KR100252699B1 - Minocycline composition for the periodontal disease treatment - Google Patents

Minocycline composition for the periodontal disease treatment Download PDF

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KR100252699B1
KR100252699B1 KR1019980009095A KR19980009095A KR100252699B1 KR 100252699 B1 KR100252699 B1 KR 100252699B1 KR 1019980009095 A KR1019980009095 A KR 1019980009095A KR 19980009095 A KR19980009095 A KR 19980009095A KR 100252699 B1 KR100252699 B1 KR 100252699B1
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minocycline
polyethylene glycol
composition
magnesium
periodontitis
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KR19990075100A (en
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김완섭
손호모
김명국
박목순
박진규
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강재헌
동국제약주식회사
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    • 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
    • A61K31/65—Tetracyclines
    • 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
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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

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Abstract

PURPOSE: A minocycline composition improved in stability by adding polyethylene glycol, magnesium salts and hydroxypropyl methylcellulose to minocycline salts is provided, which solves problems of precipitation and stability of minocycline as a defect of conventional techniques. CONSTITUTION: In a formulation for the treatment of periodontitis, the composition contains 70 to 95%(w/w) polyethylene glycol 200 to 6,000 and 0.1 to 0.5%(w/w) magnesium salts as a solvent and a stabilizer, and 5 to 10%(w/w) hydroxypropyl methylcellulose as an aqueous polymer with 0.5 to 5%(w/w) minocycline salts.

Description

치주염 치료용 미노사이클린 조성물Minocycline composition for treatment of periodontitis

본 발명은 치주염 치료용 항생제인 미노사이클린(minocycline) 조성물에 관한 것이다. 보다 상세하게는 치주염의 원인균 퇴치에 널리 사용되고 있는 미노사이클린은 테트라사이클린(tetracycline) 계열의 항생제로 특히, 테트라사이클린에 내성을 나타내는 스타필로코커시(Staphylococci)에도 강한 항생력을 가지고 있으므로 치주염 치료용의 제형개발을 위한 미노사이클린 조성물에 관한 것이다.The present invention relates to a minocycline composition that is an antibiotic for treating periodontitis. More specifically, minocycline, which is widely used for combating the causative agent of periodontitis, is a tetracycline-based antibiotic, and especially has a strong antibiotic ability against Staphylococci, which is resistant to tetracycline. It relates to a minocycline composition for development.

미노사이클린은 건조된 분말상태에서는 안정한 상태를 유지하지만 일반적으로 빛과 산화에 매우 민감하고 수용성 상태에서는 에피머반응(Epimerization)과 산화반응(Oxidation)으로 매우 불안정한 물질이므로 연고제와 같은 제형에 있어서는 미노사이클린을 주제로하여 안정한 조성물을 제조하기 위해서는 안정화제와 이들의 조성비가 중요하다.Although minocycline is stable in a dry powder state, it is generally very sensitive to light and oxidation, and is very unstable due to epimerization and oxidation in water-soluble state. Therefore, minocycline is used in formulations such as ointments. In order to produce a stable composition, stabilizers and their composition ratios are important.

치주염에 대한 국소치료를 위한 안정호된 미노사이클린 연고제에 대한 종래기술로서 미국특허 제4,701,320는 용제(Base)로서 글리세린(glycerin), 에틸렌글리콜(ethylene glycol), 디에틸렌글리콜(diethylene glycol), 프로필렌글리콜(prophylene glycol)과 같은 알칸디올(alkane-diol) 혹은 알칸트리올(alkane-triol)이 고농도의 마그네슘(magnesium)과 함께 미노사이클린을 안정화시킨다고 하였으나, 단점으로 고농도의 마그네슘이 미노사이클린과 킬레이트(chelate)를 형성하여 침전 현상이 발생하며 이러한 현상은 치료효과를 위한 체내 흡수에도 나쁜 영향을 줄수가 있다는 단점이 있으며 이러한 사실은 미국약학회지[American Journal of Pharmacy, November-December, 1974, p179-191, Compatibility Information]에도 지적되어 있다.As a prior art for stable minocycline ointment for topical treatment for periodontitis, US Pat. No. 4,701,320 discloses glycerin, ethylene glycol, diethylene glycol, propylene glycol as a base. Alkane-diol or alkane-triol, such as glycol, stabilizes minocycline with a high concentration of magnesium, but the disadvantage is that high concentrations of magnesium form chelates with minocycline. Sedimentation occurs, which has the disadvantage of adversely affecting the absorption of the body for therapeutic effects. This fact is also found in the American Journal of Pharmacy, November-December, 1974, p179-191, Compatibility Information. It is pointed out.

