WO2014157852A1 - Sustained-release medicinal composition containing eperisone as active ingredient - Google Patents

Sustained-release medicinal composition containing eperisone as active ingredient Download PDF

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WO2014157852A1
WO2014157852A1 PCT/KR2014/001932 KR2014001932W WO2014157852A1 WO 2014157852 A1 WO2014157852 A1 WO 2014157852A1 KR 2014001932 W KR2014001932 W KR 2014001932W WO 2014157852 A1 WO2014157852 A1 WO 2014157852A1
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acid
release
sustained
active ingredient
weight
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PCT/KR2014/001932
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French (fr)
Korean (ko)
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김기운
이승후
정숙인
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초당약품공업 주식회사
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin

Definitions

  • the present invention relates to a sustained release formulation composition containing eferison as an active ingredient. More particularly, the present invention relates to a sustained-release preparation composition containing erythrosone having hydroxypropylmethylcellulose (HPMC) and a release-controlling polymer added to an erythrosine pharmaceutical composition comprising erythrosone and an acidifying agent.
  • Eperisone pharmaceutical composition in the sustained-release preparation of the present invention is an eperisone pharmaceutical composition which is stable to storage and pH change of the acid added to the pericone, and the perison pharmaceutical composition is stably sustained to the pH change in the gastrointestinal tract.
  • a sustained release formulation composition capable of releasing an active ingredient.
  • Eperisone is a drug used in the treatment of stiff paralysis due to neuromuscular diseases including painful muscle spasms associated with musculoskeletal diseases by acting as a relaxant on musculoskeletal smooth muscle and vascular smooth muscle represented by the following formula (1): It is short and the product which takes 50-150mg of dose three times a day is marketed now.
  • Eperisone having such a chemical structure has a problem of pH stability because the piperidine ring can be easily opened in an alkaline environment.
  • the development of the eferisone composition has been in progress to improve the pH stability and storage stability, and in particular, the sustained-release pharmaceutical composition in which an acidic pH adjusting agent is added to the eferison has been disclosed.
  • Korea Patent Registration No. 10-1156054 'Stable Ephericone-containing sustained-release pharmaceutical composition' includes a specific type of acidifying agent such as carbomer, citric acid and the like to be formulated to a pH range of 5.6 or lower, so that the long-term storage stability of the preparation and the long term in the gastrointestinal tract Due to the characteristics of sustained-release preparations, eferison sustained-release pharmaceutical compositions that can inhibit the decomposition of the main ingredient without changing the dissolution properties in extreme environments such as pH change are disclosed.
  • the patent document includes an acidifying agent selected from an acidic pH adjusting agent or an excipient exhibiting a pH of 5.0 or less when suspended, dissolved, swelled or blended in water, and has an acidity when prepared with a 0.5% (W / V) aqueous solution.
  • an acidifying agent selected from an acidic pH adjusting agent or an excipient exhibiting a pH of 5.0 or less when suspended, dissolved, swelled or blended in water, and has an acidity when prepared with a 0.5% (W / V) aqueous solution.
  • a stable eferisone-containing sustained-release pharmaceutical composition having a pH of 0.5 to 5.6 is disclosed, and acidic pH regulators used herein include alginic acid, acetic acid, formic acid, adipic acid, edetic acid, fumaric acid, lactic acid, malic acid, maleic acid, At least one selected from the group consisting of palmitic acid, propionic acid, sorbic acid, stearic acid, tartaric acid, ascorbic acid, erythorbic acid, citric acid, oxalic acid, succinic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, hydrochloric acid, phosphoric acid and sulfuric acid It is starting.
  • acidic pH regulators used herein include alginic acid, acetic acid, formic acid, adipic acid, edetic acid, fumaric acid, lactic acid, malic acid, maleic acid, At least one selected from the group consisting of
  • the present inventors have applied D-glucaric acid and D-glucoascorbic acid to epherizone to improve the storage and pH stability of eferison in the 'ephericone pharmaceutical composition with improved storage and pH stability' filed as the same as the present application.
  • a patent application has been disclosed for an eperison pharmaceutical composition in which at least one acid selected from nicotinic acid or chlorogenic acid is added as an acidifying agent and polyvinylpyrrolidone is added as a binder to form a stable composition between the eferison and the acidifying agent.
  • epherisone is prepared to be taken in three doses per day, but in the case of non-steroidal anti-inflammatory drugs (NSAIDs) co-prescribed in combination with the eferison preparation, it is usually to be taken in two doses per day.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • the patient's compliance with medications tends to be lowered when co-prescribing a combination, and thus, there has been a further demand for the development of a sustained-release formulation of eperisone that can be taken twice daily.
  • the present inventors have added hydroxypropylmethylcellulose (HPMC) and a release-controlling polymer to the eferison pharmaceutical composition in which the acidifier and the polyvinylpyrrolidone binder have been added to the eferison already developed by the present inventors.
  • HPMC hydroxypropylmethylcellulose
  • the present invention has been completed by developing a sustained release formulation composition containing a.
  • the problem to be solved by the present invention is to develop a sustained-release formulation containing eferisone that has a sustained release properties that can be taken in a dose twice a day, the present inventors have added an acidifier and a binder to the eferison already developed
  • the present invention aims to develop a sustained-release formulation composition containing erypoxyson, in which hydroxypropylmethylcellulose (HPMC) and a release-controlling polymer are added to a lysone pharmaceutical composition.
  • HPMC hydroxypropylmethylcellulose
  • HPMC hydroxypropylmethylcellulose
  • the epherizone pharmaceutical composition having the storage and pH stability is 20 to 60% by weight of esperison or a pharmaceutically acceptable salt thereof; D-glucarboxylic acid, D-glucoascorbic acid, gluconic acid, D-glucuronic acid, gluconolactone, glucuronolactone, glutamic acid, itaconic acid, caffeic acid, glycyric acid, ethanesulfonic acid, benzenesulfonic acid, dehydro 1 to 30% by weight of at least one acidifying agent selected from ascorbic acid, salicylic acid, salicylic sulfonic acid, molar assets, nicotinic acid or chlorogenic acid; 0.5 to 8 wt% binder as binder; And 10 to 80% by weight of a diluent.
  • HPMC hydroxypropyl methyl cellulose
  • the release control polymer is characterized in that at least one selected from microcrystalline cellulose, starch, crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glyconate, sodium croscarmellose, calcium carboxymethyl cellulose or magnesium aluminum silicate. .
  • the sustained-release preparation composition containing eferison as the active ingredient is 30 to 55% by weight of the total content within 60 minutes of the initial dissolution in a buffer of pH 1.2, 55 to 85% by weight within 3 hours, and 85% within 5 hours. It is characterized by eluting more than%.
  • another object of the present invention is to use the Ephericone pharmaceutical composition having the above storage and pH stability as the immediate release layer and the sustained release formulation composition containing Ephericone as the active ingredient as a sustained release layer of the epherisone in the form of a bilayer It is to provide a sustained-release tablet containing.
  • another object of the present invention is to provide an efferison complex combination comprising a non-steroidal anti-inflammatory drug (NSAID) in addition to the sustained-release preparation composition containing eferison as the active ingredient.
  • NSAID non-steroidal anti-inflammatory drug
  • the non-steroidal anti-inflammatory drugs are celecoxib, aceclofenac, diclofenac, ibuprofen, dexibuprofen, loxoprofen, zaltoprofen, ketoprofen, meloxycamp, naproxen, etodollac, nabu It is characterized in that at least one selected from meton, felbinac, nimesulide.
  • the effect of the present invention is to provide a sustained-release preparation containing eperisone that has a sustained release property, which can be taken in two doses per day, to an eperison pharmaceutical composition in which an acidifying agent and a polyvinylpyrrolidone binder are added to the eferison It is to provide a sustained release formulation composition containing hydroxypropyl methyl cellulose (HPMC) and the eferison to which the release controlling polymer is added as a release controlling agent.
  • HPMC hydroxypropyl methyl cellulose
  • the present invention is 50-90% by weight of the epherisone pharmaceutical composition with storage and pH stability; 1-20% by weight of hydroxypropylmethylcellulose (HPMC) as a release controlling agent; And 5 to 45% by weight of a release controlling polymer. It relates to a sustained-release preparation composition containing eferison as an active ingredient.
  • HPMC hydroxypropylmethylcellulose
  • the ephericone pharmaceutical composition in the sustained-release preparation is an eperisone pharmaceutical composition which is stable to storage and pH change of the acid added to the epherisone, and the eperison active ingredient is continuously stable to the pH change in the gastrointestinal tract. It relates to a sustained release formulation composition capable of releasing a drug.
