KR100341664B1 - Amitriptyline granule as a controlled release system and the preparation method thereof - Google Patents
Amitriptyline granule as a controlled release system and the preparation method thereof Download PDFInfo
- Publication number
- KR100341664B1 KR100341664B1 KR1019990039518A KR19990039518A KR100341664B1 KR 100341664 B1 KR100341664 B1 KR 100341664B1 KR 1019990039518 A KR1019990039518 A KR 1019990039518A KR 19990039518 A KR19990039518 A KR 19990039518A KR 100341664 B1 KR100341664 B1 KR 100341664B1
- Authority
- KR
- South Korea
- Prior art keywords
- granules
- amitriptyline
- methacrylic acid
- coating
- grams
- Prior art date
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- 230000005062 synaptic transmission Effects 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
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- 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
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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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
- A61K9/5089—Processes
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Abstract
본 발명은 제어방출형 아미트리프틸린 과립 및 그의 제조방법에 관한 것이다. 더욱 구체적으로, 본 발명은 아미트리프틸린의 약물동력학적 특성을 반영한 모의 용출곡선을 컴퓨터 시뮬레이션을 이용해 작성한 후 실제 용출이 모의용출곡선에 일치하도록 결정핵에 2중 코팅을 하여 매트릭스 제어와 막 제어가 동시에 가능한 과립제를 제조하는 방법에 관한 것이다. 본 발명에 따라 제공되는 아미트리프틸린 제어방출형 과립제는 위액과 장액에서 모의용출곡선에 맞게끔 지속적으로 방출되어 이상적인 혈중농도곡선을 나타내며 지속적인 흡수 및 높은 생체이용율을 나타내고 생산공정이 용이하며 생산수율이 높은 이점이 있다.The present invention relates to controlled release amitriptyline granules and a method for producing the same. More specifically, the present invention creates a simulated dissolution curve reflecting the pharmacokinetic properties of amitriptyline by computer simulation, and then double-coated the crystal nuclei so that the actual dissolution matches the simulated dissolution curve. At the same time relates to a method for producing possible granules. Amitriptyline controlled release granules provided in accordance with the present invention are continuously released to match the simulated dissolution curves in gastric and intestinal fluids, indicating an ideal blood concentration curve, continuous absorption and high bioavailability, and easy to produce and yield. This has a high advantage.
Description
본 발명은 제어방출형 아미트리프틸린 과립 및 그의 제조방법에 관한 것이다.The present invention relates to controlled release amitriptyline granules and a method for producing the same.
아미트리프틸린은 삼환계 항우울제로서 지금까지 수십년 동안 가장 널리 사용되어 온 약물이다. 약리작용기전은 아직까지 명확하게 밝혀지지는 않았지만 대뇌의 신경전달과정에서 세로토닌(serotonin), 노르에피네프린(norepinephrine)등 아민신경전달물질이 시냅스에서 시냅스전 신경말단으로 재흡수되는 것을 차단하여 신경전달물질의 유효성(availability)을 증가시킴으로써 항우울 효능을 갖는 것으로 알려져 있다. 특히 아미트리프틸린은 세로토닌을 주로 차단하는 약물로 노르에피네프린을 주로 차단하는 약물들에 비해 진정작용이 크다. 그러나 이 약물은 항콜린성 작용에 기인한 부작용 (구갈, 변비, 뇨의 정체, 빈맥, 부정맥, 체위성 저혈압 등)과 항히스타민 작용에 기인한 졸음 등의 부작용이 있고, 자살을 기도할 우려가 있는 우울증 환자에 있어서 다량 복용에 의한 사망 가능성이 높아 사용의 제한이따르는 단점이 있다. 최근에 개발된 세로토닌 선택성 재흡수 억제제(SSRI제)가 부작용이 적고 안전역이 크다는 장점이 있지만, 임상적으로 강박증을 동반한 우울증이나 신경성 식욕부진증 및 거식증에는 삼환계 항우울제가 더 유효한 것으로 알려져 있어, 대개 삼환계 항우울제가 1차 선택 약물로 이용되고 있다.Amitriptyline is a tricyclic antidepressant and has been the most widely used drug for decades. The mechanism of pharmacological action has not yet been elucidated, but the neurotransmitter blocks the reabsorption of amine neurotransmitters such as serotonin and norepinephrine from synapses to presynaptic nerve endings during cerebral neurotransmission. It is known to have antidepressant efficacy by increasing its availability. In particular, amitriptyline is a drug that mainly blocks serotonin and has a greater sedation effect than drugs that block norepinephrine. However, the drug has side effects due to anticholinergic action (eg, constipation, constipation, urine stagnation, tachycardia, arrhythmia, postural hypotension) and drowsiness due to antihistamine action, and depression that may cause suicide. In patients, there is a disadvantage in that there is a high possibility of death due to high doses, which leads to limitation of use. Although recently developed serotonin selective reuptake inhibitors (SSRIs) have fewer side effects and a greater safety margin, tricyclic antidepressants are known to be more effective for clinically compulsive depression, anorexia nervosa and anorexia. Tricyclic antidepressants are being used as the first choice drug.
그러나, 아미트리프틸린제제로서 일반정제 (속방성 당의정 10 mg, 25 mg/정)는 급격한 혈중농도 상승으로 인한 상기와 같은 여러가지 부작용이 나타나 환자가 복용을 꺼려하는 경우가 종종 나타나며, 복용법 또한 1일 3회 복용으로 환자의 복약순응도가 매우 낮았다.However, as amitriptyline, regular tablets (10 mg, 25 mg / tablet of rapid-acting dragees) have various side effects due to the rapid rise in blood concentrations, and patients are often reluctant to take them. Three doses per day resulted in very poor patient compliance.
따라서 장기복용이 요구되는 아미트리프틸린제제의 특성상 환자순응도를 높일 수 있도록 1일 1회 복용이 가능하고, 최적의 혈중농도를 나타내어 최고의 치료효과가 가능하도록 아미트리프틸린을 지속적으로 방출시킬 수 있는 제어방출형 제제의 개발이 요구되어 왔다.Therefore, it is possible to take once a day to increase patient compliance due to the nature of amitriptyline, which requires long-term use, and can continuously release amitriptyline to achieve the best therapeutic effect by showing optimal blood concentration. There has been a need for the development of controlled release formulations.
지금까지의 서방형 과립 제조 기술로서는 유일하게, 사로텐 리타드 (Saroten retard, Lundbeck)라는 상품명으로 시판되고 있는 제제가 있다. 이 경우, 속방성 과립과 함께, 고분자막으로 코팅하여 방출속도를 조절한 서방성 과립을 혼합하여 약물의 방출속도를 조절하였다. 이러한 방법은 한 제제당 2차례 이상의 공정을 거쳐 2종 이상의 과립을 제조한 후 함량 및 용출속도를 측정하여 혼합비를 계산한 후 혼합하여 제조하여야 하기때문에 제법이 까다롭고 생산수율이 낮은 단점이 있으며, 또한 pH에 따른 용출양상도 달라 인체의 위장관 pH변화에 따라 용출 양상이 달라지는 문제점이 지적되어 왔다. pH에 따라 용출이 변화된다는 것은 복용 시간, 음식섭취, 환자의 건강상태 등에 따라 아미트리프틸린의 흡수가 달라져 목적으로 하는 최고의 약효를 부작용 없이 얻는 것이 불가능하다는 것을 의미한다.As the sustained-release granule manufacturing technology up to now, there is a formulation commercially available under the trade name Saroten retard (Lundbeck). In this case, together with the immediate release granules, the release rate of the drug was controlled by mixing the sustained release granules coated with a polymer membrane to control the release rate. This method has a disadvantage in that the manufacturing method is difficult and the production yield is low because the two or more granules are prepared per two formulations, and then the content and the dissolution rate are calculated to calculate the mixing ratio and then mixed. In addition, it has been pointed out that the dissolution pattern varies depending on the pH of the human gastrointestinal tract. The change in dissolution according to pH means that the absorption of amitriptyline varies depending on the time taken, food intake, and the patient's health, making it impossible to obtain the desired drug without side effects.