본 발명의 기술적 과제는 종래기술의 단점으로 지적되어 왔던 미노사이클린제제에 있어서 침전현상과 안정성의 문제를 해결하는데 있다. 종래에는 0.5%이하의 저농도 염화마그네슘(magnesium chloride)과 용제로 알칸-디올 이나 알칸-트리올 용제들을 사용할 경우 미노사이클린의 안정성이 문제되었다. 본 발명에서는 폴리에틸렌글리콜(Polyethylene glycol) 200 내지 6,000을 0.1-0.5% 범위의 마그네슘을 저농도로 사용하고 0-10%의 하이드록시프로필메칠셀루로우스를 첨가하여 안정성이 향상된 치주염 치료용 미노사이클린 조성물을 제공하는데 있다.The technical problem of the present invention is to solve the problems of precipitation phenomenon and stability in the minocycline formulation has been pointed out as a disadvantage of the prior art. Conventionally, when using alkane-diol or alkane-triol solvents with a low concentration of magnesium chloride (magnesium chloride) of less than 0.5%, the stability of minocycline has been a problem. The present invention provides a minocycline composition for treating periodontitis with improved stability by using polyethylene glycol 200 to 6,000 in a low concentration of 0.1-0.5% of magnesium and adding 0-10% of hydroxypropylmethylcellulose. It is.

본 발명의 용제(base) 및 안정화제로 사용되는 폴리에틸렌 글리콜 200, 400, 600, 1,500, 4,000, 6,000들은 단독으로 또는 혼합하여 사용할수 있으며 특히 폴리에틸렌 글리콜 400이나 600이 더욱 바람직한 용제라는 것이 밝혀 졌다. 본 발명의 용제들은 종래의 용제와는 달리 수 %의 수분이 함유되어도 안정성에 영향을 주지 않는다.Polyethylene glycol 200, 400, 600, 1,500, 4,000, 6,000 used as the base and stabilizer of the present invention can be used alone or in combination, it was found that polyethylene glycol 400 or 600 is a more preferred solvent. Unlike the conventional solvents, the solvents of the present invention do not affect the stability even if they contain a few% of moisture.

본 발명의 용제들과 마그네슘 이온의 농도를 0.1-2% 바람직하게는 0.1-0.5%의 저농도로 사용할 경우 미노사이클린의 킬레이트 현상이 최소화되어 침전이 생기지 않고 안정성에 있어서도 100%이상 향상된다는 것을 본 발명의 가혹시험을 통하여 확인하였다.When the concentration of the solvent and the magnesium ion of the present invention is used at a low concentration of 0.1-2%, preferably 0.1-0.5%, the chelating phenomenon of minocycline is minimized, so that precipitation does not occur and the stability is improved by 100% or more. It was confirmed through the harsh test.