  • Ephericone pharmaceutical compositions with storage and pH stability for use in the sustained release formulation compositions of the present invention comprise 20 to 60% by weight of epherisone or a pharmaceutically acceptable salt thereof; D-glucarboxylic acid, D-glucoascorbic acid, gluconic acid, D-glucuronic acid, gluconolactone, glucuronolactone, glutamic acid, itaconic acid, caffeic acid, glycyric acid, ethanesulfonic acid, benzenesulfonic acid, dehydro 1 to 30% by weight of at least one acidifying agent selected from ascorbic acid, salicylic acid, salicylic sulfonic acid, molar assets, nicotinic acid or chlorogenic acid; 0.5-8 wt.% Binder; And 10 to 80% by weight of a diluent.
  • the diluent used in the eferison pharmaceutical composition having the storage and pH stability may include at least one selected from microcrystalline cellulose, lactose hydrate, anhydrous lactose, starch, dextrose, sugar, maltitol, calcium hydrogen phosphate or mannitol.
  • At least one selected from D-glucuronic acid, gluconolactone, and glucuronolactone is preferable.
  • the content of the acidifying agent is an amount capable of adjusting the pH of the 1.0% (w / v) aqueous solution of the epherisone pharmaceutical composition to 2.0 to 5.5.
  • hydroxypropylmethylcellulose (HPMC) as a release control agent used in the sustained-release preparation composition of the present invention has a viscosity in the range of 6 to 10,000 cps. If the viscosity exceeds 10,000 cps, the dissolution of the drug is lowered.
  • the controlled release polymer used in the sustained-release preparation composition of the present invention is microcrystalline cellulose, starch, crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate, croscarmellose sodium, carboxymethyl cellulose calcium or magnesium aluminum silicate
  • At least one selected from the group and the release-controlling polymer can be used in combination with each other hydroxypropylmethylcellulose (HPMC) used as a release control agent to be able to more stably control the release of the efericone pharmaceutical composition with storage and pH stability .
  • HPMC hydroxypropylmethylcellulose
  • the active ingredient of the present invention is preferably in the form of hydrochloride, and the content of eferison hydrochloride contained in a single dose is preferably 75 to 150 mg.
  • the sustained-release preparation composition containing eferison as the active ingredient is 30 to 55% by weight of the total content within 60 minutes of the initial dissolution in a buffer of pH 1.2, 55 to 85% by weight within 3 hours, and 85% within 5 hours. It is characterized by eluting more than%.
  • another object of the present invention is to use the Ephericone pharmaceutical composition having the above storage and pH stability as the immediate release layer and the sustained release formulation composition containing Ephericone as the active ingredient as a sustained release layer of the epherisone in the form of a bilayer It is to provide a sustained-release tablet containing.
  • the rapid-release layer has the characteristic of eluting more than 85% by weight of the active ingredient within 60 minutes, and by taking the two-day dose more conveniently by preparing a sustained-release tablet containing eferisone in the form of a double layer by combining the two layers. Make it possible.
  • the present invention is to provide an anti-erythrone combination formulation including a non-steroidal anti-inflammatory analgesic (NSAID) in addition to the sustained-release preparation composition containing eferison as the active ingredient.
  • NSAID non-steroidal anti-inflammatory analgesic
  • Sustained-release formulation compositions containing eperisons of the present invention may additionally comprise non-steroidal anti-inflammatory drugs (NSAIDs), for example celecoxib, aceclofenac, diclofenac, ibuprofen, dexibuprofen, roxofero
  • NSAIDs non-steroidal anti-inflammatory drugs
  • aceclofenac diclofenac
  • ibuprofen ibuprofen
  • dexibuprofen roxofero
  • pen zaltoprofen
  • ketoprofen meloxycamp
  • naproxen etodolak
  • nabumethone felbinac and nimesulide
  • Concomitantly administering the sustained-release preparation composition containing eferisone, which can be taken in a twice daily dose of the present invention, and a non-steroidal anti-inflammatory drug, which is taken twice a day, further improves the patient's convenience and improves medication compliance. You can.
  • the sustained-release preparation composition containing the epherisone of the present invention can be prepared by mixing each of the composition components through a conventional direct method, a wet method, a dry method, and the like, as well as general granular bead pellet tablet capsule pills, as well as their multilayer tablets, It may be formulated in the form of coated tablets, nucleated tablets, or matrix.
  • ephericone hydrochloride 100 g of ephericone hydrochloride, 20 g of glucuronic acid as an acidifying agent, and 175 g of lactose hydrate as a diluent were quantified, and apples were added to a 24 mesh sieve and mixed for 5 minutes.
  • a binder 5 g of polyvinylpyrrolidone (PVP K30) was dissolved in 50 ml of isopropanol to form a binding solution, and then 300 g of eferison pharmaceutical composition was prepared from the mixture.
  • PVP K30 polyvinylpyrrolidone
  • the content of the sustained-release preparation containing ephericone as the final active ingredient was 75 mg of epherisone hydrochloride, 15 mg of glucuronic acid, 131.25 mg of lactose hydrate, 8.75 mg of polyvinylpyrrolidone, 36 mg of HPC, and 30 mg of microcrystalline cellulose. .
  • the preparation was carried out in the same manner as in Preparation Example 1, except that 30 g of low-substituted hydroxypropyl cellulose was used instead of 30 g of microcrystalline cellulose as the release controlling polymer.
  • the content of sustained-release preparations containing ephericone as the final active ingredient is 75 mg of epherisone hydrochloride, 15 mg of glucuronic acid, lactose hydrate 131.25 mg, polyvinylpyrrolidone 8.75 mg, HPMC 36 mg, low-substituted hydroxide It was 30 mg of oxypropyl cellulose.
  • Example 1 In Example 1 except that 30 g of sodium starch glycolate was used instead of 30 g of microcrystalline cellulose as the release-controlling polymer, it was prepared in the same manner as in Example 1.
  • the content of sustained-release preparations containing eferison as the final active ingredient is 75 mg of eferison hydrochloride, 15 mg of glucuronic acid, lactose hydrate 131.25 mg, polyvinylpyrrolidone 8.75 mg, HPMC 36 mg, sodium starch glycolate per tablet 30 mg.
  • Preparation Example 1 Instead of adding the HPMC added in Preparation Example 1 was prepared in the same manner as in Preparation Example 1 by increasing the content of the release control polymer microcrystalline cellulose to 66g instead of 30g.
  • the component content of the sustained-release preparation containing ephericone as the final active ingredient was 75 mg of eferison hydrochloride, 15 mg of glucuronic acid, 131.25 mg of lactose hydrate, 8.75 mg of polyvinylpyrrolidone, and 66 mg of microcrystalline cellulose per tablet.
  • Preparation Example 1 Instead of adding the release control polymer microcrystalline cellulose added in Preparation Example 1 was prepared in the same manner as in Preparation Example 1 by increasing the content of HMPC to 66g instead of 36g.
  • the content of the sustained-release preparation containing ephericone as the final active ingredient was 75 mg of eperisone hydrochloride, 15 mg of glucuronic acid, 131.25 mg of lactose hydrate, 8.75 mg of polyvinylpyrrolidone, and 66 mg of HPMC per tablet.
  • Preparation Example 1 An eperison pharmaceutical composition was prepared by adding 20 g of glucuronic acid used as an acidifying agent in step 1 to prepare the epherison pharmaceutical composition in step 1 and instead increasing the content of the diluent lactose hydrate to 195 g. 225 g of the obtained eferrizone pharmaceutical composition was added to Preparation Example 1 Step 2 to prepare the same method as Preparation Example 1.
  • the content of the sustained-release preparation containing ephericone as the final active ingredient was 75 mg of eferison hydrochloride, 146.25 mg of lactose hydrate, 8.75 mg of polyvinylpyrrolidone, 36 mg of HPMC, and 30 mg of microcrystalline cellulose per tablet.
  • the sustained-release preparation composition containing eferison prepared according to the method of the present invention showed a stable and constant dissolution pattern compared to the sustained-release preparation composition prepared by the Preparation Comparative Example.
  • the tablet does not completely disintegrate during the time of staying in the stomach as well as the time passing through the small intestine, and the drug is continuously contained in the tablet. Done. In other words, while remaining in the stomach, only a part of the active ingredient, epherisone, is released and the remaining amount is gradually released as it passes through the small intestine remaining in the disintegrated tablet.

Abstract

The present invention relates to a sustained-release medicinal composition containing eperisone as an active ingredient, the composition containing 50-90 wt% of an eperisone pharmaceutical composition having preservability and pH stability; 1-20 wt% of hydroxypropyl methylcellulose (HPMC) as a release controller; and 5-45 wt% of a release controlling polymer.