이에 본 발명자들은 장기복용이 요구되는 아미트리프틸린제제의 특성에 비추어 환자순응도를 높이기 위해 1일 1회 복용이 가능하고, 최적의 혈중농도를 나타내어 최고의 치료효과가 가능하도록 아미트리프틸린을 지속적으로 방출시킬 수 있으면서, 또한 제조공정도 간편한 아미트리프틸린 제제를 개발하기 위해 본 발명을 수행하였으며, 특히 고분자의 종류와 양의 조절을 통한 매트릭스 제어 및 막 제어가 가능한 제제에 대하여 집중적인 연구를 수행하여 본 발명을 완성하였다.Therefore, the present inventors can take once a day to increase patient compliance in view of the characteristics of amitriptyline, which requires long-term use, and continue to use amitriptyline to achieve the best therapeutic effect by showing the optimal blood concentration. The present invention was carried out to develop amitriptyline formulations which can be released in a simple manner and also have a simple manufacturing process. In particular, intensive studies have been conducted on formulations capable of controlling matrix and controlling membranes by controlling the type and amount of polymer. The present invention is completed by carrying out.
도 1은 제어방출형 아미트리프틸린 과립이 최적의 약물동력학적 특성을 갖도록 컴퓨터 시뮬레이션을 통해 작성한 모의 용출곡선을 표현한 모식도이다.FIG. 1 is a schematic diagram showing a simulated dissolution curve prepared through computer simulation so that controlled-release amitriptyline granules have optimal pharmacokinetic properties.
도 2는 본 발명에서 제어방출형 아미트리프틸린 과립의 제조를 위해 사용될 수 있는 원심과립기(CF-granulator)의 한 예로서 그의 간단한 모식도이다.Figure 2 is a simple schematic diagram of an example of a centrifugal granulator (CF-granulator) that can be used for the production of controlled release amitrifthilin granules in the present invention.
도 3은 본 발명에 따라 제조된 과립의 주사현미경(SEM) 사진이다. 용매분사법(Solvent spraying method)으로 제조한 실시예 11의 과립에 대하여 도 3aa는 전체적인 모폴로지를, 그리고 도 3ab는 과립의 표면을 확대하여 보여주는 사진이며, 분말도포법(Powder layering method)으로 제조한 실시예 1의 과립에 대하여 도 3ba는 전체적인 모폴로지를, 그리고 도 3bb는 과립의 표면을 확대하여 보여주는 사진이다.Figure 3 is a scanning microscope (SEM) picture of the granules prepared according to the present invention. For the granules of Example 11 prepared by the solvent spraying method, FIG. 3aa is an enlarged view of the morphology, and FIG. 3ab is a photograph showing an enlarged surface of the granules, prepared by the powder layering method. For the granules of Example 1, Figure 3ba is an overall morphology, and Figure 3bb is an enlarged photograph showing the surface of the granules.
도 4는 본 발명에 따라 제조된 실시예 1의 과립에 대한 용출곡선을, 컴퓨터 시뮬레이션을 이용해 작성한 모의 용출곡선과 비교하여 나타낸 그래프이다.Figure 4 is a graph showing the dissolution curve for the granules of Example 1 prepared according to the present invention, compared with the simulated dissolution curve created using computer simulation.
도 5는 본 발명에 따라 제조된 실시예 1의 과립을 충진한 경질캅셀제와 아미트리프틸린 일반정제를 아미트리프틸린으로서 50mg 해당량을 건강한 성인 남자에게 투여한 후, 시간 경과에 따른 아미트리프틸린의 혈중농도 변화 추이를 나타낸 그래프이다.Figure 5 is a hard capsule filled with the granules of Example 1 prepared in accordance with the present invention and amitriftillin general tablets as amitriptyline 50mg equivalent dose to a healthy adult male, amit over time It is a graph showing the change in blood concentration of riftillin.
도 6a는 아미트리프틸린 일반정제에 대하여, 도 6b는 시판 중인 서방성 제제 사로텐 리타드에 대하여, 그리고 도 6c는 본 발명에 따라 실시예 1에서 제조된 과립에 대하여 pH 조건에 따른 용출양상 변화를 나타낸 그래프이다.Figure 6a is for amitriphthylin tablets, Figure 6b is a commercially released sustained-release formulation Sarotene Ritad, and Figure 6c is a dissolution pattern according to pH conditions for the granules prepared in Example 1 according to the present invention It is a graph showing the change.
본 발명은 제어방출형 아미트리프틸린 과립 및 그의 제조방법에 관한 것이다. 더욱 구체적으로는, 당으로 구성된 결정핵에 1) 1차 코팅층으로서, 아미트리프틸린, 매트릭스층용 방출조절제 및 결합제를 포함하는 매트릭스층이 도포되어 있고 2) 여기에 2차 코팅층으로서, 막형성용 고분자물질를 포함하는 피막층이 도포되어 있어서, 매트릭스 제어와 막 제어의 이중 방출 조절 기전을 갖는 제어방출형 아미트리프틸린 과립 및 그의 제조방법에 관한 것이다.The present invention relates to controlled release amitriptyline granules and a method for producing the same. More specifically, 1) a primary coating layer is coated on a crystal nucleus composed of sugar, and a matrix layer containing amitriptyline, a release control agent and a binder for the matrix layer, and 2) a secondary coating layer is used for forming a film. A coating layer comprising a polymer material is applied, and the present invention relates to a controlled-release type amitriptyline granule having a dual release control mechanism of matrix control and membrane control, and a method for producing the same.
본 발명의 과립제 중심에는 결정핵이 존재하며, 이 결정핵은 당 단독 또는당과 침강탄산칼슘, 탈크, 전분의 혼합물로 구성된다. 결정핵이 당 단독으로 구성되는 경우에, 사용되는 당의 예로는 백당, D-만니톨, D-소르비톨 등이 포함되며, 바람직하게는 상품명 논파레일(Nonpareil, Freund Co., Japan)로 시판되는 결정핵을 사용할 수 있다. 당과 함께 침강탄산칼슘, 탈크, 전분과의 혼합물로 구성되는 경우에는, 구성 당의 예로는 백당, D-만니톨, D-소르비톨 등이 포함되며 입자 크기별로 선별된 당과 침강탄산칼슘, 탈크, 전분 등의 혼합물을 에칠셀룰로오스(ethylcellulose), 히드록시프로필셀룰로오스, 히드록시프로필메칠셀룰루오스, 포비돈, 크로스포비돈, 폴록사머류, 젤라틴 등의 적절한 결합제, 바람직하게는 젤라틴을 사용하여 원심과립기 또는 유동층 과립기를 사용하여 제조된 것을 사용할 수 있다.In the center of the granules of the present invention, crystal nuclei exist, which are composed of sugar alone or a mixture of sugar and precipitated calcium carbonate, talc, and starch. In the case where the crystal nucleus is composed of sugar alone, examples of the sugar used include sucrose, D-mannitol, D-sorbitol, and the like, and are preferably sold under the trade name Nonpareil (Freund Co., Japan). Can be used. When composed of precipitated calcium carbonate, talc, and starch together with sugars, examples of constituent sugars include white sugar, D-mannitol, D-sorbitol, etc., and sugars selected by particle size and precipitated calcium carbonate, talc, starch. The mixture of the same or the like is centrifugal granulator or fluidized bed using an appropriate binder such as ethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, crospovidone, poloxamers, gelatin, preferably gelatin. What is manufactured using a granulator can be used.