추가적으로, 본 발명의 안정한 조성물이 연고제로제로서 점도를 증가시키고 0-10%의 하이드록시프로필메칠셀루로우스(hydroxyprophylmethylcellulose)를 첨가하였던바 미노사이클린의 안정성을 향상시킨다는 것을 확인하였다. 또한 단순히 점도를 향상시키기 위해서는 용제인 폴리에틸렌 글리콜 1,500 이상의 것 중에서 농도를 증가시키는 것으로도 가능함을 알게 되었다. 즉, 치주염치료를 위한 항생제 미노사이클린의 안정한 연고제조성물을 구성하기 위하여는 폴리에틸렌 글리콜 200에서 6,000까지의 용제에 0.1-0.5%의 마그네슘이 포함되도록 하고, 미노사이클린의 안정성과 점도향상을 위해서는 하이드록시프로필메칠셀루로우스을 첨가하는 것이 좋다. 본 발명의 바람직한 조성물과 조성비율은 아래의 표 1과 같다.In addition, it was confirmed that the stable composition of the present invention increased the viscosity as an ointment agent and improved the stability of minocycline by adding 0-10% of hydroxyprophylmethylcellulose. In addition, it was found that it is possible to increase the concentration in the solvent of polyethylene glycol 1,500 or more in order to simply improve the viscosity. That is, in order to form a stable ointment composition of antibiotic minocycline for the treatment of periodontitis, 0.1 to 0.5% of magnesium should be included in the solvent from polyethylene glycol 200 to 6,000, and hydroxypropyl methyl cellulose for stability and viscosity improvement of minocycline. It is good to add loose. Preferred compositions and composition ratios of the present invention are shown in Table 1 below.

다음의 실시예는 본 발명을 보다 상세히 설명하기 위한 것으로 이들 실시예에 의하여 본 발명의 범위가 한정되는 것은 아니다.The following examples are intended to illustrate the present invention in more detail, and the scope of the present invention is not limited by these examples.

[실시예 1]Example 1

폴리에칠렌 글리콜 400을 97.9g 정량하여 250ml 비이커에 넣은 후 염화마그네슘 0.1g을 첨가하여 40-50℃에서 30분간 교반하여 완전히 용해시켰다. 이 혼합액에 미노사이클린 하이드로크로라이드을 2g 첨가하고 200rpm, 40-50℃로 30분간 교반하여 완전히 혼합하였다. 이 조성물을 40℃에서 3개월보관시 99.2%의 염화미노사이클린(minocycline chloride)의 함량을 확인하였다.97.9 g of polyethylene glycol 400 was quantified and placed in a 250 ml beaker, and 0.1 g of magnesium chloride was added thereto, followed by stirring at 40-50 ° C. for 30 minutes to completely dissolve it. 2 g of minocycline hydrochloride was added to the mixed solution, and the mixture was stirred at 200 rpm and 40-50 ° C. for 30 minutes to thoroughly mix. When the composition was stored at 40 ° C. for 3 months, the content of 99.2% of minocycline chloride was confirmed.

[실시예 2]Example 2

폴리에칠렌 글리콜 400을 75g, 폴리에칠렌 글리콜 6,000을 22.7g을 정량하여 250ml 비이커에 넣고 염화마그네슘 0.3g을 첨가하여 60-70℃에서 30분간 교반하여 완전히 용해시켰다. 이 혼합액을 40-50℃로 유지하면서 미노사이클린 하이드로크로라이드 2g을 첨가하여 200rpm으로 30분간 교반하여 완전히 혼합하였다. 이 조성물을 40℃에서 3개월 보관시 99.4%의 염화미노사이클린의 함량이 확인되었다.75 g of polyethylene glycol 400 and 22.7 g of polyethylene glycol 6,000 were weighed into a 250 ml beaker, and 0.3 g of magnesium chloride was added thereto, followed by stirring at 60-70 ° C. for 30 minutes to dissolve completely. While maintaining the mixture at 40-50 ° C., 2 g of minocycline hydrochloride was added and stirred at 200 rpm for 30 minutes to mix thoroughly. When the composition was stored at 40 ° C. for 3 months, a content of minocycline chloride of 99.4% was confirmed.