Description

활성 성분으로 에페리손을 함유하는 서방성 제제 조성물Sustained-release formulation compositions containing eferison as active ingredient
본 발명은 활성 성분으로 에페리손을 함유하는 서방성 제제 조성물에 관한 것이다. 더욱 상세하게는 에페리손과 산성화제를 포함하는 에페리손 의약 조성물에 방출 조절제로서 하이드록시프로필메틸셀룰로오스(HPMC) 및 방출 조절 고분자를 첨가시킨 에페리손을 함유하는 서방성 제제 조성물에 관한 것이다. 본 발명의 서방성 제제 내의 에페리손 의약 조성물은 에페리손에 산성화제를 첨가시킨 저장 및 pH 환경 변화에 안정한 에페리손 의약 조성물로서 상기 에페리손 의약 조성물을 위장관 내에서 pH 변화에 안정하게 지속적으로 에페리손 활성 성분을 방출시킬 수 있는 서방성 제제 조성물에 관한 것이다.The present invention relates to a sustained release formulation composition containing eferison as an active ingredient. More particularly, the present invention relates to a sustained-release preparation composition containing erythrosone having hydroxypropylmethylcellulose (HPMC) and a release-controlling polymer added to an erythrosine pharmaceutical composition comprising erythrosone and an acidifying agent. Eperisone pharmaceutical composition in the sustained-release preparation of the present invention is an eperisone pharmaceutical composition which is stable to storage and pH change of the acid added to the pericone, and the perison pharmaceutical composition is stably sustained to the pH change in the gastrointestinal tract. A sustained release formulation composition capable of releasing an active ingredient.
에페리손(Eperisone)은 하기 화학식 1로 표시되는 근골격계 평활근 및 혈관계 평활근에 이완제로 작용하여 근골격계 질환에 수반되는 동통성 근육연축을 비롯한 신경계 질환에 의한 경직성 마비의 치료에 사용되는 약물이며 혈액 내 반감기가 짧아서 현재로서는 1일 용량 50∼150mg을 1일 3회 복용하는 제품이 시판되고 있다.Eperisone (Eperisone) is a drug used in the treatment of stiff paralysis due to neuromuscular diseases including painful muscle spasms associated with musculoskeletal diseases by acting as a relaxant on musculoskeletal smooth muscle and vascular smooth muscle represented by the following formula (1): It is short and the product which takes 50-150mg of dose three times a day is marketed now.
[화학식 1][Formula 1]
Figure PCTKR2014001932-appb-I000001
Figure PCTKR2014001932-appb-I000001
상기와 같은 화학 구조를 지닌 에페리손은 알칼리 환경에서 피페리딘 고리가 쉽게 개환될 수 있는 이유로 pH 안정성에 문제가 있다. 또한 상기 약물을 제제화하여 보관 시에도 경시 변화에 따른 저장 안정성의 문제가 있었던 것이다. Eperisone having such a chemical structure has a problem of pH stability because the piperidine ring can be easily opened in an alkaline environment. In addition, there was a problem of storage stability with the change over time even when the drug is formulated and stored.
따라서 이러한 pH 안정성 및 저장 안정성의 개선을 위해 에페리손 조성물의 개발이 진행되어왔고 특히 에페리손에 산성 pH 조절제를 첨가시킨 서방성 의약 조성물이 개시되어 왔다. Therefore, the development of the eferisone composition has been in progress to improve the pH stability and storage stability, and in particular, the sustained-release pharmaceutical composition in which an acidic pH adjusting agent is added to the eferison has been disclosed.
대한민국 특허등록 제10-1156054호 '안정한 에페리손 함유 서방성 의약 조성물'에서는 카보머, 시트르산 등의 특정 종류의 산성화제를 포함시켜 pH 5.6 이하 범위로 제제화 함으로써 제제의 장기 보관 안정성과 위장관내에서 장시간 체류해야 하는 서방성 제제의 특성상 pH 변화 등의 극한 환경에서도 용출 특성의 변화없이 주성분 분해를 억제할 수 있는 에페리손 서방성 의약 조성물을 개시하고 있다. Korea Patent Registration No. 10-1156054 'Stable Ephericone-containing sustained-release pharmaceutical composition' includes a specific type of acidifying agent such as carbomer, citric acid and the like to be formulated to a pH range of 5.6 or lower, so that the long-term storage stability of the preparation and the long term in the gastrointestinal tract Due to the characteristics of sustained-release preparations, eferison sustained-release pharmaceutical compositions that can inhibit the decomposition of the main ingredient without changing the dissolution properties in extreme environments such as pH change are disclosed.
또한 상기 특허문헌에서는 산성 pH 조절제 또는 물에 현탁, 용해, 팽윤 또는 혼화되었을 때 pH 5.0 이하를 나타내는 부형제 중에서 선택된 산성화제를 포함하며, 0.5%(W/V) 수성용액으로 제조했을 때의 산도가 pH 0.5∼5.6인 것을 특징으로 하는 안정한 에페리손 함유 서방성 의약조성물을 개시하고 있으며 이때 사용되는 산성 pH 조절제로서는 알긴산, 아세트산, 포름산, 아디프산, 에데트산, 푸마르산, 젖산, 말산, 말레산, 팔미트산, 프로피온산, 소르빈산, 스테아르산, 주석산, 아스코르빈산, 에리소르빈산, 시트르산, 옥살산, 숙신산, 톨루엔설폰산, 메탄설폰산, 질산, 염산, 인산 및 황산으로 이루어진 그룹 중에서 선택된 1종 이상을 개시하고 있다. In addition, the patent document includes an acidifying agent selected from an acidic pH adjusting agent or an excipient exhibiting a pH of 5.0 or less when suspended, dissolved, swelled or blended in water, and has an acidity when prepared with a 0.5% (W / V) aqueous solution. A stable eferisone-containing sustained-release pharmaceutical composition having a pH of 0.5 to 5.6 is disclosed, and acidic pH regulators used herein include alginic acid, acetic acid, formic acid, adipic acid, edetic acid, fumaric acid, lactic acid, malic acid, maleic acid, At least one selected from the group consisting of palmitic acid, propionic acid, sorbic acid, stearic acid, tartaric acid, ascorbic acid, erythorbic acid, citric acid, oxalic acid, succinic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, hydrochloric acid, phosphoric acid and sulfuric acid It is starting.
한편으로는 에페리손 함유 서방형 제제의 개발도 진행되고 있는 바, 대한민국 공개특허공보 10-2012-52080호 '에페리손 함유 서방정 및 이의 제조방법'에서는 에페리손에 폴리비닐아세테이트, 비닐피롤리돈-비닐아세테이트 공중합체 및 하이드록시프로필메틸셀룰로스를 포함한 서방정 형태의 조성물이 개시되어 있다.On the other hand, the development of esperidone-containing sustained-release preparations is also in progress. In Korean Patent Laid-Open Publication No. 10-2012-52080, 'Eperisone-containing sustained-release tablets and preparation methods thereof' include polyvinylacetate and vinylpyrrolidone- Sustained release compositions are disclosed, including vinyl acetate copolymers and hydroxypropylmethylcellulose.
그러나 다양한 환경에 장시간 노출되어도 에페리손 염산염의 안정성에 문제가 없는 저장 및 pH 안정성이 개선된 에페리손 의약 조성물의 개발은 충분치 않은 바, 이러한 에페리손 염산염의 안정성 저하 문제로 에페리손 방출을 지연시켜 서방성 제형으로서의 완전한 개발이 어려웠던 것이다.However, the development of the eferisone pharmaceutical composition with improved storage and pH stability, which is not a problem in the stability of the eferison hydrochloride even after prolonged exposure to various environments, is not sufficient. Full development as a sex formulation was difficult.