본 발명에 따르는 과립제 중 결정핵의 함량은 제조된 과립제 총중량에 대하여 5 내지 60%를 차지한다.The content of crystal nuclei in the granules according to the present invention accounts for 5 to 60% based on the total weight of the granules produced.
본 발명에 따르는 과립제 중 원료 아미트리프틸린의 함량은 과립제 총중량에 대하여 5 내지 50%이다.The content of raw amitriptyline in the granules according to the invention is 5 to 50% by weight of the granules total weight.
본 발명에 따르는 과립제의 매트릭스층용 방출조절제로는 카르복시메칠셀룰로오스 칼슘, 카르복시메칠셀룰로오스 나트륨, 히드록시메칠셀룰로오스, 히드록시프로필메칠셀룰로오스, 포비돈, 크로스포비돈, 폴록사머류, 폴리에칠렌옥사이드류, 젤라틴, 자인(zein), 쉘락, 마이바세트(Myvacet), 메타크릴산디메칠아미노에칠·메타크릴산메칠 코폴리머, 메타크릴산에칠·메타크릴산염화트리메칠암모늄에칠 코폴리머, 메타크릴산·아크릴산에칠코폴리머, 메타크릴산·메타크릴산메칠 코폴리머 60, 기타 메타크릴산 코폴리머 유도체로 이루어진 군에서 선택되는 1종 이상의 성분을 사용할 수 있다.The release control agent for the matrix layer of the granules according to the present invention includes carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, povidone, crospovidone, poloxamers, polyethylene oxides, gelatin, zein), shellac, myvacet, methacrylate methyl methacrylate methyl methacrylate copolymer, methacrylate methacrylate trimethylammonium ethylene copolymer, methacrylic acid acrylic acid One or more components selected from the group consisting of ethyl copolymer, methacrylic acid and methacrylic acid methyl copolymer 60, and other methacrylic acid copolymer derivatives can be used.
본 발명에 따르는 과립제 중 매트릭스층용 방출조절제 함량은 과립제 총 중량에 대하여 10 내지 80% 이다.The release control agent content for the matrix layer in the granules according to the present invention is 10 to 80% based on the total weight of the granules.
본 발명에 따르는 과립제의 매트릭스층에 포함되는 결합제는 약물 및 매트릭스층용 방출조절제를 결정핵에 코팅시키기 위하여 사용되며 포비돈, 히드록시메칠셀룰로오스, 히드록시프로필메칠셀룰로오스, 크로스포비돈, 젤라틴, 메타크릴산디메칠아미노에칠·메타크릴산메칠코폴리머, 메타크릴산에칠·메타크릴산염화트리메칠암모늄에칠코폴리머, 메타크릴산·아크릴산에칠코폴리머, 메타크릴산·메타크릴산메칠코폴리머60 및 기타 메타크릴산코폴리머 유도체로 이루어진 군에서 선택되는 1종 이상의 성분이 사용될 수 있다. 본 발명에 따르는 과립제 중 결합제의 함량은 과립제 총중량에 대하여 0.1 내지 5%이다.The binder included in the matrix layer of the granules according to the present invention is used to coat the crystal nuclei with the drug and the release control agent for the matrix layer.Povidone, hydroxymethylcellulose, hydroxypropylmethylcellulose, crospovidone, gelatin, methacrylate Aminoethyl Methacrylic Acid Methyl Copolymer, Methacrylic Acid Ethyl Methacrylate Trimethylammonium Ethyl Copolymer, Methacrylic Acid, Acrylic Acid Ethyl Copolymer, Methacrylic Acid, Methacrylic Acid Methyl Copolymer 60 and Others One or more components selected from the group consisting of methacrylic acid copolymer derivatives may be used. The content of the binder in the granules according to the invention is 0.1 to 5% by weight of the granules total weight.
또한 본 발명에 따르는 과립제의 매트릭스층은 부형제 및 활택제가 추가로 포함될 수 있다. 부형제 및 활택제는 분말상태로서 적용되며 매트릭스층 형성을 용이하게 도와 주며 나아가서 매트릭스층의 붕해를 촉진하는 것과 같이 그 물성에 영향을 줄 수 있다. 부형제의 예로서는 미결정셀룰로오스 (Avicel 류), 인산일수소칼슘, 유당, 백당, 전분 등을 들 수 있으며, 활택제의 예로서는 탈크, 스테아린산 마그네슘, 경질무수규산 등을 들 수 있다.In addition, the matrix layer of the granules according to the present invention may further contain excipients and lubricants. Excipients and glidants are applied in powder form and can facilitate the formation of the matrix layer and further influence its properties, such as promoting disintegration of the matrix layer. Examples of the excipient include microcrystalline cellulose (Avicel), calcium dihydrogen phosphate, lactose, white sugar, starch and the like, and examples of the lubricant include talc, magnesium stearate, and hard silicic anhydride.
본 발명에 따르는 과립제의 피막층을 형성하는 막형성용 고분자물질로서는, 메타크릴산디메칠아미노에칠·메타크릴산메칠코폴리머, 메타크릴산에칠·메타크릴산염화트리메칠암모늄에칠코폴리머, 메타크릴산·아크릴산에칠코폴리머, 메타크릴산·메타크릴산메칠코폴리머60, 기타 메타크릴산코폴리머 유도체, 폴리에칠렌옥사이드류, 에칠셀룰로오스, 젤라틴, 카르보폴류, 폴록사머류, 카르복시메칠셀룰로오스나트륨, 카르복시메칠셀룰로오스칼슘, 메칠셀룰로오스, 쉘락, 마이바세트, 자인, 폴리에칠렌글리콜류, 프로필렌글리콜류, 디부칠프탈레이트, 디메칠프탈레이트, 트리에칠시트레이트(triethylcitrate) 및 폴리옥시에칠렌소르비탄모노라우레이트로 이루어진 군에서 선택된 1종 이상의 성분을 사용할 수 있다. 본 발명에 따르는 과립제 중 막형성용 고분자물질 함량은 과립제 총 중량에 대하여 1 내지 30% 이다.Examples of the film-forming polymer material for forming the coating layer of the granules according to the present invention include methacrylate methylmethacrylate, methacrylate methacrylate, methacrylate methacrylate trimethylammonium ethylene copolymer, and meta. Methacrylic acid, acrylic acid ethyl copolymer, methacrylic acid, methacrylic acid methyl copolymer 60, other methacrylic acid copolymer derivatives, polyethylene oxides, ethyl cellulose, gelatin, carbopols, poloxamers, sodium carboxymethyl cellulose, carboxy Methyl Cellulose Calcium, Methyl Cellulose, Shellac, Mybaset, Zine, Polyethylene Glycol, Propylene Glycol, Dibutyl Phthalate, Dimethyl Phthalate, Triethylcitrate and Polyoxyethylene Sorbitan Monolaurate One or more components selected from the group can be used. The film-forming polymer material content of the granules according to the present invention is 1 to 30% based on the total weight of the granules.
