KR20010069756A - Method for controlled release of acemetacin in the intestinal tract and more particularly in the colon - Google Patents

Method for controlled release of acemetacin in the intestinal tract and more particularly in the colon Download PDF

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KR20010069756A
KR20010069756A KR1020010024824A KR20010024824A KR20010069756A KR 20010069756 A KR20010069756 A KR 20010069756A KR 1020010024824 A KR1020010024824 A KR 1020010024824A KR 20010024824 A KR20010024824 A KR 20010024824A KR 20010069756 A KR20010069756 A KR 20010069756A
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dissolved
soluble polymer
drug
composition
acid
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KR1020010024824A
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Korean (ko)
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김학형
한건
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유형선
(주)다산메디켐
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Preparation (AREA)

Abstract

PURPOSE: The titled composition having a drug delivery system for controlling release of acemetacin as an anti-inflammatory and analgesia on the colon and large intestine route is provided, which can be used for a fast-integration capsule, a packed granule injected only one time and a formulation contained in a tablet and injected several times. CONSTITUTION: This oral pharmaceutical composition comprises a pH dependent soluble polymer material dissolved at a pH of 7 or more in an alimentary canal as a first film material and one or more kinds of pH independent soluble polymer materials, which cannot be dissolved by gastric juice and has permeability.

Description

소염진통제인 아세메타신을 함유하며 장관내 특히 대장에서의 약물 방출 속도가 조절되는 약물 전달 체계에 대한 약제학적 경구용 조성물 및 그에 대한 제조 방법{Method for controlled release of acemetacin in the intestinal tract and more particularly in the colon}Pharmaceutical oral composition for the drug delivery system containing anti-inflammatory analgesic agent acemethacin and controlled rate of drug release in the intestine, especially the large intestine, and a method for preparing the same.Method for controlled release of acemetacin in the intestinal tract and more particularly in the colon}

Indole acetate acid계 비스테로이드성 항소염진통제로서, 아세메타신 자체로서 또는 주활성형 대사체인 indomethacin에 의하여 항염증, 진통, 해열 효과 및 혈소판 응집 억제효과를 나타내며, Cyclo-oxygenase의 활성을 감소시켜 prostaglandin의 전구체 생성이 감소하는 작용기전을 갖아, 임상적으로 골관절염, 류마티스 관절염 등 염증성 질환, 류마티스성 질환의 치료및 다양한 원인에 의한 통증의 완하여 사용되며 이 약물은 경구 투여후 신속하게 흡수되여 1회투여시 약 66%, 반복투여시 거의 100%의 생체내 이용율(Bioavailability)을 나타내며, 체내에서 염증 부위에 잘 분포되는 선택성이 있고, 주로 간에서 활성형인 indomethacin및기타 비활성형 대사체로 대사되는 약물이다. 경구복용시 임상적인 성인량은 염증성 질환및 류마티스성 질환인 경우 속방형 일반 제제는 1일 3회 투여시 30 ~ 60mg이며, 서방형 제제는 1일 2회투여하여 1회 90mg씩 복용한다.Indole acetate acid type nonsteroidal anti-inflammatory drugs, anti-inflammatory, analgesic, antipyretic and platelet aggregation inhibitory effect as acemethacin itself or by indomethacin, the main active metabolite, prostaglandin by reducing the activity of cyclo-oxygenase It has a mechanism of action that reduces the production of precursors, and is used clinically for the treatment of inflammatory diseases such as osteoarthritis and rheumatoid arthritis, rheumatoid diseases, and for the relief of pain caused by various causes. It is bioavailability of about 66% when administered and almost 100% when administered repeatedly, and is a drug that is well distributed in the inflammatory site in the body and is mainly metabolized to indomethacin and other inactive metabolites which are active in the liver. . In the case of oral administration, the clinical adult amount is 30 to 60 mg of the immediate release general formulation three times a day for inflammatory diseases and rheumatic diseases, and 90 mg of the sustained release formulation is administered twice a day.