[실시예 3]Example 3

폴리에칠렌 글리콜 400을 97.5g 정량하여 250ml 비이커에 넣고 염화마그네슘 0.5g을 첨가하여 40-50℃에서 30분간 교반하여 염화마그네슘을 완전히 용해시켰다. 이 혼합액에 미노사이클린 하이드로크로라이드를 2g 첨가하여 200rpm, 40-50℃로 30분간 교반하여 완전히 혼합하였다. 이 조성물을 40℃에서 3개월 보관시 99.1%의 염화미노사이클린의 함량이 확인되었다.97.5 g of polyethylene glycol 400 was quantified and placed in a 250 ml beaker, 0.5 g of magnesium chloride was added thereto, and stirred at 40-50 ° C. for 30 minutes to completely dissolve magnesium chloride. 2 g of minocycline hydrochloride was added to the mixed solution, and the mixture was stirred at 200 rpm and 40-50 ° C. for 30 minutes to completely mix. When the composition was stored at 40 ° C. for 3 months, a content of 99.1% of minocycline chloride was confirmed.

[실시예 4]Example 4

폴리에칠렌 글리콜 400을 87.7g 정량하여 250ml 비이커에 넣고 하이드록시프로필메칠셀루로우즈 10g을 첨가하여 100-110℃ 로 200rpm으로 5분간 교반하여 용해시켰다. 이후 염화마그네슘 0.3g을 첨가하여 30분간 100-200rpm으로 교반하여 염화마그네슘을 완전히 용해시켰다. 조제 온도를 50℃이하로 냉각시킨 후 미노사이클린 하이드로크로라이드을 2g 첨가한후 100-200rpm, 40-50℃로 30분간 교반하여 완전히 혼합하였다. 이 조성물을 40℃에서 3개월 보관시 99.6%의 염화미노사이클린의 함량이 확인되었다.87.7 g of polyethylene glycol 400 was quantified and placed in a 250 ml beaker, and 10 g of hydroxypropylmethylcellulose was added thereto, and the mixture was dissolved by stirring at 100-110 ° C. at 200 rpm for 5 minutes. Thereafter, 0.3 g of magnesium chloride was added thereto, followed by stirring at 100-200 rpm for 30 minutes to completely dissolve magnesium chloride. After the preparation temperature was cooled to 50 ° C. or lower, 2 g of minocycline hydrochloride was added, followed by stirring at 100-200 rpm and 40-50 ° C. for 30 minutes to completely mix. When the composition was stored at 40 ° C. for 3 months, a content of 99.6% of minocycline chloride was confirmed.

[시험예 1-7][Test Example 1-7]

조성물의 성분과 조성비율(표 2)에 따른 미노사이클린의 안정성을 시험하기 위하여 실시예 4의 방법과 동일하게 제조한 후, 40℃에서 3개월 보관하여 제품의 안정성을 확인하였다.In order to test the stability of the minocycline according to the composition and composition ratio (Table 2) of the composition was prepared in the same manner as in Example 4, and then stored for 3 months at 40 ℃ to confirm the stability of the product.

이상의 시험예에서 나타난 바와 같이 염화마그네슘 0.5% 이상을 사용할 경우 킬레이트 형성에 의하여 침전물이 시험관의 바닥에 형성되기 시작하였으며 에피머반응과 산화반응에 의한 미노사이클린 변성물이 적색으로 나타났다.As shown in the above test examples, when 0.5% or more of magnesium chloride was used, precipitates began to form at the bottom of the test tube due to chelate formation, and the minocycline denatured by epimer and oxidation reactions appeared red.

본 발명의 조성물은 치주염 치료를 위한 안정한 미노사이클린 함유 제제의 치과용 치료제로서 본 발명에서는 폴리에틸렌글리콜(Polyethylene glycol) 200 내지 6,000을 용제로 하여 0.1-0.5%까지의 저농도 마그네슘을 사용하여도 장기간, 고온에서도 안정성을 유지하므로 종래 미노사이클린 제제의 단점을 해결할 수 있는 안정성이 향상된 미노사이클린 조성물을 제공한다.The composition of the present invention is a dental therapeutic agent of a stable minocycline-containing formulation for the treatment of periodontitis. It provides a minocycline composition with improved stability to maintain the stability to solve the disadvantages of conventional minocycline formulations.