본 발명에 따르는 제어방출형 아미트리프틸린 과립은 결정핵을 중심으로 하여 1) 1차 코팅층으로서, 유효약물인 아미트리프틸린과 함께 매트릭스층용 방출조절제, 결합제를 함유하는 매트릭스층과 2) 2차 코팅층으로서, 막형성용 고분자물질를 포함하는 피막층으로 구성되어 있어서 약물인 아미트리프틸린의 방출이 매트릭스제어 및 막제어가 함께 이루어지며, 체내흡수가 위에서부터 소장전반에 걸쳐 일어나는 아미트리프틸린의 특성에 맞추어 체내 최대흡수를 위해 컴퓨터 시뮬레이션에 의해 계산해 낸 모의용출곡(도 1)과 일치하는 용출양상을 나타낸다. 여기에서 컴퓨터 시뮬레이션은 다음과 같은 이론을 토대로 다음의 방법으로 실시하였다:Controlled-release amitriptyline granules according to the present invention are based on crystal nuclei, 1) as a primary coating layer, a matrix layer containing a release control agent, a binder for the matrix layer together with an effective drug amitriptyline, and 2) 2 As a primary coating layer, it is composed of a film layer containing a film-forming polymer material, and the release of the drug, amitriptyline, is controlled by matrix control and membrane control. The dissolution patterns consistent with the simulated dissolution curves (FIG. 1) calculated by computer simulation for maximum absorption in the body according to the characteristics are shown. Here computer simulations were carried out in the following way based on the following theories:
염산아미트리프틸린의 흡수속도정수는 3.0 h-1으로서 매우 빨리 흡수되어 최고 혈중농도에 도달한다. 이렇게 흡수속도가 빠른 약물은 약물의 방출속도가 곧 약물의 흡수속도가 된다. 따라서 약물의 방출속도를 조절하여 약물의 흡수속도를 조절하고 이를 통하여 약물의 혈중농도를 조절하는 것이다. 아미트리프틸린은 위에서부터 소장전반에 걸쳐 흡수가 일어나므로 제어방출형 제제의 요건을 갖추고 있으며, 최적의 혈중농도를 유지하기 위한 최적의 방출속도를 컴퓨터 시뮬레이션을 이용하여 구하였다. 변수를 F=0.66, ke=0.027, Vd=770000 및 D=75000으로 하여 시뮬레이션한 결과 아미트리프틸린의 최적 흡수속도는 0.3으로 나타났으며 이를 근거로, 와그너-넬슨법(Wagner-Nelson method)에 따라 제제설계 및 모의용출곡선(도 1)을 구하였다.The absorption rate constant of amitriptyline hydrochloride is 3.0 h −1, which is absorbed very quickly and reaches the highest blood concentration. This fast absorption rate drug is the drug release rate is the drug absorption rate. Therefore, by adjusting the release rate of the drug to control the rate of absorption of the drug through it to control the blood concentration of the drug. Amitriptyline is absorbed from above and throughout the small intestine, so it meets the requirements for controlled release formulations. Simulation results for the parameters F = 0.66, ke = 0.027, Vd = 770000, and D = 75000 showed that the optimal absorption rate of amitriptyline was 0.3, based on the Wagner-Nelson method. According to the formulation design and simulation dissolution curve (Fig. 1) was obtained.
본 발명의 또다른 태양은, 본 발명에 따르는 제어방출형 아미트리프틸린 과립을 원심과립기, 유동층과립기 또는 이와 유사한 장치상에서 결정핵을 회전시키면서 (1) 아미트리프틸린과 매트릭스제어용 방출조절제를 함유한 분말을 첨가하면서, 용매에 녹인 결합제를 분무하여 매트릭스층으로 1차 코팅하고 (2) 생성된 코팅과립에, 용매에 녹인 막형성용 고분자물질을 분무하여 2차 코팅함으로써 제조하는 방법에 관한 것이다.(이하 첫번째의 제조방법이라 칭한다.)Another aspect of the present invention is to provide a controlled release of amitrifthilin granules according to the present invention in a centrifugal granulator, fluidized bed granulator or similar device while rotating the crystal nuclei. While adding the powder containing, spraying the binder dissolved in the solvent to the primary coating with the matrix layer (2) to the resulting coating granules, by spraying the secondary polymer by spraying the film-forming polymer material dissolved in the solvent (Hereinafter referred to as first manufacturing method)
본 발명의 또다른 태양은, 본 발명에 따르는 제어방출형 아미트리프틸린 과립을 원심과립기, 유동층과립기 또는 이와 유사한 장치상에서 결정핵을 회전시키면서 (1) 매트릭스제어용 방출조절제를 함유한 분말을 첨가하면서, 용매에 녹인 아미트리프틸린과 결합제를 분무하여 매트릭스층으로 1차 코팅하고 (2) 생성된 코팅과립에, 용매에 녹인 막형성용 고분자물질을 분무하여 2차 코팅함으로써 제조하는 방법에 관한 것이다. (이하 두번째의 제조방법이라 칭한다.)Another aspect of the present invention is to provide a controlled release amitrifthilin granules according to the present invention, wherein the granules are rotated on a centrifugal granulator, fluidized bed granulator or similar device, and (1) a powder containing a release control agent for controlling the matrix. While adding, by spraying amitriptyline and a binder dissolved in a solvent to the first coating with a matrix layer (2) to the resulting coating granules, by spraying a secondary polymer by spraying a film-forming polymer material dissolved in a solvent It is about. (Hereinafter referred to as a second manufacturing method.)
상기 1차 코팅에서 결합제를 녹이는 용매로서는 물, 알콜, 아세톤, 아세토니트릴, 염화메칠렌, 에테르, 헥산, 클로로포름, 테트라히드로푸란, 디메칠설폭사이드, 에칠아세테이트 및 메칠아세테이트로 구성되는 군에서 선택되는 1종 이상을 성분을 사용할 수 있으며, 이중 가장 바람직하게는 물과 에탄올, 메탄올과 같은 알콜용매를 사용할 수 있다. 용매의 사용량은 결합제 중량에 대해 5 내지 50 중량부의 양으로 사용된다.The solvent for dissolving the binder in the primary coating is selected from the group consisting of water, alcohol, acetone, acetonitrile, methylene chloride, ether, hexane, chloroform, tetrahydrofuran, dimethylsulfoxide, ethyl acetate and methyl acetate. One or more components may be used, and most preferably water and alcohol solvents such as ethanol and methanol may be used. The amount of solvent used is used in an amount of 5 to 50 parts by weight based on the weight of the binder.