본 발명자들은 아세메타신이 상당히 우수한 소염 진통력을 갖고, 약제학적인 생체내 거동을 보이는 약물로서 골 관절염 및 류마티스 관절염인 환자는 상당히 장기간 이 약물을 복용하여 증상의 경감및 치료를 하여야 하지만 이 제제는 1일 3회 및 1일 2회 경구용제만이 개발되어 시중에 시판되고 있다. 한편, 본 제제의 약물은 장기간 치료를 해야 되는 골관절염및 류마티스관절염 환자들이 오랜 기간 이러한 약물을 복용하여 왔고, 계속적으로 복용하는 과정중에서 위장관 자극 및 복용 횟수에 의한 불편함으로 약믈의 일정한 체내 혈중 농도를 유지하여 약효를 나타내도록 해야 함에도 불구하고, 환자의 순응도가 떨어져 일정하고 안정적인 약리학적 작용을 못하게 할 수 있다. 이에 본 발명자들은 복용 편리성을 높여 환자의 순응도를 향상시키고, 위장관내에서의 약물의 직접적인 접촉을 회피하여 위장 자극을 감소하여 장기 복용시에 나타나는 위장 장애를 극복하고자 발명하였다.The present inventors have shown that acemethacin has a very good anti-inflammatory analgesic effect and a pharmaceutical in vivo behavior. Patients with osteoarthritis and rheumatoid arthritis should take this drug for a long time to alleviate and treat symptoms. Only three times a day and twice a day oral solvent is developed and commercially available. On the other hand, the drugs of this formulation have been used by patients with osteoarthritis and rheumatoid arthritis for long-term treatment, and maintain constant blood levels of the drug due to discomfort caused by gastrointestinal irritation and the number of doses during the continuous treatment. In spite of having to show the efficacy of the drug, the patient's compliance can be prevented to prevent constant and stable pharmacological action. Accordingly, the present inventors have invented to improve the compliance of the patient to improve the convenience of taking, to overcome the gastrointestinal disorders appearing in long-term administration by avoiding direct contact of drugs in the gastrointestinal tract and reducing gastrointestinal irritation.

약물이 위장관을 직접 접촉하여 위장 자극을 못하게 하면서 복용횟수를 줄이는 방법으로는 1일 1회 복용하여 위장 및 소장 상부에서 약물이 방출되는것을 막고 대장관내 pH 7.0 이상에서 방출되도록 하는 신규 약물 방출 제어 체계를 만들어야 한다.A new drug release control system that prevents drug release from the stomach and upper intestine and releases it above pH 7.0 in the intestinal tract by taking the drug once a day to reduce the number of doses while preventing direct gastrointestinal irritation. You should create

이러한 약물 전달 체계를 달성하기 위해서는 인체내 소화관의 pH에 반응하는 약제학적으로 허용되는 고분자물질 및 인체내 소화관에서의 소화효소에 의하여 분해되는 고분자 물질을 사용하여 약물의 방출 조절을 제어하여야 한다.In order to achieve such a drug delivery system, it is necessary to control the release control of the drug by using a pharmaceutically acceptable polymer that reacts to the pH of the human digestive tract and a polymer that is degraded by the digestive enzymes in the human digestive tract.

제공되어지는 발명의 장관내 특히 대장에서의 약물이 흡수되어 약리학적 작용을 갖도록 약물의 방출을 조절하고, 표적화되는 약제학적 조성물을 얻기위한 방법을 나타내는 것이다. 본 발명의 주요 구성은 주 약물이 함유된 코아를 피복하고 있는 고분자 물질로 첫번째는 인체 소화관내 pH에 대하여 비의존성인 고분자와 미결정 셀룰로오스로 구성된 것과 인체 소화관 pH에 대한 의존성 고분자를 함유하는것으로 구성됨을 특징으로 한다. pH 비의존성 고분자 물질과 함께 사용되는 미결정셀룰로오스는 대장내에 존재하는 특이 효소와 박테리아에 의하여 소화되기 때문에 약물을 함유하는 코아의 붕해를 이루어 지도록 하기에 필요하다.It provides a method for controlling the release of a drug such that the drug is absorbed in the intestinal tract, particularly in the large intestine, to have a pharmacological action, and to obtain a targeted pharmaceutical composition. The main composition of the present invention is a polymer material coated with a core containing the main drug, the first of which is composed of a polymer which is independent of pH in the human digestive tract and microcrystalline cellulose and a polymer which is dependent on the pH of the human digestive tract. It is done. Microcrystalline cellulose used in conjunction with a pH-independent polymer material is necessary for the disintegration of drug-containing cores because they are digested by specific enzymes and bacteria present in the large intestine.