이에 본 발명자들은 본 출원과 동일자로 출원된 '저장 및 pH 안정성이 개선된 에페리손 의약 조성물'에서 에페리손의 저장 및 pH 안정성을 개선시키기 위해 에페리손에 D-글루카르산, D-글루코아스코르브산, 글루콘산, D-글루쿠론산, 글루코노락톤, 글루쿠로노락톤, 글루탐산, 이타콘산, 카페인산, 글리시리진산, 에탄술폰산, 벤젠술폰산, 데하이드로아스코르브산, 살리실산, 살리실술폰산, 몰식자산, 니코틴산 또는 클로로겐산에서 선택된 1종 이상의 산을 산성화제로 첨가하고 에페리손과 산성화제 간의 안정적 조성을 형성하기 위해 폴리비닐피롤리돈을 결합제로 첨가시킨 에페리손 의약 조성물을 특허 출원하여 개시한 바 있다. Accordingly, the present inventors have applied D-glucaric acid and D-glucoascorbic acid to epherizone to improve the storage and pH stability of eferison in the 'ephericone pharmaceutical composition with improved storage and pH stability' filed as the same as the present application. , Gluconic acid, D-glucuronic acid, gluconolactone, glucuronolactone, glutamic acid, itaconic acid, caffeic acid, glycyrrhizin acid, ethanesulfonic acid, benzenesulfonic acid, dehydroascorbic acid, salicylic acid, salicylicsulfonic acid, A patent application has been disclosed for an eperison pharmaceutical composition in which at least one acid selected from nicotinic acid or chlorogenic acid is added as an acidifying agent and polyvinylpyrrolidone is added as a binder to form a stable composition between the eferison and the acidifying agent.
한편, 통상 시판되고 있는 에페리손은 1일 3회 용량으로 복용하게 제조되고 있으나 에페리손 제제와 병용 처방되는 비-스테로이드성 소염진통제(NSAID)의 경우 통상 1일 2회 용량으로 복용하게 되어있는 바 상호간 투여 회수가 일치하지 않음에 따라 병용 처방시 환자들의 복약 순응도가 낮아지는 경향이 있어 1일 2회 용량으로 복용할 수 있는 에페리손 서방성 제제의 개발이 더욱 요구되어 왔던 것이다. Meanwhile, commercially available epherisone is prepared to be taken in three doses per day, but in the case of non-steroidal anti-inflammatory drugs (NSAIDs) co-prescribed in combination with the eferison preparation, it is usually to be taken in two doses per day. As the number of mutual administrations is inconsistent, the patient's compliance with medications tends to be lowered when co-prescribing a combination, and thus, there has been a further demand for the development of a sustained-release formulation of eperisone that can be taken twice daily.
따라서 본 발명자들은 본 발명자들이 이미 개발한 에페리손에 산성화제와 폴리비닐피롤리돈 결합제를 첨가시킨 에페리손 의약 조성물에 방출 조절제로서 하이드록시프로필메틸셀룰로오스(HPMC)와 방출 조절 고분자를 첨가시킨 에페리손을 함유하는 서방성 제제 조성물을 개발함으로써 본 발명을 완성하게 된 것이다. Therefore, the present inventors have added hydroxypropylmethylcellulose (HPMC) and a release-controlling polymer to the eferison pharmaceutical composition in which the acidifier and the polyvinylpyrrolidone binder have been added to the eferison already developed by the present inventors. The present invention has been completed by developing a sustained release formulation composition containing a.
본 발명이 해결하고자 하는 과제는 1일 2회 용량으로 복용 가능한 서방출 특성을 갖는 에페리손 함유 서방성 제제를 개발코자 한 것으로, 본 발명자들이 이미 개발한 에페리손에 산성화제와 결합제를 첨가시킨 에페리손 의약 조성물에 방출 조절제로서 하이드록시프로필메틸셀룰로오스(HPMC)와 방출 조절 고분자를 첨가시킨 에페리손을 함유하는 서방성 제제 조성물을 개발코자 한 것이다.The problem to be solved by the present invention is to develop a sustained-release formulation containing eferisone that has a sustained release properties that can be taken in a dose twice a day, the present inventors have added an acidifier and a binder to the eferison already developed The present invention aims to develop a sustained-release formulation composition containing erypoxyson, in which hydroxypropylmethylcellulose (HPMC) and a release-controlling polymer are added to a lysone pharmaceutical composition.
본 발명의 목적은 저장 및 pH 안정성을 지닌 에페리손 의약 조성물 50∼90 중량%; 방출 조절제로서 하이드록시프로필메틸셀룰로오스(HPMC) 1∼20 중량%; 및 방출 조절 고분자 5∼45 중량%;를 포함하는 활성 성분으로 에페리손을 함유하는 서방성 제제 조성물을 제공하는 것이다. It is an object of the present invention to provide 50-90% by weight of epherisone pharmaceutical composition with storage and pH stability; 1-20% by weight of hydroxypropylmethylcellulose (HPMC) as a release controlling agent; And 5 to 45% by weight of the release-controlling polymer; to provide a sustained-release formulation composition containing eferison as an active ingredient comprising.
이때 상기 저장 및 pH 안정성을 지닌 에페리손 의약 조성물은 에페리손 또는 그의 약제학적으로 허용 가능한 염 20∼60 중량%; D-글루카르산, D-글루코아스코르브산, 글루콘산, D-글루쿠론산, 글루코노락톤, 글루쿠로노락톤, 글루탐산, 이타콘산, 카페인산, 글리시리진산, 에탄술폰산, 벤젠술폰산, 데하이드로아스코르브산, 살리실산, 살리실술폰산, 몰식자산, 니코틴산 또는 클로로겐산에서 선택된 1종 이상의 산성화제 1∼30 중량%; 결합제로서 결합제 0.5∼8 중량%; 및 희석제 10∼80 중량%;를 포함함을 특징으로 한다.At this time, the epherizone pharmaceutical composition having the storage and pH stability is 20 to 60% by weight of esperison or a pharmaceutically acceptable salt thereof; D-glucarboxylic acid, D-glucoascorbic acid, gluconic acid, D-glucuronic acid, gluconolactone, glucuronolactone, glutamic acid, itaconic acid, caffeic acid, glycyric acid, ethanesulfonic acid, benzenesulfonic acid, dehydro 1 to 30% by weight of at least one acidifying agent selected from ascorbic acid, salicylic acid, salicylic sulfonic acid, molar assets, nicotinic acid or chlorogenic acid; 0.5 to 8 wt% binder as binder; And 10 to 80% by weight of a diluent.
또한 상기 방출 조절제로서 하이드록시프로필메틸셀룰로오스(HPMC)는 점도가 6∼10,000 cps 범위인 것을 특징으로 한다. In addition, the hydroxypropyl methyl cellulose (HPMC) as the release regulator is characterized in that the viscosity ranges from 6 to 10,000 cps.
한편 상기 방출 조절 고분자는 미결정셀룰로오스, 전분, 크로스포비돈, 저치환도 히드록시프로필셀룰로오스, 전분글리콘산나트륨, 크로스카멜로오스나트륨, 카르복시메틸셀룰로오스 칼슘 또는 마그네슘알루미늄실리케이트 중에서 선택된 1종 이상임을 특징으로 한다.On the other hand, the release control polymer is characterized in that at least one selected from microcrystalline cellulose, starch, crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glyconate, sodium croscarmellose, calcium carboxymethyl cellulose or magnesium aluminum silicate. .
또한 상기 활성 성분으로 에페리손을 함유하는 서방성 제제 조성물은 pH 1.2의 완충액 내에서 용출 초기 60분 이내 전체 함량의 30∼55 중량%, 3시간 이내 55∼85 중량%, 그리고 5시간 이내 85 중량% 이상 용출됨을 특징으로 한다.In addition, the sustained-release preparation composition containing eferison as the active ingredient is 30 to 55% by weight of the total content within 60 minutes of the initial dissolution in a buffer of pH 1.2, 55 to 85% by weight within 3 hours, and 85% within 5 hours. It is characterized by eluting more than%.
한편 본 발명의 또 다른 목적은 속방출층으로 상기 저장 및 pH 안정성을 지닌 에페리손 의약 조성물을 사용하고 서방출층으로 상기 활성 성분으로 에페리손을 함유하는 서방성 제제 조성물을 사용한 이중층 형태의 에페리손 함유 서방정을 제공하는 것이다. On the other hand, another object of the present invention is to use the Ephericone pharmaceutical composition having the above storage and pH stability as the immediate release layer and the sustained release formulation composition containing Ephericone as the active ingredient as a sustained release layer of the epherisone in the form of a bilayer It is to provide a sustained-release tablet containing.
한편 본 발명의 또 다른 목적은 상기 활성 성분으로 에페리손을 함유하는 서방성 제제 조성물에 추가적으로 비-스테로이드성 소염진통제(NSAID)를 포함하는 에페리손 복합제제를 제공하는 것이다. On the other hand, another object of the present invention is to provide an efferison complex combination comprising a non-steroidal anti-inflammatory drug (NSAID) in addition to the sustained-release preparation composition containing eferison as the active ingredient.