Claims (6)

치주염 치료용 국소전달제형에 있어서, 미노사이클린염에 용제 및 안정화제로서 폴리에틸렌 글리콜과 마그네슘염을, 수용성폴리머로서 하이드록시프로필메칠셀루로우즈를 포함하는 것을 특징으로 하는 치주염 치료용 미노사이클린 조성물.A topical delivery agent for the treatment of periodontitis, wherein the minocycline salt comprises polyethylene glycol and magnesium salts as a solvent and a stabilizer, and hydroxypropylmethylcellulose as a water-soluble polymer. 제1항에 있어서, 용제 및 안정화제로서 폴리에틸렌 글리콜은 폴리에틸렌 글리콜 200, 폴리에틸렌 글리콜 400, 폴리에틸렌 글리콜 600, 폴리에틸렌 글리콜 1,600, 폴리에틸렌 글리콜 3,500-4,000, 폴리에틸렌 글리콜 6,000을 단독 또는 혼합하여 75-99.8%(w/w) 사용함을 특징으로 하는 치주염 치료용 미노사이클린 조성물.The method of claim 1, wherein the polyethylene glycol as a solvent and a stabilizer is 75-99.8% (w) or a mixture of polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1,600, polyethylene glycol 3,500-4,000, polyethylene glycol 6000 / w) minocycline composition for treatment of periodontitis, characterized in that used. 제1항에 있어서, 마그네슘염은 염화마그네슘, 황산마그네슘, 글루콘산마그네슘, 초산마그네슘, 탄산마그네슘중에서 선택된 마그네슘염을 0.1 내지 0.5%(w/w)의 범위내에서 사용함을 특징으로 하는 치주염 치료용 미노사이클린 조성물.The method of claim 1, wherein the magnesium salt is a magnesium salt selected from magnesium chloride, magnesium sulfate, magnesium gluconate, magnesium acetate, magnesium carbonate within the range of 0.1 to 0.5% (w / w). Minocycline composition. 제1항에 있어서, 수용성폴리머로는 하이드록시프로필메칠셀루로우즈를 0.1 내지 10%(w/w)의 범위내에서 사용함을 특징으로 하는 치주염 치료용 미노사이클린 조성물.The minocycline composition for treating periodontitis according to claim 1, wherein hydroxypropyl methylcellulose is used within the range of 0.1 to 10% (w / w) as the water-soluble polymer. 치주염 치료용 연고제형에 있어서 미노사이클린염, 폴리에틸렌 글리콜 400, 염화마그네슘, 하이드록시프로필메칠셀루로우스가 포함되는 것을 특징으로 하는 치주염 치료용 미노사이클린 조성물.A minocycline composition for treating periodontitis, which comprises minocycline salt, polyethylene glycol 400, magnesium chloride, hydroxypropylmethylcellulose in an ointment for treating periodontitis. 제5항에 있어서, 조성물에는 미노사이클린염산염 0.5-5%(w/w), 폴리에틸렌 클리콜 400이 70-95%(w/w), 염화마그네슘 0.1-0.5%(w/w), 하이드록시프로필메칠셀루로우스 5-10%(w/w)가 포함되는 것을 특징으로 하는 치주염 치료용 미노사이클린 조성물.The composition of claim 5 wherein the composition comprises 0.5-5% (w / w) of minocycline hydrochloride, 70-95% (w / w) of polyethylene glycol 400, 0.1-0.5% (w / w) of magnesium chloride, hydroxypropyl Minocycline composition for treating periodontitis, characterized in that 5-10% (w / w) of methylcellulose is included.
KR1019980009095A 1998-03-17 1998-03-17 Minocycline composition for the periodontal disease treatment KR100252699B1 (en)

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ES2501042T3 (en) * 2011-12-12 2014-10-01 Unilever N.V. Anhydrous antiperspirant compositions
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WO2018124324A1 (en) * 2016-12-27 2018-07-05 주식회사 쿠보텍 Ointment composition for improving periodontitis
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