WO2012121461A1

WO2012121461A1 - Stable fast-dissolving film formulation for oral dosage form

Info

Publication number: WO2012121461A1
Application number: PCT/KR2011/006860
Authority: WO
Inventors: 정경태; 전창욱
Original assignee: (주)차바이오앤디오스텍
Priority date: 2011-03-04
Filing date: 2011-09-16
Publication date: 2012-09-13
Also published as: UY33935A; KR101077468B1; TW201302248A; AR085610A1

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

Stable Oral Film Preparation

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 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.

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.

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.

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.

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:

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.

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 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.

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.

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.

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.

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. 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.

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.

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.

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.

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.

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."

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.

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.

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.

In one embodiment, the phosphate salt may include potassium dihydrogen phosphate, dipotassium phosphate or a combination thereof, but is not limited thereto.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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%.

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

The additional additive components are described in detail as follows.

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.

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.

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.

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.

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. 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.

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. 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.

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.

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.

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.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present application is not limited thereto.

The name and place of purchase of the materials used in the following examples and comparative examples are shown in Table 1 below:

Table 1

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:

Column: Phenomenex LUNA phenyl-hexyl, 10 cm x 4.6 mm ID, 3 μm

Guard column: Phenomenex Phenyl (phenylpropyl), 4 mm x 3.0 ID,

-Flow rate: 1.3 ml / min

-Column temperature: 40 ℃

Injection volume: 15 μl

Detector: Self-absorption spectrophotometer (wavelength: 255 nm)

Duration: 30 minutes

Mobile phase A: 0.2% aqueous trifluoroacetic acid solution

Mobile phase B: methanol / acetonitrile: 60/40

<실시예 1><Example 1>

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>

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>

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>

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

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

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

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>

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 .

TABLE 2

TABLE 3

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

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.

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

As a stable oral fast-acting film formulation containing a pharmaceutically active ingredient,

A stable oral fast-acting film formulation containing both an antioxidant and a synergist.
The method of claim 1,

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.
The method of claim 1,

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. .
The method of claim 1,

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.
The method of claim 3, wherein

The phosphate salt comprises potassium dihydrogen phosphate, di potassium phosphate, or a combination thereof, stable oral film preparation for oral use.
The method of claim 1,

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.
The method of claim 6,

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.
The method of claim 1,

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.
The method of claim 7, wherein

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.
The method of claim 9,

The antioxidant synergist is to include a phosphate, stable oral fast-acting film formulation.
The method of claim 10,

The phosphate salt comprises potassium dihydrogen phosphate, di potassium phosphate, or a combination thereof, stable oral film preparation for oral use.
The method of claim 9,

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.
The method of claim 9,

Wherein the antioxidant is a butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) or a combination thereof, stable oral film preparation for oral use.
The method of claim 9,

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.
The method of claim 9,

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.
The method of claim 15,

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.
The method of claim 9,

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.
The method of claim 1,

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.
The method of claim 18,

The after-improving agent comprises a stevioside-based sweetener, stable oral film preparation for oral use.
The method of claim 18,

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.