제공되어지는 발명은 단일 투여 되어지는 제형 대신에 다회 투여 되어지는 제형이상으로 여러가지 잇점이 있다. 제제의 다회 투여는 위장관 경로에서 약물의 분포가 넓게 확산되어 체내에서 약물의 고농도에 의한 점막 자극 문제를 경감하고 줄여 약물의 흡수를 향상시킨다. 더우기, 본 발명은 대장내에서 약물을 함유하는 코아 또는 막의 붕해가 이루어지지 않고, 약물의 용출을 서서히 하기 위하여 코팅막은 그대로 남아 있어 15분 부터 8시간 방출을 조절하여, 대장에서 흡수하게 하여 약물의 약리학적 작용을 연장하게 하는 것이다.The invention provided provides several advantages over formulations that are administered multiple times instead of formulations that are administered single. Multiple administrations of the agent improve the absorption of the drug by reducing the spread of the drug in the gastrointestinal tract, thereby reducing and reducing mucosal irritation problems caused by high concentrations of the drug in the body. Furthermore, the present invention does not perform disintegration of the core or the membrane containing the drug in the large intestine, and the coating film remains in order to slowly dissolve the drug, controlling the release from the 15 minutes to 8 hours, allowing the large intestine to absorb the drug. It is to extend the pharmacological action.

pH 의존성 용해성을 갖는 막으로 코아를 코팅하는것에 의하여 본 발명은 얻어질 수 있고 더우기 위에서 막이 용해되지 않고 그대로 유지하고 장관내에서 pH7.0 이상 도달하였을때 용해되어 약물이 방출될 수 있는 고분자가 바람직하다.By coating the core with a membrane having a pH dependent solubility, the present invention can be obtained and furthermore, a polymer which can be dissolved in the intestinal tract without dissolving it and dissolving and releasing the drug when reaching pH7.0 or higher in the intestine is preferred. Do.

pH 의존성 용해도를 갖는 막과 소장액이 투과되고 이에 불용성을 갖는 고분자가 분리되어 적용되어짐에 의하여 약물의 용출이 지연되고 대장 전체에서 작용이 이루워질 수 있게 된다. 실제 pH 6이상에서 용해되는 고분자(예를 들면, Eudragit S)에 의하여 피막이 형성된 제제는 pH 6.2에서 초기 3시간에 용출액에서 매우 낮은 방출을 나타내고 pH 7.2에서 약물의 방출이 신속하게 증가한다.The permeation of the membrane and the small intestine with the pH-dependent solubility and the insoluble polymer are separated and applied, thereby delaying the dissolution of the drug and effecting the entire colon. In fact, formulations encapsulated by polymers that dissolve above pH 6 (eg Eudragit S) show very low release in the eluate at pH 6.2 initially and rapidly increase the release of drug at pH 7.2.

일차 코팅 피막 물질위에 에칠셀룰로오스와 같은 이차 코팅 피막 물질의 사용에 의하여 체액에 의하여 녹지않지만 확산될 수 막을 형성하여 약물 방출을 지연하고 약효를 연장할 수 있다.The use of a secondary coating coating material, such as ethylcellulose, on the primary coating coating material can form a film that is not dissolved by body fluids but can diffuse, thereby delaying drug release and extending drug efficacy.

