일, 육두구(nutmeg) 오일, 세이지(sage) 오일 및 아몬드(almond) 오일 등을 포함한다. 또한 인공 향료로는 레몬, 오렌지, 포도, 라임, 딸기 등의 과일의 인공합성 과일향 및 바닐라, 초코렛, 커피, 코코아, 솔잎, 인삼, 홍삼, 시트러스와 같은 인공 합성향이 사용될 수 있다.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. In addition, 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.
상기 향료의 사용량은 통상 사용되는 향료의 형태, 종류 및 원하는 강도와 같은 다수의 인자에 따라 달라지며, 일반적으로 속용 필름 전체중량 대비, 0.1 내지 15 중량%(w/w) 포함할 수 있다.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.
상기 오일 형태의 향료는 수용성 물질들과 혼화되도록 하기 위해 유화제를 함께 사용할 수 있다. 유화제는 향료의 종류 및 양에 따라 그 함량이 조절될 수 있으며, 일반적으로 속용 필름 전체중량 대비, 0.1 내지 10 중량%(w/w) 첨가될 수 있다. 비제한적 예로서, 상기 유화제는 글리세린지방산에스테르, 슈크로스지방산에스테르, 레시틴, 효소처리레시틴, 폴리솔르베이트, 솔비탄지방산 에스테르 및 프로필렌글리콜지방산에스테르로 이루어진 군으로부터 선택되는 하나 이상의 성분일 수 있다.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. As a non-limiting example, 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.
또한, 본원에 따른 상기 안정한 경구용 속용 필름 제제는 제품에 알맞은 색소를 포함할 수 있다. 상기 색소는 필요에 따라 그 함량을 적절히 조절할 수 있으며, 일반적으로 식용 필름 전체중량 대비, 0.01 내지 10 중량%(w/w) 첨가될 수 있다. 상기 색소는 천연 또는 합성 색소일 수 있다.In addition, 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.
본원에 따른 상기 안정한 경구용 속용 필름 제제는 또한 청량제를 추가로 포함할 수 있다. 청량제는 이에 제한되는 것은 아니나. 예를 들어, 상기 청량제는 WS3, WS23 또는 퀘스타이스-엘일 수 있다. 청량제는 필요에 따라 그 함량을 적절히 조절할 수 있으며, 일반적으로 속용 필름 전체중량 대비, 0.01 내지 5 중량%(w/w) 첨가될 수 있다.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. For example, 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.
본원에 따른 상기 안정한 경구용 속용 필름 제제는 매우 얇은 막 상태에서, 적절한 범위의 인장 강도와 강인성을 유지하는 박막 필름을 형성하는 것이 바람직할 것이다. 비제한적 예로서, 본원에 따른 상기 안정한 경구용 속용 필름 제제의 두께는 약 20 ㎛ 내지 약 200 ㎛이고, 바람직하게는 약 40 ㎛ 내지 약 100 ㎛이다.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. As a non-limiting example, the thickness of the stable oral rapid dissolution film preparation according to the present application is from about 20 μm to about 200 μm, preferably from about 40 μm to about 100 μm.
이하, 본원에 대하여 실시예를 이용하여 좀더 구체적으로 설명하지만, 본원이 이에 제한되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples, but the present application is not limited thereto.