이때 상기 비-스테로이드성 소염진통제(NSAID)는 셀레콕시브, 아세클로페낙, 디클로페낙, 이부프로펜, 덱시부프로펜, 록소프로펜, 잘토프로펜, 케토프로펜, 멜록시캄, 나프록센, 에토돌락, 나부메톤, 펠비낙, 니메설리드 중에서 선택된 1종 이상임을 특징으로 한다.At this time, the non-steroidal anti-inflammatory drugs (NSAIDs) are celecoxib, aceclofenac, diclofenac, ibuprofen, dexibuprofen, loxoprofen, zaltoprofen, ketoprofen, meloxycamp, naproxen, etodollac, nabu It is characterized in that at least one selected from meton, felbinac, nimesulide.
본 발명의 효과는 1일 2회 용량으로 복용 가능한 서방출 특성을 갖는 에페리손 함유 서방성 제제를 제공하기 위한 것으로, 에페리손에 산성화제와 폴리비닐피롤리돈 결합제를 첨가시킨 에페리손 의약 조성물에 방출 조절제로서 하이드록시프로필메틸셀룰로오스(HPMC)와 방출 조절 고분자를 첨가시킨 에페리손을 함유하는 서방성 제제 조성물을 제공하는 것이다. The effect of the present invention is to provide a sustained-release preparation containing eperisone that has a sustained release property, which can be taken in two doses per day, to an eperison pharmaceutical composition in which an acidifying agent and a polyvinylpyrrolidone binder are added to the eferison It is to provide a sustained release formulation composition containing hydroxypropyl methyl cellulose (HPMC) and the eferison to which the release controlling polymer is added as a release controlling agent.
도 1은 본 발명의 제조실시예 1에서 제조된 시료의 패들법에 의한 시간별 용출율을 도시한 그래프이다.1 is a graph showing the dissolution rate according to time by the paddle method of the sample prepared in Preparation Example 1 of the present invention.
본 발명은 저장 및 pH 안정성을 지닌 에페리손 의약 조성물 50∼90 중량%; 방출 조절제로서 하이드록시프로필메틸셀룰로오스(HPMC) 1∼20 중량%; 및 방출 조절 고분자 5∼45 중량%;를 포함하는 활성 성분으로 에페리손을 함유하는 서방성 제제 조성물에 관한 것이다. The present invention is 50-90% by weight of the epherisone pharmaceutical composition with storage and pH stability; 1-20% by weight of hydroxypropylmethylcellulose (HPMC) as a release controlling agent; And 5 to 45% by weight of a release controlling polymer. It relates to a sustained-release preparation composition containing eferison as an active ingredient.
이때 서방성 제제 내의 에페리손 의약 조성물은 에페리손에 산성화제를 첨가시킨 저장 및 pH 환경 변화에 안정한 에페리손 의약 조성물로서 상기 에페리손 의약 조성물을 위장관 내에서 pH 변화에 안정하게 지속적으로 에페리손 활성 성분을 방출시킬 수 있는 서방성 제제 조성물에 관한 것이다. Herein, the ephericone pharmaceutical composition in the sustained-release preparation is an eperisone pharmaceutical composition which is stable to storage and pH change of the acid added to the epherisone, and the eperison active ingredient is continuously stable to the pH change in the gastrointestinal tract. It relates to a sustained release formulation composition capable of releasing a drug.
이하 본 발명을 더욱 상세히 설명한다. Hereinafter, the present invention will be described in more detail.
본 발명의 서방성 제제 조성물 내에 사용되는 저장 및 pH 안정성을 지닌 에페리손 의약 조성물은 에페리손 또는 그의 약제학적으로 허용 가능한 염 20∼60 중량%; D-글루카르산, D-글루코아스코르브산, 글루콘산, D-글루쿠론산, 글루코노락톤, 글루쿠로노락톤, 글루탐산, 이타콘산, 카페인산, 글리시리진산, 에탄술폰산, 벤젠술폰산, 데하이드로아스코르브산, 살리실산, 살리실술폰산, 몰식자산, 니코틴산 또는 클로로겐산에서 선택된 1종 이상의 산성화제 1∼30 중량%; 결합제 0.5∼8 중량%; 및 희석제 10∼80 중량%;를 포함하는 것이다. Ephericone pharmaceutical compositions with storage and pH stability for use in the sustained release formulation compositions of the present invention comprise 20 to 60% by weight of epherisone or a pharmaceutically acceptable salt thereof; D-glucarboxylic acid, D-glucoascorbic acid, gluconic acid, D-glucuronic acid, gluconolactone, glucuronolactone, glutamic acid, itaconic acid, caffeic acid, glycyric acid, ethanesulfonic acid, benzenesulfonic acid, dehydro 1 to 30% by weight of at least one acidifying agent selected from ascorbic acid, salicylic acid, salicylic sulfonic acid, molar assets, nicotinic acid or chlorogenic acid; 0.5-8 wt.% Binder; And 10 to 80% by weight of a diluent.
상기 저장 및 pH 안정성을 지닌 에페리손 의약 조성물 내에 사용되는 희석제로서는 미결정셀룰로오스, 유당 수화물, 무수 유당, 전분, 덱스트로즈, 설탕, 말티톨, 인산수소칼슘 또는 만니톨에서 선택된 1종 이상을 들 수 있다. The diluent used in the eferison pharmaceutical composition having the storage and pH stability may include at least one selected from microcrystalline cellulose, lactose hydrate, anhydrous lactose, starch, dextrose, sugar, maltitol, calcium hydrogen phosphate or mannitol.
또한 상기 산성화제로서는 D-글루쿠론산(D-glucuronic acid), 글루코노락톤(gluconolactone) 또는 글루쿠로노락톤(glucuronolactone)에서 선택된 1종 이상이 바람직하다.As the acidifying agent, at least one selected from D-glucuronic acid, gluconolactone, and glucuronolactone is preferable.
한편 상기 산성화제의 함량은 상기 에페리손 의약조성물의 1.0%(w/v) 수용성 용액의 pH를 2.0∼5.5로 조정시킬 수 있는 양이다.On the other hand, the content of the acidifying agent is an amount capable of adjusting the pH of the 1.0% (w / v) aqueous solution of the epherisone pharmaceutical composition to 2.0 to 5.5.
또한 본 발명의 서방성 제제 조성물에 사용되는 방출 조절제로서 하이드록시프로필메틸셀룰로오스(HPMC)는 점도가 6∼10,000 cps 범위인 것으로 이때 점도가 10,000 cps를 초과하면 약물의 용출이 낮아지는 문제가 있다. In addition, hydroxypropylmethylcellulose (HPMC) as a release control agent used in the sustained-release preparation composition of the present invention has a viscosity in the range of 6 to 10,000 cps. If the viscosity exceeds 10,000 cps, the dissolution of the drug is lowered.
또한 본 발명의 서방성 제제 조성물에 사용되는 방출 조절 고분자는 미결정셀룰로오스, 전분, 크로스포비돈, 저치환도 히드록시프로필셀룰로오스, 전분글리콘산나트륨, 크로스카멜로오스나트륨, 카르복시메틸셀룰로오스 칼슘 또는 마그네슘알루미늄실리케이트 중에서 선택된 1종 이상이며 상기 방출 조절 고분자는 방출 조절제로 사용하는 하이드록시프로필메틸셀룰로오스(HPMC)와 서로 혼합하여 사용함으로써 저장 및 pH 안정성을 지닌 에페리손 의약 조성물의 방출을 더욱 안정적으로 조절할 수 있게 한다.In addition, the controlled release polymer used in the sustained-release preparation composition of the present invention is microcrystalline cellulose, starch, crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate, croscarmellose sodium, carboxymethyl cellulose calcium or magnesium aluminum silicate At least one selected from the group and the release-controlling polymer can be used in combination with each other hydroxypropylmethylcellulose (HPMC) used as a release control agent to be able to more stably control the release of the efericone pharmaceutical composition with storage and pH stability .
또한 본 발명의 활성성분인 에페리손은 염산염 형태가 바람직하고, 1회 투여 용량 내 함유된 염산 에페리손의 함량은 75∼150mg가 바람직하다.In addition, the active ingredient of the present invention, eferison, is preferably in the form of hydrochloride, and the content of eferison hydrochloride contained in a single dose is preferably 75 to 150 mg.
또한 상기 활성 성분으로 에페리손을 함유하는 서방성 제제 조성물은 pH 1.2의 완충액 내에서 용출 초기 60분 이내 전체 함량의 30∼55 중량%, 3시간 이내 55∼85 중량%, 그리고 5시간 이내 85 중량% 이상 용출됨을 특징으로 한다.In addition, the sustained-release preparation composition containing eferison as the active ingredient is 30 to 55% by weight of the total content within 60 minutes of the initial dissolution in a buffer of pH 1.2, 55 to 85% by weight within 3 hours, and 85% within 5 hours. It is characterized by eluting more than%.