본 발명을 이루기 위하여 사용될 수 있는 1차 코팅 형성 물질로서는 메타아크릴산 공중합체(유드라진 - S, - L), 프탈산 초산 셀룰로오스, 프탈산 히드록시 프로필메칠셀룰로오스, 프탈산 초산 폴리비닐, 셀락, 호박산 초산 히드록시 프로필 메칠 셀룰로오스, 카르복시 메칠 셀룰로오스, 셀룰로오스 아세테이트 트리메리테이트, 말레인산과 프탈산의 공중합체 유도체등을 사용할 수 있고, 가소제로서 폴리에칠렌 글리콜 디부틸 프탈레이트, 디에칠 프탈레이트, 구연산 에스테르등이며, 활제로서 탈크, 경질 무수 규산, 이산화 티탄, 스테아린산 마그네슘등이 사용될 수 있다. 한편 2차 코팅물질은 pH 비의존 용해성 피막 형성 코팅 물질로서 메타아크릴산 에스테르 공중합체(유트라짓 RS/RL/NE), 에칠셀룰로오스, 폴리에칠렌, 폴리실록산과 pH 비의존성 수용성 고분자 물질인 히드록시프로필메칠셀룰로오스, 히드록시프로필셀룰로오스, 히드록시 에칠세룰로오스, 메칠셀룰로오스, 폴리피롤리돈과 같이 혼합하여 사용될 수 있다.Primary coating forming materials that can be used to achieve the present invention include methacrylic acid copolymers (eudrazin-S, -L), phthalic acid cellulose, phthalic acid hydroxypropylmethylcellulose, polyvinyl acetate phthalate, shellac, hydroxyacetic acid hydroxy Propyl methyl cellulose, carboxymethyl cellulose, cellulose acetate trimellitate, copolymer derivatives of maleic acid and phthalic acid can be used, and as plasticizers, such as polyethylene glycol dibutyl phthalate, dimethyl phthalate, citric acid esters, talc, hard anhydride, etc. Silicic acid, titanium dioxide, magnesium stearate and the like can be used. On the other hand, the secondary coating material is a pH independent soluble coating film-forming coating material, such as methacrylic acid ester copolymer (eutragit RS / RL / NE), ethyl cellulose, polyethylene, polysiloxane and hydroxypropyl methyl cellulose which is a pH independent water soluble polymer material, It can be used in combination with hydroxypropyl cellulose, hydroxy ethylcellulose, methyl cellulose, polypyrrolidone.

다음의 실시예 및 실험예는 본 발명을 좀 더 상세히 설명하는 것이지만, 본 발명의 범주를 한정하는 것은 아니다.The following Examples and Experimental Examples illustrate the present invention in more detail, but do not limit the scope of the invention.

실시예Example

A. 1차 코팅막 형성A. Primary coating film formation

유동층 과립기내에서 Acemetacine 2400g을 결합제를 사용하여 입자를 300 ~ 800um로 제조된 과립을 다음의 코팅 조성으로 유동층 코팅기내에서 Bottom spray 방법으로 코팅하여 대한 약전 용출 시험법에 따라 인공 위액 제 1액에서 2시간, pH 6.2 용출액에서 1시간 한 후, 계속하여 pH 7.2 용출액에서 영출시험을 하였다.In the fluidized bed granulator, the granules prepared in the range of 300 to 800um using a binder of 2400 g of Acemetacine were coated with a bottom spray method in a fluidized bed coater with the following coating composition. After 1 hour in pH 6.2 eluate, the elution test was continued in pH 7.2 eluate.

코팅조성물Coating Composition

유드라짓 S 166.8gEudragit S 166.8 g

디부칠 프탈레이트 16.5gD-butyl phthalate

메칠렌 크로라이드 1404gMethylene Chloride 1404g

이소프로필 알코올 468gIsopropyl Alcohol 468g

탈크 84gTalc 84 g

B. 2차 코팅막 제조B. Secondary Coating Film Preparation

1차 코팅막과 같은 방법으로 다음과 같은 조성으로 코팅하며 1차 코팅막의 용출시험 방법과 같이 용출시험을 한다.Coating with the following composition in the same way as the primary coating film and dissolution test as the dissolution test method of the primary coating film.