이하 실시예 및 비교예에서 사용된 물질들의 명칭 및 구입처는 하기 표 1에 나타낸 바와 같다: The name and place of purchase of the materials used in the following examples and comparative examples are shown in Table 1 below:
또한, 이하 실시예 및 비교예에서 HPLC (high performance liquid chromatography)를 이용한 유연물질 분석조건은 하기와 같다:In addition, in the following Examples and Comparative Examples, the conditions for analysis of the flexible material using high performance liquid chromatography (HPLC) are as follows:
- 칼럼 : Phenomenex LUNA phenyl-hexyl, 10 cm x 4.6 mm ID, 3 ㎛Column: Phenomenex LUNA phenyl-hexyl, 10 cm x 4.6 mm ID, 3 μm
- Guard 칼럼 : Phenomenex Phenyl(phenylpropyl), 4 mm x 3.0 ID,Guard column: Phenomenex Phenyl (phenylpropyl), 4 mm x 3.0 ID,
- 유속 : 1.3 ml/min-Flow rate: 1.3 ml / min
- 칼럼온도 : 40℃-Column temperature: 40 ℃
- 주입량 : 15 ㎕Injection volume: 15 μl
- 검출기 : 자의부흡광광도계(측정파장 : 255 nm)Detector: Self-absorption spectrophotometer (wavelength: 255 nm)
- 지속시간 : 30분Duration: 30 minutes
- 이동상 A : 0.2% 트리플루오로아세트산 수용액Mobile phase A: 0.2% aqueous trifluoroacetic acid solution
- 이동상 B : 메탄올/아세토니트릴 : 60/40 Mobile phase B: methanol / acetonitrile: 60/40
<실시예 1><Example 1>
빛이 차단된 반응기에서 물 256 cc에 포타슘디하이드로겐포스페이트와 디포타슘포스페이트를 용해시키고, 온도를 30℃로 조절한 후 유화제, 향료, 감미제, 색소, 이형제, 증점제, 항산화제를 하기 표 2에 기재된 함량과 같이 순차적으로 첨가하였다. 항산화제로서 BHT와 BHA는 에탄올에 미리 용해시킨 후 투입하였다. 몬테루카스트나트륨을 18.2 g 투입하고 분산이 잘되도록 1 시간 동안 교반시켰다. 몬테루카스트나트륨을 잘 용해시킨 뒤 필름형성제인 풀루란을 첨가하고 성형하기에 적당한 용액(점도 약 7,000 cps)을 제조하였다. 약 80℃의 성형기에서 필름을 성형하고, 가로세로 2.2 cm x 3.7 cm의 크기로 잘라 알루미늄 파우치에 넣고 40℃, RH 75에서 6개월 가속 실험을 실시한 후 함량 및 유연물질을 HPLC를 이용하여 분석을 하였다. 분석결과는 하기 표 3에 기술하였다.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.
<실시예 2><Example 2>
빛이 차단된 반응기에서 물 256 cc에 포타슘디하이드로겐포스페이트와 디포타슘포스페이트를 용해시키고, 온도를 30℃로 조절한 후 유화제, 향료, 감미제, 색소, 이형제, 증점제, 항산화제를 표 2에 기재된 함량과 같이 순차적으로 첨가하였다. BHT와 BHA는 에탄올에 미리 용해시킨 후 투입하였다. 몬테루카스트나트륨을 15 g 투입한 후 분산이 잘되도록 1 시간 교반시켰다. 몬테루카스트나트륨을 잘 용해시킨 뒤 필름형성제인 풀루란을 첨가하고 성형하기에 적당한 용액(점도 약 7,000 cps)을 제조하였다. 약 80℃의 성형기에서 필름을 성형하고, 가로세로 2.2 cm x 3.7 cm의 크기로 잘라 알루미늄 파우치에 넣고 40℃, RH 75에서 6개월 가속 실험을 실시한 후 함량 및 유연물질 분석을 하였다. 분석결과는 하기 표 3에 기술하였다.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.
<실시예 3><Example 3>
빛이 차단된 반응기에서 물 256 cc에 폴리비닐알콜을 첨가하고 1 시간 85℃로 가열시켰다. 30℃로 냉각시킨 후 포타슘디하이드로겐포스페이트와 디포타슘포스페이트를을 용해시키고, 유화제, 향료, 감미제, 색소, 증점제, 이형제, 항산화제를 하기 표 2에 기재된 함량과 같이 순차적으로 첨가하였다. BHT와 BHA는 에탄올에 미리 용해시킨 후 투입하였다. 몬테루카스트나트륨을 16 g 투입하고 분산이 잘되도록 0.5 시간 동안 교반시켰다. 몬테루카스트나트륨을 잘 용해시킨 뒤 필름형성제인 풀루란을 첨가하고 성형하기에 적당한 용액(점도 약 7,000 cps)을 제조하였다. 약 80℃의 성형기에서 필름을 성형하고, 가로세로 2.2 cm x 3.7 cm의 크기로 잘라 알루미늄 파우치에 넣고 40℃, RH 75에서 6개월 가속 실험을 실시한 후 함량 및 유연물질 분석을 하였다. 분석결과는 하기 표 3에 기술하였다.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. 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.