결정핵에 매트릭스층을 형성시킬 때 아미트리프틸린을 첨가하는 방법에는 아미트리프틸린을 분말상으로 첨가하는 분말도포법(상기 첫번째의 제조방법)과 아미트리프틸린을 결합액에 혼합 용해시켜 분사하는 용매분사법(상기 두번째의 제조방법)이 있으며, 분무액의 점도상의 문제와 과립의 외관상의 문제에서는 분말도포법을 사용하는 것이 바람직하다. 분말도포법에서 매트릭스제어용 방출조절제는 약물과 함께 분말상태로서 결정핵에 첨가시킬 수 있다,The method of adding amitriptyline when forming the matrix layer on the crystal nuclei includes a powder coating method (a first production method described above) in which amitriptyline is added in powder form, and amitriptyline is mixed and dissolved in a binder solution and sprayed. There is a solvent spraying method (the second production method described above), and it is preferable to use the powder coating method in the problem of the viscosity of the spray liquid and the problem of the appearance of the granules. In powder coating, the matrix-controlled release controlling agent can be added to the crystal nucleus as a powder together with the drug.
상기 2차 코팅에서 막형성용 고분자물질을 녹이는 용매로서는 물, 알콜, 아세톤, 염화메칠렌, 에테르, 클로로포름, 테트라히드로푸란 및 에칠아세테이트로 구성된 군에서 선택되는 1종 이상의 성분을 사용할 수 있으며 가장 바람직하게는 에탄올, 메탄올과 같은 알콜 용매를 사용할 수 있다. 용매의 사용량은 고분자물질의종류에 따라 달라질 수 있으나 일반적으로 막형성용 고분자물질의 중량에 대해 10 내지 100 중량부의 양으로 사용된다.As the solvent for dissolving the polymer for forming a film in the secondary coating, one or more components selected from the group consisting of water, alcohol, acetone, methylene chloride, ether, chloroform, tetrahydrofuran and ethyl acetate may be used, and most preferably. Preferably, alcohol solvents such as ethanol and methanol can be used. The amount of the solvent may vary depending on the type of the polymer material, but is generally used in an amount of 10 to 100 parts by weight based on the weight of the polymer material for film formation.
본 발명의 제조방법에 따르면, 매트릭스 층과 피막층으로 구성되어 약물방출이 매트릭스 제어 방식과 막 제어 방식이 혼합된 형태로 나타나는 본 발명의 제어방출형 아미트리프틸린 과립을 용이하게 제조할 수 있다.According to the production method of the present invention, it is possible to easily prepare the controlled-release amitriphthrin granules of the present invention, which is composed of a matrix layer and a coating layer, and the drug release is a mixture of the matrix control method and the membrane control method.
상기한 바와 같이 본 발명의 과립은 결정핵이나 과립을 회전 또는 부유시키면서 분말을 첨가하고 코팅액을 분무하여 피복시킬 수 있는 장치, 예를 들면 유동층과립기, 원심 과립기 또는 이와 유사한 장치를 사용하여 제조할 수 있다. 예를 들어 원심 과립기를 사용하여 본 발명의 코팅과립제를 제조하는 경우 일반적으로 유입공기의 온도는 실온 내지 80℃, 로터 (rotor) 회전수는 100 내지 300 rpm, 분무액 송출 펌프 속도는 5 내지 100 rpm이 적당하다. 도 2는 본 발명에 사용될 수 있는 원심과립기의 예를 그 모식도로 나타낸 것이다.As described above, the granules of the present invention are prepared using an apparatus capable of coating by spraying the coating solution with the addition of powder while rotating or floating the crystal nucleus or granules, for example, fluidized bed granulator, centrifugal granulator or the like. can do. For example, when preparing the coating granules of the present invention using a centrifugal granulator, generally, the temperature of the inlet air is from room temperature to 80 ° C., the rotor rotation speed is from 100 to 300 rpm, and the spray liquid delivery pump speed is from 5 to 100. rpm is suitable. Figure 2 shows an example of a centrifugal granulator that can be used in the present invention.
본 발명에 따라 제조되는 제어방출형의 아미트리프틸린 과립은 바람직하게는 경질캅셀에 충진하여 캅셀제로 제형화 할 수 있다. 본 발명의 과립제가 캅셀제로 제형화되는 경우에 아미트리프틸린의 용량을 고려하여 1 캅셀당 아미트리프틸린으로서 25 mg 및 50 mg이 함유되도록 하는 것이 바람직하다.The controlled release amitriptyline granules prepared according to the present invention may be preferably filled into hard capsules and formulated into capsules. When the granules of the present invention are formulated as capsules, it is preferred to contain 25 mg and 50 mg as amitriptyline per capsule, taking into account the dose of amitriptyline.
상기한 바와 같이 본 발명에 따라 제형화된 아미트리프틸린 캅셀에 있어서아미트리프틸린 25 mg을 함유한 캅셀제는 시판되고 있는 기존의 10 mg 함유 정제를 1일 3회 투여한 경우와 유사한 생체내 이용율을 나타내며, 따라서 본 발명에 따라 제조된 아미트리프틸린 캅셀제를 사용하는 경우에 아미트리프틸린의 1일 유효용량을 고려할 때 환자에 대한 투약량 감소 및 이에 따른 부작용 발현의 감소, 1일 3회 복용에서 1일 1회 복용으로의 복용횟수 감소로 인한 환자순응도 개선 등의 이점이 있어 약제학적으로 매우 유리하다. 또한 본 발명에 따르는 제제기술은 약물을 함유한 매트릭스층과 고분자피막층으로 구성되어 있어 매트릭스 제어 방출조절과 막 제어 방출조절의 이중효과를 나타내어 체내에서 최대흡수를 나타낼 수 있으며, 모의용출곡선에 일치하는 용출양상을 보여주어 소량의 약물로 복용횟수를 줄이면서 약물이용율을 최대로 높여 최대의 효과를 기대할 수 있다.As described above, in the amitriptyline capsules formulated according to the present invention, a capsule containing 25 mg of amitrifthilin is similar in vivo to the case of administering a commercially available 10 mg tablet three times a day. Utilization rate, and therefore, in consideration of the daily effective dose of amitriptyline capsules prepared according to the present invention, a decrease in the dosage and subsequent onset of side effects, 3 times daily It is very pharmacologically advantageous because there is an advantage of improving patient compliance due to a decrease in the number of doses from dose to once daily. In addition, the formulation technology according to the present invention is composed of a matrix layer and a polymer coating layer containing a drug to exhibit a dual effect of the matrix controlled release control and the membrane controlled release control to show the maximum absorption in the body, which is consistent with the simulated dissolution curve It can be expected to maximize the drug utilization rate by reducing the number of doses with a small amount of drugs by showing the dissolution pattern, the maximum effect.
본 발명은 하기 실시예에 의해 더욱 구체적으로 설명된다. 그러나 본 발명의 범위가 이들 실시예에 의해 어떤 식으로든 제한되는 것은 아니다.The invention is further illustrated by the following examples. However, the scope of the present invention is not limited in any way by these examples.