코팅조성물Coating Composition

에틸셀룰로오스 12.9g12.9 g of ethyl cellulose

히드록시프로필메칠셀룰로오스 25.8gHydroxypropyl Methyl Cellulose 25.8g

디아세틸화된 모노글리세리드 4.5g4.5 g diacetylated monoglycerides

메칠렌 크로라이드 597gMethylene Chloride 597g

에탄올 132g132 g of ethanol

표1) 용출시험 결과Table 1 Dissolution test results

1시간1 hours 2시간2 hours 3시간3 hours 4시간4 hours 5시간5 hours 6시간6 hours 7시간7 hours 8시간8 hours 9시간9 hours 10시간10 hours 1차코팅물Primary coating 55 1515 3030 5050 9898 2차코팅물2nd coating 55 88 1111 1515 2020 4949 9595

(단위: %)(unit: %)

상기와 같이 본 발명이 제공하는것은 비스테로이드성 소염진통제인 에세메타신을 일차 코팅물질로서 pH의존 용해성을 갖는 고분자 물질과 체내 소화효소및 박테리아에 의하여 분해되는 미결정셀룰로오스를 함유하는 1차 코팅 피막층과 바로 이 위에 pH비의존 용해성을 갖고 약물이 장액에 투과 확산되어 방출제어 가능한 2차 코팅물질로 피막이 형성되는것을 특징으로 하는 약물 전달 체계에 관한것으로, 특히 이러한 조성물은 속붕해되는 캅셀제, 단회투여되는 포장된 과립물, 정제에 함유되어 사용되어 다회 투여 되는 제제와 같은 방출 시스템을 만들 수 있도록 하는제제이다.As described above, the present invention provides a primary coating film layer containing a non-steroidal anti-inflammatory analgesic agent, ecemetasin, as a primary coating material and a microcrystalline cellulose decomposed by digestive enzymes and bacteria in the body having a pH-dependent solubility, and digestive enzymes and bacteria. The drug delivery system is characterized in that the coating is formed by a secondary coating material having a pH-independent solubility and the drug is permeately diffused into the intestinal fluid to control the release, in particular, the composition is a disintegrating capsule, a single dose package It is a formulation that can be used in granules and tablets to make a release system such as a multidose formulation.

Claims (4)

인체내 결장 및 대장 경로에서 소염진통제인 아세메타신의 방출 조절하기 위한 약물 방출 제어 시스템에 관한 조성물에 관한 것으로 입자의 크기가 5mm이하이며, 체내 소화관내의 pH7.0이상에서 용해되는 pH 의존 용해성 고분자 물질을 1차 피막물질로 구성되고, 위액에 의하여 용해되지 않고 투과성을 갖는 pH 비의존 용해성 고분자 물질을 1종 또는 그 이상으로 구성됨을 특징으로 하는 경구용 의약 조성물.A composition related to a drug release control system for controlling the release of acemethacin, an anti-inflammatory analgesic agent in the colon and colorectal pathways in the human body, wherein the particle size is 5 mm or less, and the pH-dependent soluble polymer is dissolved at pH 7.0 or higher in the digestive tract of the body. A pharmaceutical composition for oral use, characterized in that the substance is composed of a primary coating material, and is composed of one or more of pH independent soluble polymer materials which are not dissolved by gastric fluid and have permeability. 1항에 있어서 pH 의존 용해성 고분자 물질이라 함은, 메타아크릴산과 메타아크릴산 메칠 에스테르, 프탈산 초산 셀룰로오스, 프탈산 히드록시프로필메칠셀룰로오스, 프탈산 폴리비닐 아세테이트, 셀락, 호박산 히드록시프로필메칠셀룰로오스 아세테이트, 카르복시-메칠셀룰로오스, 셀룰로오스 아세테이트 트리메리테이트, 말레신산과 프탈산유도체의 공중합체를 기본으로 하는 음이온성 고분자 물질로 구성된 그룹을 함유하는 조성물.According to claim 1, the pH-dependent soluble high molecular substance means methacrylic acid and methacrylic acid methyl ester, phthalic acid cellulose acetate, phthalic acid hydroxypropylmethylcellulose, phthalic acid polyvinyl acetate, shellac, succinate hydroxypropylmethylcellulose acetate, carboxy-methyl A composition containing a group consisting of anionic polymeric materials based on cellulose, cellulose acetate trimellitate, a copolymer of maleic acid and a phthalic acid derivative. 1항에 있어서 위액에 의하여 용해되지 않고 투과성을 갖는 pH 비의존 용해성 고분자 물질이라 함은, 4급 암모니움기의 낮은 함량을 갖는 아크릴산과 메타크릴산 에스테르, 에칠 아크릴레이트와 메타크릴레이트를 기본으로 하는 중성 코폴리머, 에칠셀룰로오스, 폴리에칠렌, 폴리실록산을 함유하는 조성물.According to claim 1, pH independent soluble polymer material which is not dissolved by gastric fluid and has permeability is neutral based on acrylic acid and methacrylic acid ester, ethyl acrylate and methacrylate having low content of quaternary ammonium group. A composition containing a copolymer, ethylcellulose, polyethylene, polysiloxane. 1항에 있어서 pH 의존 용해성 고분자 물질은 코아와 직접 접촉하는 내부에 피막을 형성함을 특징으로 하는 조성물.The composition of claim 1 wherein the pH dependent soluble polymeric material forms a coating therein in direct contact with the core.
KR1020010024824A 2001-05-08 2001-05-08 Method for controlled release of acemetacin in the intestinal tract and more particularly in the colon KR20010069756A (en)