<실시예 4><Example 4>
빛이 차단된 반응기에서 물 300 cc에 폴리비닐알콜을 넣고 1시간 동안 85℃로 가열하였다. 30℃로 냉각시킨 후 포타슘디하이드로겐포스페이트와 디포타슘포스페이트를 용해시키고, 유화제, 향료, 감미제, 색소, 증점제, 이형제, 항산화제를 하기 표 2에 기재된 함량과 같이 순차적으로 첨가하였다. BHT와 BHA는 에탄올에 미리 용해시킨 후 투입하였다. 몬테루카스트나트륨을 16 g 투입한 후 분산이 잘되도록 0.5시간 동안 교반시켰다. 몬테루카스트나트륨을 잘 용해시킨 뒤 필름형성제인 HPMC을 넣고 성형하기에 적당한 용액(점도 약 7,000 cps)을 제조하였다. 약 80℃의 성형기에서 필름을 성형하고, 가로세로 2.2 cm x 3.7 cm의 크기로 잘라 알루미늄 파우치에 넣고 40℃, RH 75에서 6개월 가속 실험을 실시한 후 함량 및 유연물질 분석을 하였다. 분석결과는 하기 표 3에 기술하였다.In a light-blocked reactor, 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.
<비교예 1>Comparative Example 1
빛이 차단된 반응기에서 물 256 cc에 인산을 용해시키고, pH를 9로 조절한 다음 온도를 70℃로 조절하고 유화제, 향료, 감미제, 보습제, 색소, 충전제, 이형제를 하기 표 2에 기재된 함량으로 순차적으로 첨가한 뒤 몬테루카스트나트륨을11.44 g 투입한 후 분산이 잘되도록 1 시간 동안 교반시켰다. 몬테루카스트나트륨을 잘 용해시킨 뒤 필름형성제인 풀루란을 넣고 성형하기에 적당한 용액를 제조하였다. 이때의 점도는 7,000 cps 이였다. 약 80℃의 성형기에서 필름을 성형하고, 가로세로 2.2 cm x 3.7 cm의 크기로 잘라 알루미늄 파우치에 넣고 40℃, RH 75에서 6개월 가속 실험을 실시한 후 함량 및 유연물질 분석을 하였다. 분석결과는 표 3에 기술하였다.In a light-blocked reactor, 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. After adding sequentially, 11.44 g of montelukast sodium was added, followed by stirring for 1 hour so that the dispersion was good. After dissolving montelukast sodium well, 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.
<비교예 2>Comparative Example 2
빛이 차단된 반응기에서 물 256 cc에 포타슘디하이드로겐포스페이트와 디포타슘포스페이트를 용해시켰다. 온도를 30℃로 조절하고 유화제, 향료, 감미제, 보습제, 색소, 증점제, 이형제를 하기 표 2에 기재된 함량과 같이 순차적으로 첨가한 뒤 몬테루카스트나트륨을 18.2 g 투입하고 분산이 잘되도록 1 시간 교반시켰다. 몬테루카스트나트륨을 잘 용해시킨 뒤 필름형성제인 풀루란을 넣고 성형하기에 적당한 용액(점도 약 7,000 cps)을 제조하였다. 약 80℃의 성형기에서 필름을 성형하고, 가로세로 2.2 cm x 3.7 cm의 크기로 잘라 알루미늄 파우치에 넣고 40℃, RH 75에서 6개월 가속 실험을 실시한 후 함량 및 유연물질 분석을 하였다. 분석결과는 하기 표 3에 기술하였다.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.
<비교예 3>Comparative Example 3
빛이 차단된 반응기에서 물 256 cc에 포타슘디하이드로겐포스페이트와 디포타슘포스페이트를 용해시키고, 온도를 30℃로 조절한 후 유화제, 향료, 감미제, 보습제, 색소, 증점제, 이형제를 하기 표 2에 기재된 함량과 같이 순차적으로 첨가하였다. 몬테루카스트나트륨을 18.2 g 투입한 후 분산이 잘되도록 1 시간 동안 교반시켰다. 몬테루카스트나트륨을 잘 용해시킨 뒤 필름형성제인 풀루란을 첨가하고 성형하기에 적당한 용액(점도 약 7,000 cps)을 제조하였다. 약 80℃의 성형기에서 필름을 성형하고, 가로세로 2.2 cm x 3.7 cm의 크기로 잘라 알루미늄 파우치에 넣고 40℃, RH 75에서 6개월 가속 실험을 실시한 후 함량 및 유연물질 분석을 하였다. 분석결과는 하기 표 3에 기술하였다.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.