실시예 1Example 1
A. 1차 코팅A. Primary Coating
결 정 핵 : 논파레일(nonpareil) 400 그램Core: 400 grams of nonpareil
약 물 : 염산아미트리프틸린 1,000 그램Medicines: 1,000 grams of amitriptyline hydrochloride
방출조절제 : 카르복시메칠셀룰로오스나트륨 400 그램Release Controlling Agent: Sodium Carboxymethyl Cellulose 400g
유당 1,300 그램1,300 grams of lactose
탈크 400 그램Talc 400 grams
결 합 제 : 포비돈 40 그램Binder: 40 grams of povidone
용 매 : 에탄올 1,000 그램Solvent: 1,000 grams of ethanol
결정핵을 원심과립기에서 회전시키면서 약물과 방출조절제분말을 도포하기 위해 상기 결합제를 상기의 용매에 용해시킨 결합액을 분사하여 코팅하였다(분말도포법). 이때 원심과립기는 하기 표 1에 기재된 조건으로 작동시켰으며, 아미트리프틸린의 활성저하를 방지하기 위하여 실온으로 유지하였다.In order to apply the drug and the release control agent powder while rotating the crystal nuclei in a centrifugal granulator, the binder solution dissolved in the solvent was sprayed and coated (powder coating method). At this time, the centrifugal granulator was operated under the conditions shown in Table 1, and was maintained at room temperature to prevent deactivation of amitriptyline.
B. 2차 코팅B. Secondary Coating
결정핵 : A의 과립 1,000 그램Seed: 1,000 grams of granules of A
코팅액 : 메타크릴산에칠·메타크릴산염화트리메칠암모늄Coating solution: Ethyl methacrylate / methacrylate trimethylammonium
에칠 코폴리머 70 그램70 grams of ethyl copolymer
메타크릴산·메타크릴산메칠 코폴리머60 7 그램Methacrylic acid, methacrylic acid methyl copolymer 60 7 grams
트리에칠시트레이트(triethylcitrate) 7 그램7 grams of triethylcitrate
탈크 35 그램Talc 35 grams
에탄올 1,400 그램1,400 grams of ethanol
상기 A에서 제조된 코팅과립을 결정핵으로 하여 원심과립기에서 회전시키면서 상기한 바와 같이 구성된 코팅액을 분사하여 코팅시켰다. 이때, 원심과립기는하기 표 1에서 기재된 조건으로 작동시켰으며, 원심과립기의 유입공기는 45℃ 이하가 되도록 유지시켰다.The coating granules prepared in A were used as the crystal nuclei and coated by spraying the coating liquid configured as described above while rotating in a centrifugal granulator. At this time, the centrifugal granulator was operated under the conditions described in Table 1 below, and the inlet air of the centrifugal granulator was maintained at 45 ° C. or less.
실시예 1에서 사용된 원심과립기의 작동조건은 다음 표 1에 기재하였다.The operating conditions of the centrifugal granulator used in Example 1 are described in Table 1 below.
실시예 2Example 2
A. 1차 코팅A. Primary Coating
결 정 핵 : 논파레일(nonpareil) 200 그램Core: 200 grams of nonpareil
약 물 : 염산아미트리프틸 1,000 그램Medicine: 1,000 grams of amitriphthyl hydrochloride
방출조절제 : 히드록시프로필메칠셀룰로오스 200 그램Release control agent: 200 grams of hydroxypropylmethylcellulose
인산일수소칼슘 1,300 그램1,300 grams of calcium monohydrogen phosphate
탈크 40 그램Talc 40 grams
결 합 제 : 메타크릴산에칠·메타크릴산염화트리메칠암모늄Binder: Ethyl methacrylate / methacrylate trimethylammonium
에칠 코폴리머 40 그램Ethyl Copolymer 40g
용 매 : 에탄올 1,000 그램Solvent: 1,000 grams of ethanol
상기의 처방을 사용한 것을 제외하고는 실시예 1과 동일한 방법으로 1차코팅을 실시하였다.The first coating was carried out in the same manner as in Example 1, except that the above prescription was used.
B. 2차 코팅B. Secondary Coating
결정핵 : A의 과립 1,000 그램Seed: 1,000 grams of granules of A
코팅액 : 에칠셀룰로오스 70 그램Coating solution: 70 grams of ethyl cellulose
디메칠프탈레이트 3 그램3 grams of dimethylphthalate
탈크 20 그램20 grams of talc
에탄올 1,400 그램1,400 grams of ethanol
상기 A에서 제조된 코팅과립을 결정핵으로 하여 상기 처방의 코팅액을 분사하여 코팅시켰다. 코팅 조건은 실시예 1과 동일하였다.The coating granules prepared in A were used as crystal nuclei to coat the coating solution of the formulation by spraying. Coating conditions were the same as in Example 1.
실시예 3Example 3
A. 1차 코팅A. Primary Coating
결 정 핵 : 논파레일(nonpareil) 600 그램Core: 600 grams of nonpareil
약 물 : 염산아미트리프틸린 1,000 그램Medicines: 1,000 grams of amitriptyline hydrochloride
방출조절제 : 포비돈 K30 600 그램Release control: Povidone K30 600 grams
전분 1,000 그램1,000 grams of starch
탈크 600 그램Talc 600 grams
결 합 제 : 젤라틴 40 그램Binder: 40 grams of gelatin
용 매 : 정제수 1,000 그램Solvent: 1,000 grams of purified water
상기의 처방을 사용한 것을 제외하고는 실시예 1과 동일한 방법으로 1차코팅을 실시하였다.The first coating was carried out in the same manner as in Example 1, except that the above prescription was used.
B. 2차 코팅B. Secondary Coating
결정핵 : A의 과립 1,000 그램Seed: 1,000 grams of granules of A
코팅액 : 쉘락 100 그램Coating solution: 100 grams of shellac
디메칠프탈레이트 20 그램20 grams of dimethylphthalate
탈크 80 그램Talc 80 grams
에탄올 1,400 그램1,400 grams of ethanol
상기 A에서 제조된 코팅과립을 결정핵으로 하여 상기 처방의 코팅액을 분사하여 코팅시켰다. 코팅 조건은 실시예 1과 동일하였다.The coating granules prepared in A were used as crystal nuclei to coat the coating solution of the formulation by spraying. Coating conditions were the same as in Example 1.
실시예 4Example 4
A. 1차 코팅A. Primary Coating
결 정 핵 : 논파레일(nonpareil) 3,000 그램Core: 3,000 grams of nonpareil
약 물 : 염산아미트리프틸린 500 그램Medicines: 500 grams of amitriptyline hydrochloride
방출조절제 : 포비돈 300 그램Release Control: Povidone 300 grams
미결정셀룰로오스 300 그램300 grams of microcrystalline cellulose
스테아린산마그네슘 300 그램300 grams of magnesium stearate
결 합 제 : 포비돈 20 그램Binder: 20 grams of povidone
용 매 : 에탄올 1,000 그램Solvent: 1,000 grams of ethanol
상기의 처방을 사용한 것을 제외하고는 실시예 1과 동일한 방법으로 1차코팅을 실시하였다.The first coating was carried out in the same manner as in Example 1, except that the above prescription was used.
B. 2차 코팅B. Secondary Coating
결정핵 : A의 과립 1,000 그램Seed: 1,000 grams of granules of A
코팅액 : 메타크릴산에칠·메타크릴산염화트리메칠암모늄Coating solution: Ethyl methacrylate / methacrylate trimethylammonium
에칠코폴리 70 그램Ethyl copoly 70 g
메타크릴산·메타크릴산메칠코폴리머60 10 그램Methacrylic acid, methacrylic acid methyl copolymer 60 10 g
트리에칠시트레이트(triethylcitrate) 14 그램14 grams of triethylcitrate
탈크 70 그램70 grams of talc
에탄올 1,400 그램1,400 grams of ethanol
상기 A에서 제조된 코팅과립을 결정핵으로 하여 상기 처방의 코팅액을 분사하여 코팅시켰다. 코팅 조건은 실시예 1과 동일하였다.The coating granules prepared in A were used as crystal nuclei to coat the coating solution of the formulation by spraying. Coating conditions were the same as in Example 1.