한편 본 발명의 또 다른 목적은 속방출층으로 상기 저장 및 pH 안정성을 지닌 에페리손 의약 조성물을 사용하고 서방출층으로 상기 활성 성분으로 에페리손을 함유하는 서방성 제제 조성물을 사용한 이중층 형태의 에페리손 함유 서방정을 제공하는 것이다. On the other hand, another object of the present invention is to use the Ephericone pharmaceutical composition having the above storage and pH stability as the immediate release layer and the sustained release formulation composition containing Ephericone as the active ingredient as a sustained release layer of the epherisone in the form of a bilayer It is to provide a sustained-release tablet containing.
이때 속방출층은 60분 이내에 활성성분의 85 중량% 이상 용출되는 특성을 지니며 이러한 2개 층의 결합을 통한 2중층 형태의 에페리손 함유 서방정을 제조함으로써 더욱 편리하게 1일 2회 용량으로 복용 가능케 한다. At this time, the rapid-release layer has the characteristic of eluting more than 85% by weight of the active ingredient within 60 minutes, and by taking the two-day dose more conveniently by preparing a sustained-release tablet containing eferisone in the form of a double layer by combining the two layers. Make it possible.
한편 본 발명은 상기 활성 성분으로 에페리손을 함유하는 서방성 제제 조성물에 추가적으로 비-스테로이드성 소염진통제(NSAID)를 포함하는 에페리손 복합제제를 제공하는 것이다. On the other hand, the present invention is to provide an anti-erythrone combination formulation including a non-steroidal anti-inflammatory analgesic (NSAID) in addition to the sustained-release preparation composition containing eferison as the active ingredient.
본 발명의 에페리손을 함유하는 서방성 제제 조성물은 추가적으로 비-스테로이드성 소염진통제(NSAID)를 포함할 수 있으며, 예를 들면 셀레콕시브, 아세클로페낙, 디클로페낙, 이부프로펜, 덱시부프로펜, 록소프로펜, 잘토프로펜, 케토프로펜, 멜록시캄, 나프록센, 에토돌락, 나부메톤, 펠비낙, 니메설리드 중에서 선택된 1종 이상을 열거할 수 있다. Sustained-release formulation compositions containing eperisons of the present invention may additionally comprise non-steroidal anti-inflammatory drugs (NSAIDs), for example celecoxib, aceclofenac, diclofenac, ibuprofen, dexibuprofen, roxofero One or more selected from pen, zaltoprofen, ketoprofen, meloxycamp, naproxen, etodolak, nabumethone, felbinac and nimesulide may be listed.
본 발명의 1일 2회 용량으로 복용 가능한 에페리손을 함유하는 서방성 제제 조성물과 1일 2회 복용하는 비-스테로이드성 소염진통제를 병용 투여하면 환자들의 복용 편리성을 증진시켜 복약 순응도를 더욱 향상시킬 수 있다.Concomitantly administering the sustained-release preparation composition containing eferisone, which can be taken in a twice daily dose of the present invention, and a non-steroidal anti-inflammatory drug, which is taken twice a day, further improves the patient's convenience and improves medication compliance. You can.
본 발명의 에페리손을 함유하는 서방성 제제 조성물은 각각의 조성 성분을 혼합시킨 후 통상적인 직타법이나 습식법, 건식법 등을 통해 제조할 수 있으며 일반적인 과립 비드 펠렛 정제 캡슐 환제 뿐 아니라 이들의 다층정, 코팅정, 유핵정, 매트릭스 형태로 제형화할 수 있다. The sustained-release preparation composition containing the epherisone of the present invention can be prepared by mixing each of the composition components through a conventional direct method, a wet method, a dry method, and the like, as well as general granular bead pellet tablet capsule pills, as well as their multilayer tablets, It may be formulated in the form of coated tablets, nucleated tablets, or matrix.
이하 본 발명을 제조실시예, 제조비교예 및 실시예를 통하여 더욱 상세히 설명한다. 그러나 본 발명의 실시예들로 본 발명의 범위를 한정하는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Preparation Examples, Preparation Examples and Examples. However, the embodiments of the present invention are not intended to limit the scope of the present invention.
(제조실시예 1) 본 발명의 활성 성분으로 에페리손을 함유하는 서방성 제제 조성물의 제조Preparation Example 1 Preparation of Sustained Release Formulations Containing Eperisone as Active Ingredient of the Present Invention
(단계 1)(Step 1)
염산에페리손 100g, 산성화제로서 글루쿠론산 20g, 희석제로서 유당 수화물 175g을 정량하여 24 메쉬체에 사과한 후 투입하여 5분간 혼합하였다. 결합제로서 폴리비닐피롤리돈(PVP K30) 5g을 이소프로판올 50ml에 녹여 결합액을 만든 후 상기 혼합물로 에페리손 의약 조성물 300g을 제조하였다. 100 g of ephericone hydrochloride, 20 g of glucuronic acid as an acidifying agent, and 175 g of lactose hydrate as a diluent were quantified, and apples were added to a 24 mesh sieve and mixed for 5 minutes. As a binder, 5 g of polyvinylpyrrolidone (PVP K30) was dissolved in 50 ml of isopropanol to form a binding solution, and then 300 g of eferison pharmaceutical composition was prepared from the mixture.
(단계 2)(Step 2)
상기 단계 1에서 제조된 조성물 225g에 하이드록시프로필메틸셀룰로오스(HPMC) 36g과 방출 조절 고분자로서 미결정셀룰로오스 30g, 폴리비닐피롤리돈 5g 및 소량의 물을 첨가하여 5분간 혼합시킨 후 과립물을 오븐에서 50℃ 조건으로 1시간 동안 건조한 후 20 메쉬체를 이용하여 정립하여 과립물을 제조하였으며 활택제로서 탤크 및 스테아르산마그네슘 각 2g을 투입하여 비닐백에서 3분간 혼합하고, 이 혼합물을 타정기에서 압축하여 1정당 염산에페리손 75mg이 함유된 300mg 정제 1000개를 제조하였다. 최종 활성 성분으로 에페리손을 함유하는 서방성 제제의 성분 함량은 1정 당 염산에페리손 75mg, 글루쿠론산 15mg, 유당 수화물 131.25mg, 폴리비닐피롤리돈 8.75mg, HPMC 36mg, 미결정셀룰로오스 30mg 이었다. 36 g of hydroxypropylmethylcellulose (HPMC) and 30 g of microcrystalline cellulose, 5 g of polyvinylpyrrolidone, and a small amount of water were added to 225 g of the composition prepared in Step 1, followed by mixing for 5 minutes. After drying at 50 ° C. for 1 hour, the granules were prepared by using a 20 mesh sieve, and 2 g of talc and magnesium stearate were added as lubricants and mixed in a plastic bag for 3 minutes, and the mixture was compressed in a tablet press. 1000 300 mg tablets containing 75 mg of eferison hydrochloride per tablet were prepared. The content of the sustained-release preparation containing ephericone as the final active ingredient was 75 mg of epherisone hydrochloride, 15 mg of glucuronic acid, 131.25 mg of lactose hydrate, 8.75 mg of polyvinylpyrrolidone, 36 mg of HPC, and 30 mg of microcrystalline cellulose. .
(제조실시예 2) 본 발명의 활성 성분으로 에페리손을 함유하는 서방성 제제 조성물의 제조Preparation Example 2 Preparation of Sustained-Release Formulation Composition Containing Eperisone as Active Ingredient of the Present Invention
제조실시예 1에서 방출 조절 고분자로서 미결정셀룰로오스 30g 대신에 저치환도히드록시프로필셀룰로오스 30g을 사용한 것을 제외하고는 제조실시에 1과 동일한 방법으로 제조하였다. 최종 활성 성분으로 에페리손을 함유하는 서방성 제제의 성분 함량은 1정 당 염산에페리손 75mg, 글루쿠론산 15mg, 유당 수화물 131.25mg, 폴리비닐피롤리돈 8.75mg, HPMC 36mg, 저치환도히드록시프로필셀룰로오스 30mg 이었다. The preparation was carried out in the same manner as in Preparation Example 1, except that 30 g of low-substituted hydroxypropyl cellulose was used instead of 30 g of microcrystalline cellulose as the release controlling polymer. The content of sustained-release preparations containing ephericone as the final active ingredient is 75 mg of epherisone hydrochloride, 15 mg of glucuronic acid, lactose hydrate 131.25 mg, polyvinylpyrrolidone 8.75 mg, HPMC 36 mg, low-substituted hydroxide It was 30 mg of oxypropyl cellulose.