<비교예 4><Comparative Example 4>
빛이 차단된 반응기에서 물 256 cc에 포타슘디하이드로겐포스페이트와 디포타슘포스페이트를을 용해시키고, 온도를 30℃로 조절한 후 유화제, 향료, 감미제, 보습제, 색소, 이형제, 증점제, 항산화제를 하기 표 2에 기재된 함량과 같이 순차적으로 첨가하였다. 항산화제로서 BHT와 BHA는 에탄올에 미리 녹인 후 투입하였다. 몬테루카스트나트륨을 18.2 g 투입한 후 분산이 잘되도록 1 시간 동안 교반시켰다. 몬테루카스트나트륨을 잘 용해시킨 뒤 필름형성제인 풀루란을 첨가하고 성형하기에 적당한 용액(점도 약 7,000 cps)을 제조하였다. 약 80℃의 성형기에서 필름을 성형하고, 가로세로 2.2 cm x 3.7 cm의 크기로 잘라 알루미늄 파우치에 넣고 40℃, RH 75에서 6개월 가속 실험을 실시한 후 함량 및 유연물질 분석을 하였다. 분석결과는 하기 표 3에 기술하였다.
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 .
상기 표 3에서 나타낸 바와 같이, 포타슘디하이드로겐포스페이트 및/또는 디포타슘포스페이트 등의 인산염 및 산화방지제로서 BHA 및/또는 BHT를 모두 포함하는 경우, 6 개월 가속실험(40℃, RH 75%)에서도 불순물(유연물질들)의 함량이 규제치 이하로 조절됨을 확인할 수 있었다.As shown in Table 3 above, in the case of containing both BHA and / or BHT as phosphate and antioxidant such as potassium dihydrogen phosphate and / or dipotassium phosphate, even in a 6 month accelerated experiment (40 ° C., RH 75%) It was confirmed that the content of impurities (flexible materials) is controlled to below the regulation value.
<실험예 1>Experimental Example 1
실시예 3의 조건에 따라 제조한 10 mg의 몬테루카스트 구강붕해 필름 제제(CHA Bio Montelukast 10 mg OTF), 시판되는 Singulair 10 mg 코팅정 및 Singulair 5 mg 츄어블 정제(Merck, USA)의 비교 용출을 0.5% SDS 용액에서 온도 37℃, rpm=50, 용출액 900ml의 조건에서 패들법으로 실시하였다. 결과는 도 1에 나타냈다. 도 1에서 나타난 바와 같이, 본원의 몬테루카스트 구강붕해 필름 제제가 시판 Singulair 제제와 용출면에서 큰 차이가 없음을 알 수 있다.Comparative dissolution of 10 mg of montelukast orally disintegrating film preparation (CHA Bio Montelukast 10 mg OTF), commercially available Singulair 10 mg coated tablets and Singulair 5 mg chewable tablets (Merck, USA) prepared according to the conditions of Example 3 was 0.5 It was carried out by paddle method in the conditions of temperature 37 ℃, rpm = 50, eluent 900ml in a% SDS solution. The results are shown in FIG. As shown in Figure 1, it can be seen that the montelukast orally disintegrating film formulation of the present application is not significantly different from the commercially available Singulair formulation in terms of elution.
이상, 구현예 및 실시예를 들어 본원을 상세하게 설명하였으나, 본원은 상기 구현예 및 실시예들에 한정되지 않으며, 여러 가지 다양한 형태로 변형될 수 있으며, 본원의 기술적 사상 내에서 당 분야에서 통상의 지식을 가진 자에 의하여 여러 가지 많은 변형이 가능함이 명백하다.Hereinbefore, the present invention has been described in detail with reference to the embodiments and examples, but the present invention is not limited to the above embodiments and embodiments, and may be modified in various forms, and is commonly used in the art within the technical spirit of the present application. It is evident that many variations are possible by those of skill in the art.
Claims (20)
- 의학적 활성 성분을 함유하는 안정한 경구용 속용 필름 제제로서,As a stable oral fast-acting film formulation containing a pharmaceutically active ingredient,산화방지제 및 항산화 상승제(synergist)를 동시에 함유하는, 안정한 경구용 속용 필름 제제.A stable oral fast-acting film formulation containing both an antioxidant and a synergist.
- 제 1 항에 있어서, The method of claim 1,상기 산화방지제는 BHA(butylated hydroxyanisole), BHT(butylated hydroxytoluene), 세사몰, 고시폴, 레시틴, 토코페롤류, 프로필갈레이트, 및 이들의 조합으로 이루어진 군에서 선택되는 것을 포함하는 것인, 안정한 경구용 속용 필름 제제.The antioxidant is stable oral, including those selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sesamol, gosipol, lecithin, tocopherols, propylgallate, and combinations thereof. Genus film formulation.