실시예 5Example 5
A. 1차 코팅A. Primary Coating
결 정 핵 : 논파레일(nonpareil) 400 그램Core: 400 grams of nonpareil
약 물 : 염산아미트리프틸린 1,000 그램Medicines: 1,000 grams of amitriptyline hydrochloride
방출조절제 : 카르복시메칠셀룰로오스칼슘 400 그램Release Controlling Agent: Carboxymethyl Cellulose Calcium 400g
전분 1,300 그램1,300 grams of starch
스테아린산마그네슘 400 그램400 grams of magnesium stearate
결 합 제 : 메타크릴산에칠·메타크릴산염화트리메칠암모늄Binder: Ethyl methacrylate / methacrylate trimethylammonium
에칠코폴리머 40 그램Ethyl Copolymer 40g
용 매 : 에탄올 1,000 그램Solvent: 1,000 grams of ethanol
상기의 처방을 사용한 것을 제외하고는 실시예 1과 동일한 방법으로 1차코팅을 실시하였다.The first coating was carried out in the same manner as in Example 1, except that the above prescription was used.
B. 2차 코팅B. Secondary Coating
결정핵 : A의 과립 1,000 그램Seed: 1,000 grams of granules of A
코팅액 : 메타크릴산에칠·메타크릴산염화트리메칠암모늄Coating solution: Ethyl methacrylate / methacrylate trimethylammonium
에칠코폴리머 50 그램50 g of ethyl copolymer
디부칠푸탈레이트(Dibutylphthalate) 10 그램10 grams of dibutylphthalate
탈크 25 그램25 grams of talc
에탄올 1,400 그램1,400 grams of ethanol
상기 A에서 제조된 코팅과립을 결정핵으로 하여 상기 처방의 코팅액을 분사하여 코팅시켰다. 코팅 조건은 실시예 1과 동일하였다.The coating granules prepared in A were used as crystal nuclei to coat the coating solution of the formulation by spraying. Coating conditions were the same as in Example 1.
실시예 6Example 6
A. 1차 코팅A. Primary Coating
결 정 핵 : 논파레일(nonpareil) 400 그램Core: 400 grams of nonpareil
약 물 : 염산아미트리프틸린 1,000 그램Medicines: 1,000 grams of amitriptyline hydrochloride
방출조절제 : 포비돈 100 그램Release Control: Povidone 100 grams
유당 2,000 그램2,000 grams of lactose
경질무수규산 100 그램100 grams of hard silicic acid
결 합 제 : 포비돈 40 그램Binder: 40 grams of povidone
용 매 : 에탄올 1,000 그램Solvent: 1,000 grams of ethanol
상기의 처방을 사용한 것을 제외하고는 실시예 1과 동일한 방법으로 1차코팅을 실시하였다.The first coating was carried out in the same manner as in Example 1, except that the above prescription was used.
B. 2차 코팅B. Secondary Coating
결정핵 : A의 과립 1,000 그램Seed: 1,000 grams of granules of A
코팅액 : 메타크릴산에칠·메타크릴산염화트리메칠암모늄Coating solution: Ethyl methacrylate / methacrylate trimethylammonium
에칠코폴리머 70 그램Ethyl Copolymer 70g
폴리에칠렌글리콜6000 (Polyethyleneglycole 6000) 7 그램Polyethyleneglycol 6000 (Polyethyleneglycole 6000) 7g
탈크 35 그램Talc 35 grams
에탄올 1,400 그램1,400 grams of ethanol
상기 A에서 제조된 코팅과립을 결정핵으로 하여 상기 처방의 코팅액을 분사하여 코팅시켰다. 코팅 조건은 실시예 1과 동일하였다.The coating granules prepared in A were used as crystal nuclei to coat the coating solution of the formulation by spraying. Coating conditions were the same as in Example 1.
실시예 7Example 7
A. 1차 코팅A. Primary Coating
결 정 핵 : 논파레일(nonpareil) 800 그램Core: 800 grams of nonpareil
약 물 : 염산아미트리프틸린 1,000 그램Medicines: 1,000 grams of amitriptyline hydrochloride
방출조절제 : 폴록사머 100 그램Release Control: 100 grams of poloxamer
유당 1,400 그램1,400 grams of lactose
탈크 200 그램200 grams of talc
결 합 제 : 포비돈 40 그램Binder: 40 grams of povidone
용 매 : 에탄올 1,000 그램Solvent: 1,000 grams of ethanol
상기의 처방을 사용한 것을 제외하고는 실시예 1과 동일한 방법으로 1차코팅을 실시하였다.The first coating was carried out in the same manner as in Example 1, except that the above prescription was used.
B. 2차 코팅B. Secondary Coating
결정핵 : A의 과립 1,000 그램Seed: 1,000 grams of granules of A
코팅액 : 메타크릴산에칠·메타크릴산염화트리메칠암모늄Coating solution: Ethyl methacrylate / methacrylate trimethylammonium
에칠 코폴리머 70 그램70 grams of ethyl copolymer
메타크릴산디메칠아미노에칠·메타크릴산메칠 코폴리머Methyl methacrylate aminoethyl methacrylate methyl copolymer
10 그램10 grams
트리에칠시트레이트(triethylcitrate) 8 그램8 grams of triethylcitrate
탈크 40 그램Talc 40 grams
에탄올 1,400 그램1,400 grams of ethanol
상기 A에서 제조된 코팅과립을 결정핵으로 하여 상기 처방의 코팅액을 분사하여 코팅시켰다. 코팅 조건은 실시예 1과 동일하였다.The coating granules prepared in A were used as crystal nuclei to coat the coating solution of the formulation by spraying. Coating conditions were the same as in Example 1.
실시예 8Example 8
A. 1차 코팅A. Primary Coating
결 정 핵 : 논파레일(nonpareil) 3,000 그램Core: 3,000 grams of nonpareil
약 물 : 염산아미트리프틸린 500 그램Medicines: 500 grams of amitriptyline hydrochloride
방출조절제 : 포비돈 300 그램Release Control: Povidone 300 grams
미결정셀룰로오스 300 그램300 grams of microcrystalline cellulose
스테아린산마그네슘 300 그램300 grams of magnesium stearate
결 합 제 : 포비돈 20 그램Binder: 20 grams of povidone
용 매 : 에탄올 1,000 그램Solvent: 1,000 grams of ethanol
상기의 처방을 사용한 것을 제외하고는 실시예 1과 동일한 방법으로 1차코팅을 실시하였다.The first coating was carried out in the same manner as in Example 1, except that the above prescription was used.