(제조실시예 3) 본 발명의 활성 성분으로 에페리손을 함유하는 서방성 제제 조성물의 제조Preparation Example 3 Preparation of Sustained Release Formulations Containing Eperisone as Active Ingredient of the Present Invention
제조실시예 1에서 방출 조절 고분자로서 미결정셀룰로오스 30g 대신에 전분글리콜산나트륨 30g을 사용한 것을 제외하고는 제조실시에 1과 동일한 방법으로 제조하였다. 최종 활성 성분으로 에페리손을 함유하는 서방성 제제의 성분 함량은 1정 당 염산에페리손 75mg, 글루쿠론산 15mg, 유당 수화물 131.25mg, 폴리비닐피롤리돈 8.75mg, HPMC 36mg, 전분글리콜산나트륨 30mg 이었다.In Example 1 except that 30 g of sodium starch glycolate was used instead of 30 g of microcrystalline cellulose as the release-controlling polymer, it was prepared in the same manner as in Example 1. The content of sustained-release preparations containing eferison as the final active ingredient is 75 mg of eferison hydrochloride, 15 mg of glucuronic acid, lactose hydrate 131.25 mg, polyvinylpyrrolidone 8.75 mg, HPMC 36 mg, sodium starch glycolate per tablet 30 mg.
(제조비교예 1) HPMC의 성분 제외 (Comparative Example 1) Excluding Ingredients of HPMC
제조실시예 1에서 첨가된 HPMC를 첨가하지 않은 대신에 방출 조절 고분자 미결정셀룰로오스의 함량을 30g 대신에 66g으로 증가시켜 제조실시에 1과 동일한 방법으로 제조하였다. 최종 활성 성분으로 에페리손을 함유하는 서방성 제제의 성분 함량은 1정 당 염산에페리손 75mg, 글루쿠론산 15mg, 유당 수화물 131.25mg, 폴리비닐피롤리돈 8.75mg, 미결정셀룰로오스 66mg 이었다. Instead of adding the HPMC added in Preparation Example 1 was prepared in the same manner as in Preparation Example 1 by increasing the content of the release control polymer microcrystalline cellulose to 66g instead of 30g. The component content of the sustained-release preparation containing ephericone as the final active ingredient was 75 mg of eferison hydrochloride, 15 mg of glucuronic acid, 131.25 mg of lactose hydrate, 8.75 mg of polyvinylpyrrolidone, and 66 mg of microcrystalline cellulose per tablet.
(제조비교예 2) 방출 조절 고분자 성분 제외(Production Comparative Example 2) Excluding Release Control Polymeric Components
제조실시예 1에서 첨가된 방출 조절 고분자 미결정셀룰로오스를 첨가하지 않은 대신에 HMPC의 함량을 36g 대신에 66g으로 증가시켜 제조실시에 1과 동일한 방법으로 제조하였다. 최종 활성 성분으로 에페리손을 함유하는 서방성 제제의 성분 함량은 1정 당 염산에페리손 75mg, 글루쿠론산 15mg, 유당 수화물 131.25mg, 폴리비닐피롤리돈 8.75mg, HPMC 66mg 이었다. Instead of adding the release control polymer microcrystalline cellulose added in Preparation Example 1 was prepared in the same manner as in Preparation Example 1 by increasing the content of HMPC to 66g instead of 36g. The content of the sustained-release preparation containing ephericone as the final active ingredient was 75 mg of eperisone hydrochloride, 15 mg of glucuronic acid, 131.25 mg of lactose hydrate, 8.75 mg of polyvinylpyrrolidone, and 66 mg of HPMC per tablet.
(제조비교예 3) 에페리손 의약 조성물 내 산성화제 성분 제외Preparation Example 3 Excluding Acidifying Agent Components in Epherisone Pharmaceutical Compositions
제조실시예 1 단계 1에서 에페리손 의약 조성물을 제조하는 단계에서 산성화제로 사용된 글루쿠론산 20g을 첨가하지 않고 대신에 희석제 유당 수화물의 함량을 195g으로 증가시켜 에페리손 의약 조성물을 제조하였다. 상기 수득된 에페리손 의약 조성물 225g을 제조실시예 1 단계 2에 첨가하여 제조실시예 1과 동일한 방법으로 제조하였다. 최종 활성 성분으로 에페리손을 함유하는 서방성 제제의 성분 함량은 1정 당 염산에페리손 75mg, 유당 수화물 146.25mg, 폴리비닐피롤리돈 8.75mg, HPMC 36mg, 미결정셀룰로오스 30mg 이었다. Preparation Example 1 An eperison pharmaceutical composition was prepared by adding 20 g of glucuronic acid used as an acidifying agent in step 1 to prepare the epherison pharmaceutical composition in step 1 and instead increasing the content of the diluent lactose hydrate to 195 g. 225 g of the obtained eferrizone pharmaceutical composition was added to Preparation Example 1 Step 2 to prepare the same method as Preparation Example 1. The content of the sustained-release preparation containing ephericone as the final active ingredient was 75 mg of eferison hydrochloride, 146.25 mg of lactose hydrate, 8.75 mg of polyvinylpyrrolidone, 36 mg of HPMC, and 30 mg of microcrystalline cellulose per tablet.
(실시예) 용출 시험(패들법)Example Dissolution Test (Paddle Method)
상기 제조실시예 1 내지 3, 제조비교예 1 내지 3에서 제조된 서방형 제제 시료 1정을 37℃에서 pH 1.2 완충액에 넣어 패들법으로 50rpm의 조건에서 용출시험을 시행하였다. 각 시점에서 5mL를 채취하여 여과한 후 UV-스펙트로포토미터 흡광도측정법(261nm)으로 에페리손 염산염의 함량을 측정하여 그 누적 용출율을 표 1에 나타내었다. 또한 도 1은 제조실시예 1에서 제조된 시료의 용출 그래프를 나타낸 것이다. One tablet of the sustained-release preparation prepared in Preparation Examples 1 to 3 and Comparative Examples 1 to 3 was placed in a pH 1.2 buffer at 37 ° C., and then subjected to a dissolution test under a condition of 50 rpm using a paddle method. 5 mL of the sample was collected at each time point, filtered, and the content of eferison hydrochloride was measured by UV-spectrophotometry absorbance measurement (261 nm). In addition, Figure 1 shows the dissolution graph of the sample prepared in Preparation Example 1.
표 1 패들법에 의한 본 발명의 서방성 제제의 염산에페리손 누적 용출율(%)
시간(분)
0 30 60 180 300
제조실시예 1 0 24.1 36.9 74.8 95.4
제조실시예 2 0 29.5 41.9 79.4 98.9
제조실시예 3 0 27.2 40.1 78.9 96.2
제조비교예 1 0 70.4 98.4 98.9 99.6
제조비교예 2 0 15.9 24.6 46.3 68.1
제조비교예 3 0 22.1 35.3 71.9 94.6
Table 1 Cumulative Elution Rate of Ephericone Hydrochloride of the Sustained-release Formulation of the Present Invention by Paddle Method
Minutes
0 30 60 180 300
Preparation Example 1 0 24.1 36.9 74.8 95.4
Preparation Example 2 0 29.5 41.9 79.4 98.9
Preparation Example 3 0 27.2 40.1 78.9 96.2
Comparative Example 1 0 70.4 98.4 98.9 99.6
Comparative Example 2 0 15.9 24.6 46.3 68.1
Comparative Example 3 0 22.1 35.3 71.9 94.6
상기 표 1의 결과로부터 알 수 있는 바와 같이, 본 발명의 제조실시예 1 내지 3에서 제조된 서방성 제제(1정당 염산에페리손 75mg 함유)의 경우, 초기 60분에 전체 함량의 36 내지 42%를 방출하였고 180분에 74 내지 80%, 300분에 95% 이상의 용출율을 나타내고 있어 안정된 용출패턴을 보여주고 있다. As can be seen from the results of Table 1, in the case of the sustained-release preparation prepared in Preparation Examples 1 to 3 of the present invention (containing 75 mg of eferison hydrochloride per tablet), the total content was 36 to 42 in the first 60 minutes. % Was released, and the dissolution rate was 74-80% at 180 minutes and 95% at 300 minutes, showing a stable dissolution pattern.