- 제 1 항에 있어서, The method of claim 1,상기 항산화 상승제는 인산염, 아스코빈산, 이소아스코빈산, 구연산, 주석산, 인산, 붕산, 염산, 피틴산, 인지방질 및 이들의 조합으로 이루어진 군에서 선택되는 것을 포함하는 것인, 안정한 경구용 속용 필름 제제.The antioxidant synergist comprises a one selected from the group consisting of phosphate, ascorbic acid, isoascobic acid, citric acid, tartaric acid, phosphoric acid, boric acid, hydrochloric acid, phytic acid, phospholipids and combinations thereof, stable oral film preparations for oral use. .
- 제 1 항에 있어서, The method of claim 1,상기 필름 제제의 총 중량 기준으로, 0.015 중량% 이상의 상기 산화방지제 및 0.1 중량% 이상의 상기 항산화 상승제를 함유하는, 안정한 경구용 속용 필름 제제.A stable oral rapid dissolution film formulation containing 0.015 wt% or more of the antioxidant and 0.1 wt% or more of the antioxidant synergist, based on the total weight of the film formulation.
- 제 3 항에 있어서, The method of claim 3, wherein상기 인산염은 포타슘디하이드로겐포스페이트, 디포타슘포스페이트, 또는 이들의 조합을 포함하는 것인, 안정한 경구용 속용 필름 제제.The phosphate salt comprises potassium dihydrogen phosphate, di potassium phosphate, or a combination thereof, stable oral film preparation for oral use.
- 제 1 항에 있어서, The method of claim 1,상기 의학적 활성성분은, 당뇨병치료제; 불면증치료제; 비뇨생식기치료제; 비만치료제; 효소제; 소화성궤양용제; 진해거담제; 피부질환치료제; 항구토제; 항우울제; 항히스타민제; 해열진통소염제; 호르몬제제; 순환기용치료제; 소화기관용치료제; 정신신경용제; 발기부전치료제; 골다공증치료제; 관절염치료제; 간질치료제; 근육이완제; 뇌기능개선제; 정신분열증치료제; 면역억제제; 항생제; 항암제; 항암치료보조제; 백신제; 구강청결제; 빈혈치료제; 변비치료제; 비타민; 영양제; 유산균제제; 종합감기약; 및 건강기능식품으로 이루어진 군으로부터 선택되는 하나 이상을 포함하는 것인, 안정한 경구용 속용 필름 제제.The medically active ingredient is a diabetes treatment agent; 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; Comprehensive cold medicine; And one or more selected from the group consisting of health functional foods.
- 제 6 항에 있어서, The method of claim 6,상기 의학적 활성성분은, 트리클로산, 세틸 피리듐클로라이드, 도미펜 브로마이드, 4차암모늄염, 아연화합물, 산귀나린, 플루오라이드, 알렉시딘, 옥토니딘, EDTA, 아스피린, 아세트아미노펜, 이부프로펜, 케토프로펜, 디플루니살, 페노프로펜칼슘, 나프록센, 톨메틴나트륨, 인도메타신, 벤조나테이트, 카라미펜, 에디실레이트, 멘톨, 덱스트로메트로판 히드로브로마이드, 크로페디아놀 히드로클로라이드, 디펜히드라민, 슈도에페드린, 페닐에페린, 페닐프로판올아민, 슈도에페드린설페이트, 브롬페니르아민말레이트, 클로르페니르아민말레이트, 카르비녹사민말레이트, 클레마스틴푸마레이트, 덱스클로르페니르아민말레이트, 디펜히드라민히드로클로라이드, 디펜히드라민시트레이트, 디페닐피랄린히드로클로라이드, 독실아민숙시네이트, 프로메타진히드로클로라이드, 피릴아민말레이트, 트리펠렌아민시트레이트, 트리프롤리딘히드로클로라이드, 아크리바스틴, 로라타딘, 브롬페니르아민, 덱스브롬페니르아민, 구아이페네신, 이페칵, 칼슘아이오다이드, 테르핀히드레이트, 로페르아미드, 파모티딘, 라니티딘, 오메프라졸, 란소프라졸, 지방족알콜, 니코틴, 카페인, 스트리키닌, 피크로톡신, 펜틸렌테트라졸, 페니히단토인, 페노바르비탈, 프리미돈, 카르밤아제핀, 에토숙시미드, 메토숙시미드, 펜숙시미드, 트림메타디온, 디아제팜, 벤조디아제핀, 펜아세미드, 펜에투리드, 아세타졸아미드, 술티암, 브로마이드, 레보도파, 아만타딘, 몰핀, 헤로인, 히드로모르틴, 메토폰, 옥시모르폰, 레보르판올, 코데인, 히드로코돈, 자이코돈, 날노르핀, 날록손, 날트렉손, 살리실레이트, 페닐부타존, 인도메타신, 펜아세틴, 클로르프로마진, 메토트리메프라진, 할로페리돌, 클로자핀, 레세르핀, 이미프라민, 트라닐시프로민, 페넬진, 리듐, 아포모르핀, 실데나필, 타다라필, 바데나필, 온단세트론, 도네피질, 졸피뎀타르타레이트, 그라니세트론, 몬테루카스트, 폴코딘, 부틸스코폴아민, 펜타닐시트레이트, 염산옥시코돈, 염산부프레놀핀, 에시탈로프램옥살레이트, 리바스티그민타르타레이트, 에소메프라졸 마그네슘, 아리피프라졸, 졸미트립탄, 리자트립탄 벤조에이트, 텔미사르탄, 리스페리돈, 벤조카인, 세트리진히드로클로라이드, 밤부테롤 