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Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR910006125A (en) * 1989-09-27 1991-04-27 완다 케이.덴슨-로우 Method and apparatus for applying adhesive to optical fibers during winding
US5171580A (en) * 1988-10-20 1992-12-15 Boehringer Ingelheim Italia S.P.A. Orally-pharmaceutical preparations with colon selective delivery
KR950010881A (en) * 1993-10-07 1995-05-15 마틴 그리네 Sustained-release oral opioid formulations
US5643602A (en) * 1989-11-22 1997-07-01 Astra Aktiebolag Oral composition for the treatment of inflammatory bowel disease
WO1998027967A1 (en) * 1996-12-20 1998-07-02 Dumex-Alpharma A/S Release-controlled coated tablets
KR0175935B1 (en) * 1990-03-06 1999-03-20 카를리 파비오 Therapeutic compositions with controlled release of medicaments supported on crosslinked polymers and coated with polymer films, and their preparation process
US5900252A (en) * 1990-04-17 1999-05-04 Eurand International S.P.A. Method for targeted and controlled release of drugs in the intestinal tract and more particularly in the colon
US6039979A (en) * 1999-01-13 2000-03-21 Laboratoires Prographarm Multiparticulate pharmaceutical form with programmed and pulsed release and process for its preparation
US6156340A (en) * 1996-03-29 2000-12-05 Duquesne University Of The Holy Ghost Orally administrable time release drug containing products
KR20010006348A (en) * 1997-04-15 2001-01-26 빌프리더 하이더 Analgesic Combination

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5171580A (en) * 1988-10-20 1992-12-15 Boehringer Ingelheim Italia S.P.A. Orally-pharmaceutical preparations with colon selective delivery
KR910006125A (en) * 1989-09-27 1991-04-27 완다 케이.덴슨-로우 Method and apparatus for applying adhesive to optical fibers during winding
US5643602A (en) * 1989-11-22 1997-07-01 Astra Aktiebolag Oral composition for the treatment of inflammatory bowel disease
KR0175935B1 (en) * 1990-03-06 1999-03-20 카를리 파비오 Therapeutic compositions with controlled release of medicaments supported on crosslinked polymers and coated with polymer films, and their preparation process
US5900252A (en) * 1990-04-17 1999-05-04 Eurand International S.P.A. Method for targeted and controlled release of drugs in the intestinal tract and more particularly in the colon
KR950010881A (en) * 1993-10-07 1995-05-15 마틴 그리네 Sustained-release oral opioid formulations
US6156340A (en) * 1996-03-29 2000-12-05 Duquesne University Of The Holy Ghost Orally administrable time release drug containing products
WO1998027967A1 (en) * 1996-12-20 1998-07-02 Dumex-Alpharma A/S Release-controlled coated tablets
KR20010006348A (en) * 1997-04-15 2001-01-26 빌프리더 하이더 Analgesic Combination
US6039979A (en) * 1999-01-13 2000-03-21 Laboratoires Prographarm Multiparticulate pharmaceutical form with programmed and pulsed release and process for its preparation

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