반면 본 발명의 제조비교예 1 내지 3에서 제조된 제제(1정당 염산에페리손 75mg 함유)의 경우, 초기 60분에 전체 함량의 25 내지 99%를 방출하였고 180분에 46 내지 99%, 300분에 58 내지 100% 의 용출율을 나타내어 안정하지 않고 변화가 큰 용출패턴을 나타내고 있다.On the other hand, in the preparations prepared in Comparative Examples 1 to 3 of the present invention (containing 75 mg of periprine hydrochloride per tablet), 25 to 99% of the total content was released in the first 60 minutes, and 46 to 99% and 300 at 180 minutes. The elution rate of 58 to 100% is shown in minutes, and the elution pattern which is not stable but has a big change is shown.
따라서 본 발명의 방법에 따라 제조된 에페리손을 함유하는 서방성 제제 조성물의 경우 제조비교예에 의해 제조된 서방성 제제 조성물에 비해 안정되고 일정한 용출 패턴의 차이를 나타냄을 확인한 것이다. Therefore, it was confirmed that the sustained-release preparation composition containing eferison prepared according to the method of the present invention showed a stable and constant dissolution pattern compared to the sustained-release preparation composition prepared by the Preparation Comparative Example.
본 발명의 방법에 따라 제조된 에페리손을 함유하는 서방성 제제 조성물의 경우 위에서 체류하는 시간 뿐 아니라 소장을 통과하는 시간 동안에도 정제의 붕해가 완전히 이루어지지 않고 정제 내에 약물을 계속 함유한 상태로 이동하게 된다. 즉 위내에서 체류하는 동안에 활성성분인 에페리손이 일부만 방출되고, 그 잔량은 붕해되지 않은 정제 내에 남아 소장을 통과하면서 서서히 방출되는 양상을 나타내게 된다.In case of sustained-release preparation composition containing ephericone prepared according to the method of the present invention, the tablet does not completely disintegrate during the time of staying in the stomach as well as the time passing through the small intestine, and the drug is continuously contained in the tablet. Done. In other words, while remaining in the stomach, only a part of the active ingredient, epherisone, is released and the remaining amount is gradually released as it passes through the small intestine remaining in the disintegrated tablet.
따라서 소장 내부의 높은 pH 환경에서도 에페리손이 화학적 안정성을 유지하도록 정제 내부의 pH 환경을 낮게 유지할 필요가 있다. 이러한 기술적 요구에 따라 본 발명에서는 산성화제를 첨가함으로써 pH 6.8의 완충액 중에서 에페리손의 분해산물이 현저히 낮게 생성됨을 확인할 수 있다.Therefore, it is necessary to keep the pH environment inside the tablets low so that eferison maintains chemical stability even in the high pH environment inside the small intestine. In accordance with the technical requirements in the present invention it can be seen that by the addition of the acidifying agent is produced a significantly lower decomposition products of the eperison in the buffer of pH 6.8.

Claims (8)

  1. 저장 및 pH 안정성을 지닌 에페리손 의약 조성물 50∼90 중량%; 방출 조절제로서 하이드록시프로필메틸셀룰로오스(HPMC) 1∼20 중량%; 및 방출 조절 고분자 5∼45 중량%;를 포함하는 활성 성분으로 에페리손을 함유하는 서방성 제제 조성물.50-90% by weight of epherisone pharmaceutical composition with storage and pH stability; 1-20% by weight of hydroxypropylmethylcellulose (HPMC) as a release controlling agent; And 5 to 45% by weight of a release-controlling polymer.
  2. 제 1항에 있어서, 상기 저장 및 pH 안정성을 지닌 에페리손 의약 조성물은 에페리손 또는 그의 약제학적으로 허용 가능한 염 20∼60 중량%; D-글루카르산, D-글루코아스코르브산, 글루콘산, D-글루쿠론산, 글루코노락톤, 글루쿠로노락톤, 글루탐산, 이타콘산, 카페인산, 글리시리진산, 에탄술폰산, 벤젠술폰산, 데하이드로아스코르브산, 살리실산, 살리실술폰산, 몰식자산, 니코틴산 또는 클로로겐산에서 선택된 1종 이상의 산성화제 1∼30 중량%; 결합제 0.5∼8 중량%; 및 희석제 10∼80 중량%;를 포함함을 특징으로 하는 활성 성분으로 에페리손을 함유하는 서방성 제제 조성물.The method of claim 1, wherein the storage and pH stability of the Eperisone pharmaceutical composition is 20 to 60% by weight of Eperisone or a pharmaceutically acceptable salt thereof; D-glucarboxylic acid, D-glucoascorbic acid, gluconic acid, D-glucuronic acid, gluconolactone, glucuronolactone, glutamic acid, itaconic acid, caffeic acid, glycyric acid, ethanesulfonic acid, benzenesulfonic acid, dehydro 1 to 30% by weight of at least one acidifying agent selected from ascorbic acid, salicylic acid, salicylic sulfonic acid, molar assets, nicotinic acid or chlorogenic acid; 0.5-8 wt.% Binder; And 10 to 80% by weight of a diluent; sustained release formulation composition containing eferison as an active ingredient.
  3. 제 1항에 있어서, 상기 방출 조절제로서 하이드록시프로필메틸셀룰로오스(HPMC)는 점도가 6∼10,000 cps 범위인 것을 특징으로 하는 활성 성분으로 에페리손을 함유하는 서방성 제제 조성물.The sustained-release preparation composition according to claim 1, wherein the hydroxypropylmethylcellulose (HPMC) as the release controlling agent has an efferison as an active ingredient, characterized in that the viscosity is in the range of 6 to 10,000 cps.
  4. 제 1항에 있어서, 상기 방출 조절 고분자는 미결정셀룰로오스, 전분, 크로스포비돈, 저치환도 히드록시프로필셀룰로오스, 전분글리콘산나트륨, 크로스카멜로오스나트륨, 카르복시메틸셀룰로오스 칼슘 또는 마그네슘알루미늄실리케이트 중에서 선택된 1종 이상임을 특징으로 하는 활성 성분으로 에페리손을 함유하는 서방성 제제 조성물.The method of claim 1, wherein the release controlling polymer is one selected from microcrystalline cellulose, starch, crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate, croscarmellose sodium, carboxymethyl cellulose calcium or magnesium aluminum silicate. Sustained-release preparation composition containing eferison as an active ingredient characterized by the above.
  5. 제 1항에 있어서, 상기 활성 성분으로 에페리손을 함유하는 서방성 제제 조성물은 pH 1.2의 완충액 내에서 용출 초기 60분 이내 전체 함량의 30∼55 중량%, 3시간 이내 55∼85 중량%, 그리고 5시간 이내 85 중량% 이상 용출됨을 특징으로 하는 활성 성분으로 에페리손을 함유하는 서방성 제제 조성물.The sustained release formulation composition according to claim 1, wherein the sustained-release formulation composition containing eferison as the active ingredient is 30 to 55% by weight of the total content within 60 minutes of the initial dissolution in a buffer of pH 1.2, 55 to 85% by weight within 3 hours, and Sustained release formulation composition containing eferison as an active ingredient, eluting at least 85% by weight within 5 hours.
  6. 속방출층으로 상기 저장 및 pH 안정성을 지닌 에페리손 의약 조성물을 사용하고 서방출층으로 제 1항의 활성 성분으로 에페리손을 함유하는 서방성 제제 조성물을 사용한 이중층 형태의 에페리손 함유 서방정.Ephericone-containing sustained-release tablet in the form of a bilayer using the ephericone pharmaceutical composition having the above storage and pH stability as the immediate release layer, and using the ephericone as the active ingredient of claim 1 as the sustained release layer.
  7. 제 1항의 활성 성분으로 에페리손을 함유하는 서방성 제제 조성물에 추가적으로 비-스테로이드성 소염진통제(NSAID)를 포함하는 에페리손 복합제제.Eperison combination formulation comprising a non-steroidal anti-inflammatory analgesic (NSAID) in addition to the sustained-release formulation composition containing ephericone as an active ingredient of claim 1.
  8. 제 7항에 있어서, 상기 비-스테로이드성 소염진통제(NSAID)는 셀레콕시브, 아세클로페낙, 디클로페낙, 이부프로펜, 덱시부프로펜, 록소프로펜, 잘토프로펜, 케토프로펜, 멜록시캄, 나프록센, 에토돌락, 나부메톤, 펠비낙, 니메설리드 중에서 선택된 1종 이상임을 특징으로 하는 에페리손 복합제제.8. The method of claim 7, wherein the non-steroidal anti-inflammatory drugs (NSAIDs) are celecoxib, aceclofenac, diclofenac, ibuprofen, dexibuprofen, roxofene, zaltoprofen, ketoprofen, meloxycamp, naproxen Eperidone complex, characterized in that at least one selected from etodolak, nabumetone, felbinac, nimesulide.
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