히드로클로라이드, 갈란타민 히드로브로마이드, 니카르디핀 히드로클로라이드, 파록세틴 히드로클로라이드, 멜록시캄, 톨테리딘타르타레이트, 독사조신 메실레이트, 및 이들의 약제학적으로 허용가능한 염으로 이루어진 군에서 선택되는 1종 이상을 포함하는 것인, 안정한 경구용 속용 필름 제제.The active ingredient is triclosan, cetyl pyridium chloride, domiphen bromide, quaternary ammonium salt, zinc compound, acid guinarin, fluoride, alexidine, octonidine, EDTA, aspirin, acetaminophen, ibuprofen, ketoprofen, Diflunisal, Phenopropenecalcium, Naproxen, Tolmethinine Sodium, Indomethacin, Benzonatate, Caramiphene, Edsylate, Menthol, Dextromeropane Hydrobromide, Crofedianol Hydrochloride, Diphenhydramine, Pseudoephedrine, phenylephrine, phenylpropanolamine, pseudoephedrine sulfate, brompheniramine maleate, chlorpheniramine maleate, carbinoxamine maleate, clemastine fumarate, dexchlorpheniramine maleate, diphenhydramine Hydrochloride, Diphenhydramine Citrate, Diphenylpyrroline Hydrochloride, Doxylamine Succinate, Promethazin Drochloride, Pyrylamine Maleate, Tripelinamine Citrate, Triprolidine Hydrochloride, Acribastine, Loratadine, Bromfenyramine, Dexbromfenyramine, Guapefensin, Ifecac, Calcium Iodide Id, terpinhydrate, loperamide, pamotidine, ranitidine, omeprazole, lansoprazole, aliphatic alcohol, nicotine, caffeine, strikinin, picrotoxin, pentylenetetrazole, phenyhydrantoin, phenobarbital, primidone, Carbamezepine, etosuccimid, methosuccimid, pensuccimid, trimmethadione, diazepam, benzodiazepines, phenacemid, fenturide, acetazolamide, sultiam, bromide, levodopa, amantadine, morphine, heroin, Hydromortin, methopone, oxymorphone, levorpanol, codeine, hydrocodone, gycodone, nalnorphine, naloxone, naltrexone, salicylate, phenylbutazone, indomethacin, pena Tin, chlorpromazine, methotrimreprazine, haloperidol, clozapine, reserpin, imipramine, tranilcipromin, phenelzin, iridium, apomorphine, sildenafil, tadalafil, vardenafil, ondansetron, donepezil, zolpidem Tartarate, granitone, montelukast, polcodine, butylscopolamine, fentanyl citrate, oxycodone hydrochloride, buprenoline hydrochloride, escitalopram oxalate, rivastigmine tartarate, esomeprazole magnesium, Aripiprazole, zolmitriptan, rizatriptan benzoate, telmisartan, risperidone, benzocaine, cetrizine hydrochloride, bambuterol hydrochloride, galantamine hydrobromide, nicardidipine hydrochloride, paroxetine hydrochloride, melocampum, Tolteridine tartarate, doxazosin mesylate, and pharmaceutically acceptable salts thereof A stable oral rapid-release film formulation containing one or more selected.
- 제 1 항에 있어서, The method of claim 1,4O℃에서 상대습도 75% 하에서 6 개월 동안 저장 후에 상기 의학적 활성 성분으로부터 유래된 불순물이 2.7 중량% 이하인, 안정한 경구용 속용 필름 제제.A stable oral fast-acting film formulation having up to 2.7% by weight of impurities derived from the medically active ingredient after storage for 6 months at 75 ° C. at 75% relative humidity.
- 제 7 항에 있어서, The method of claim 7, wherein상기 몬테루카스트의 염이 몬테루카스트 나트륨이고, 상기 몬테루카스트 나트륨을 의학적 활성성분으로 포함하는 상기 속용 필름 제제가 생물학적 동등성을 갖는 것인, 안정한 경구용 속용 필름 제제.The salt of the montelukast is montelukast sodium, wherein the fast-acting film formulation containing the montelukast sodium as a medical active ingredient has a biological equivalence, stable oral film preparation for oral use.
- 제 9 항에 있어서, The method of claim 9,상기 항산화 상승제는 인산염을 포함하는 것인, 안정한 경구용 속용 필름 제제.The antioxidant synergist is to include a phosphate, stable oral fast-acting film formulation.
- 제 10 항에 있어서, The method of claim 10,상기 인산염은 포타슘디하이드로겐포스페이트, 디포타슘포스페이트, 또는 이들의 조합을 포함하는 것인, 안정한 경구용 속용 필름 제제.The phosphate salt comprises potassium dihydrogen phosphate, di potassium phosphate, or a combination thereof, stable oral film preparation for oral use.
- 제 9 항에 있어서, The method of claim 9,안정한 경구용 속용 필름 제제는 빛의 차단 또는 빛의 양을 50 Lux 이하로 감소시킨 분위기에서 제조된 것인, 안정한 경구용 속용 필름 제제.The stable oral rapid dissolution film formulation is prepared in an atmosphere in which light is blocked or the amount of light is reduced to 50 Lux or less.
- 제 9 항에 있어서, The method of claim 9,상기 항산화제는 BHA (butylated hydroxyanisole), BHT(butylated hydroxytoluene) 또는 이들의 조합을 포함하는 것인, 안정한 경구용 속용 필름 제제.Wherein the antioxidant is a butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) or a combination thereof, stable oral film preparation for oral use.
- 제 9 항에 있어서, The method of claim 9,4O℃에서 상대습도 75% 하에서 6 개월 동안 저장 후에 상기 몬테루카스트의 염으로부터 유래된 불순물이 2.7 중량% 이하인, 안정한 경구용 속용 필름 제제.A stable oral flux film formulation having less than 2.7% by weight of impurities derived from the salt of montelukast after 6 months storage at 75% relative humidity at 40 ° C.
- 제 9 항에 있어서, The method of claim 9,상기 몬테루카스트의 염으로부터 유래된 불순물이 몬테루카스트의 설폭사이드, 몬테루카스트의 cis-이성질체, 몬테루카스트의 케토카비놀 또는 이들의 조합을 포함하는 것인, 안정한 경구용 속용 필름 제제.The impurity derived from the salt of montelukast is a stable oral fast-acting film formulation comprising a sulfoxide of montelukast, cis-isomer of montelukast, ketocarbinol of montelukast or a combination thereof.
- 제 15 항에 있어서, The method of claim 15,4O℃에서 상대습도 75% 하에서 6 개월 동안 저장 후에 상기 몬테루카스트의 설폭사이드가 2.5 중량% 이하이고 상기 몬테루카스트의 cis-이성질체가 0.1 중량% 이하이고 상기 몬테루카스트의 케토카비놀이 0.1 중량% 이하인, 안정한 경구용 속용 필름 제제. Stable oral, after 6 months storage at 75 ° C. at 75% relative humidity, the montelukast sulfoxide is below 2.5 wt%, the montelukast cis-isomer is below 0.1 wt% and the montelukast ketokabinol is below 0.1 wt% Genus film formulation.
- 제 9 항에 있어서, The method of claim 9,상기 몬테루카스트 나트륨의 함량은 상기 속용 필름 제제의 총중량 기준으로 10 중량% 내지 20 중량%인, 안정한 경구용 속용 필름 제제.The content of the montelukast sodium is 10 to 20% by weight based on the total weight of the rapid film preparation, stable oral film preparation for stable.
- 제 1 항에 있어서, The method of claim 1,상기 의학적 활성 성분을 함유하는 안정한 경구용 속용 필름 제제는, 1종 이상의 의학적 활성성분, 상기 산화방지제, 상기 항산화 상승제, 1종 이상의 수용성 고분자, 후미 개선제, 및 맛 차단제로서 1종 이상의 제1 감미제를 포함하여 필름 형태로 성형된 것인, 안정한 경구용 속용 필름 제제. The stable oral fast-acting film preparation containing the medically active ingredient comprises at least one first sweetener as one or more medically active ingredients, the antioxidant, the antioxidant synergist, the one or more water soluble polymers, the aftertaste improver, and the taste blocker. It is molded in the form of a film, including, stable oral flux for preparations.
- 제 18 항에 있어서, The method of claim 18,상기 후미 개선제는 스테비오사이드계 감미제를 포함하는 것인, 안정한 경구용 속용 필름 제제.The after-improving agent comprises a stevioside-based sweetener, stable oral film preparation for oral use.
- 제 18 항에 있어서, The method of claim 18,상기 속용 필름 제제의 전체 중량 기준으로, 상기 후미 개선제 및 상기 제 1 감미제를 각각 0.1 내지 10 중량% 함유하고, 상기 후미 개선제 및 제 1 감미제는 1:3 내지 3:1의 비율(w/w)로 함유되는 것인, 안정한 경구용 속용 필름 제제.On the basis of the total weight of the fast-acting film formulation, each of the after-improving agent and the first sweetener contains 0.1 to 10% by weight, respectively, the after-improving agent and the first sweetening agent in a ratio of 1: 3 to 3: 1 (w / w) It is contained as, stable oral fast-acting film formulation.
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KR20100086140A (en) * | 2009-01-22 | 2010-07-30 | 일동제약주식회사 | A composition of fast dissolving tablets containing montelukast and it's manufacturing thereof |
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2011
- 2011-03-04 KR KR1020110019407A patent/KR101077468B1/en active IP Right Grant
- 2011-09-16 WO PCT/KR2011/006860 patent/WO2012121461A1/en active Application Filing
- 2011-10-18 TW TW100137614A patent/TW201302248A/en unknown
-
2012
- 2012-03-02 AR ARP120100701A patent/AR085610A1/en not_active Application Discontinuation
- 2012-03-02 UY UY0001033935A patent/UY33935A/en not_active Application Discontinuation
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US20080020024A1 (en) * | 1998-09-25 | 2008-01-24 | Neema Kulkarni | Fast dissolving orally consumable films |
US20060204559A1 (en) * | 2000-03-23 | 2006-09-14 | Bess William S | Fast dissolving orally consumable films containing an ion exchange resin as a taste masking agent |
KR20050048056A (en) * | 2003-11-18 | 2005-05-24 | (주)케이비피 | Composition for oral consumable film |
US20070184108A1 (en) * | 2006-02-09 | 2007-08-09 | Julia Hrakovsky | Stable pharmaceutical formulations of montelukast sodium |
KR20080023873A (en) * | 2006-09-12 | 2008-03-17 | (주) 아모젠 | Orally comsumable films |
US20100305080A1 (en) * | 2007-10-25 | 2010-12-02 | O'shea Paul | Novel Crystalline Salts of Montelukast |
KR20100086140A (en) * | 2009-01-22 | 2010-07-30 | 일동제약주식회사 | A composition of fast dissolving tablets containing montelukast and it's manufacturing thereof |
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US10195153B2 (en) | 2013-08-12 | 2019-02-05 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded immediate release abuse deterrent pill |
US10639281B2 (en) | 2013-08-12 | 2020-05-05 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded immediate release abuse deterrent pill |
US10172797B2 (en) | 2013-12-17 | 2019-01-08 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded extended 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 |
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 (en) * | 2015-04-04 | 2015-07-22 | 齐鲁制药有限公司 | Stable Montelukast oral film preparation |
EP3528796A4 (en) * | 2016-10-20 | 2020-04-29 | Intelgenx Corp. | Device and method of treating conditions associated with neuroinflammation |
US11007144B2 (en) | 2016-11-15 | 2021-05-18 | Klaria Pharma Holding Ab | Pharmaceutical formulation |
WO2018176149A1 (en) * | 2017-03-30 | 2018-10-04 | Intelgenx Corp. | Method of treatment and device for the improved bioavailability of leukotriene receptor antagonists |
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 |
WO2019224323A1 (en) * | 2018-05-23 | 2019-11-28 | Klaria Pharma Holding Ab | Pharmaceutical formulation |
US12005140B2 (en) | 2018-05-23 | 2024-06-11 | Klaria Pharma Holding Ab | Pharmaceutical formulation |
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 |
---|---|
UY33935A (en) | 2012-06-29 |
AR085610A1 (en) | 2013-10-16 |
TW201302248A (en) | 2013-01-16 |
KR101077468B1 (en) | 2011-11-07 |
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