B. 2차 코팅B. Secondary Coating
결정핵 : A의 과립 1,000 그램Seed: 1,000 grams of granules of A
코팅액 : 메타크릴산에칠·메타크릴산염화트리메칠암모늄Coating solution: Ethyl methacrylate / methacrylate trimethylammonium
에칠 코폴리머 70 그램70 grams of ethyl copolymer
메타크릴산·메타크릴산메칠코폴리머60 7 그램Methacrylic acid, methacrylic acid methyl copolymer 60 7 g
트리에칠시트레이트(triethylcitrate) 7 그램7 grams of triethylcitrate
탈크 35 그램Talc 35 grams
에탄올 1,400 그램1,400 grams of ethanol
상기 A에서 제조된 코팅과립을 결정핵으로 하여 상기 처방의 코팅액을 분사하여 코팅시켰다. 코팅 조건은 실시예 1과 동일하였다.The coating granules prepared in A were used as crystal nuclei to coat the coating solution of the formulation by spraying. Coating conditions were the same as in Example 1.
실시예 9Example 9
A. 1차 코팅A. Primary Coating
결 정 핵 : 논파레일(nonpareil) 400 그램Core: 400 grams of nonpareil
약 물 : 염산아미트리프틸린 1,000 그램Medicines: 1,000 grams of amitriptyline hydrochloride
방출조절제 : 카르복시메칠셀룰로오스나트륨 400 그램Release Controlling Agent: Sodium Carboxymethyl Cellulose 400g
유당 1,300 그램1,300 grams of lactose
탈크 400 그램Talc 400 grams
결 합 제 : 포비돈 40 그램Binder: 40 grams of povidone
용 매 : 에탄올 1,000 그램Solvent: 1,000 grams of ethanol
상기의 처방을 사용한 것을 제외하고는 실시예 1과 동일한 방법으로 1차코팅을 실시하였다.The first coating was carried out in the same manner as in Example 1, except that the above prescription was used.
B. 2차 코팅B. Secondary Coating
결 정 핵 : A의 과립 1,000 그램Crystallization Core: Granules of A 1,000 grams
코 팅 액 : 메타크릴산에칠·메타크릴산염화트리메칠암모늄Coating liquid: Ethyl methacrylate, methacrylate trimethylammonium
에칠 코폴리머 70 그램70 grams of ethyl copolymer
메타크릴산디메칠아미노에칠·메타크릴산메칠 코폴리머Methyl methacrylate aminoethyl methacrylate methyl copolymer
10 그램10 grams
트리에칠시트레이트(triethylcitrate) 8 그램8 grams of triethylcitrate
탈크 40 그램Talc 40 grams
에탄올 1,400 그램1,400 grams of ethanol
상기 A에서 제조된 코팅과립을 결정핵으로 하여 상기 처방의 코팅액을 분사하여 코팅시켰다. 코팅 조건은 실시예 1과 동일하였다.The coating granules prepared in A were used as crystal nuclei to coat the coating solution of the formulation by spraying. Coating conditions were the same as in Example 1.
실시예 10Example 10
A. 1차 코팅A. Primary Coating
결 정 핵 : 논파레일(nonpareil) 400 그램Core: 400 grams of nonpareil
약 물 : 염산아미트리프틸린 1,000 그램Medicines: 1,000 grams of amitriptyline hydrochloride
방출조절제 : 폴리에칠렌옥사이드2,000,000 200 그램Release control agent: Polyethylene oxide 2,000,000 200 grams
미결정셀룰로오스 1,500 그램1,500 grams of microcrystalline cellulose
탈크 400 그램Talc 400 grams
결 합 제 : 포비돈 40 그램Binder: 40 grams of povidone
용 매 : 에탄올 1,000 그램Solvent: 1,000 grams of ethanol
상기의 처방을 사용한 것을 제외하고는 실시예 1과 동일한 방법으로 1차코팅을 실시하였다.The first coating was carried out in the same manner as in Example 1, except that the above prescription was used.
B. 2차 코팅B. Secondary Coating
결정핵 : A의 과립 1,000 그램Seed: 1,000 grams of granules of A
코팅액 : 메타크릴산에칠·메타크릴산염화트리메칠암모늄Coating solution: Ethyl methacrylate / methacrylate trimethylammonium
에칠코폴리머 70 그램Ethyl Copolymer 70g
메타크릴산·메타크릴산메칠코폴리머60 7 그램Methacrylic acid, methacrylic acid methyl copolymer 60 7 g
트리에칠시트레이트(triethylcitrate) 7 그램7 grams of triethylcitrate
탈크 35 그램Talc 35 grams
에탄올 1,400 그램1,400 grams of ethanol
상기 A에서 제조된 코팅과립을 결정핵으로 하여 상기 처방의 코팅액을 분사하여 코팅시켰다. 코팅 조건은 실시예 1과 동일하였다.The coating granules prepared in A were used as crystal nuclei to coat the coating solution of the formulation by spraying. Coating conditions were the same as in Example 1.
실시예 11~20Examples 11-20
1차 코팅시 아미트리프틸린을 결합액에 혼합 용해시켜 분사하는 용매분사법을 사용한 것을 제외하고는 실시예 1~10과 동일한 방법으로 제어방출형 아미트리프틸린 과립을 제조하였다.Controlled-release amitrityline granules were prepared in the same manner as in Examples 1 to 10, except that a solvent injection method of mixing and dissolving amitriptyline in the binding solution and spraying the primary solution was used.
실험예 1 : 주사전자현미경 관찰Experimental Example 1 Scanning Electron Microscope
본 발명에 따르는 제어방출형 아미트리프틸린 과립을 주사전자현미경 (SEM)을 이용하여 관찰하고 그 모습을 촬영하여 도 3에 나타내었다. 도 3aa 및 도 3ab는 용매분사법으로 제조한 실시예 11의 과립이며, 도 3ba 및 도 3bb는 분말도포법으로 제조한 실시예 1의 과립이다.Controlled-release amitriptyline granules according to the present invention were observed using a scanning electron microscope (SEM) and photographed. Figures 3aa and 3ab are granules of Example 11 prepared by the solvent injection method, Figures 3ba and 3bb are granules of Example 1 prepared by the powder coating method.
분말도포법 또는 용매분사법으로 제조한 본 발명의 제어방출형 아미트리프틸린 과립은 구형에 가깝고 표면이 상당히 고르게 형성되었음을 확인할 수 있었다. 구형에 가깝고 표면이 부드럽다는 사실로 미루어 용출이 과립상의 전표면에서 고르고 균일하게 일어날 것임을 유추할 수 있다. 다만 분말도포법으로 제조한 과립의 전체적인 모폴로지(도 3ba)가 용매분사법으로 제조한 과립(도 3aa)에 비하여 더욱 우수한 결과를 나타내었다.It was confirmed that the controlled-release amitriptyline granules of the present invention prepared by the powder coating method or the solvent spraying method were close to the spherical shape and the surface was formed fairly evenly. The closeness of the spheres and the smooth surface suggest that elution will occur evenly and uniformly on the granular entire surface. However, the overall morphology of the granules prepared by the powder coating method (FIG. 3ba) showed more excellent results than the granules prepared by the solvent spray method (FIG. 3aa).
실험예 2 : 약물방출시험Experimental Example 2 Drug Release Test
실시예 1에서 제조한 과립 및 시판되고 있는 아미트리프틸린 정제 (에나폰정, 환인제약)를 아미트리프틸린으로서 50 mg에 해당하는 양 만큼 취하여 pH 1.2 용출액에서 1시간, pH 4.5 용출액에서 1시간, pH 6.8 용출액에서 6시간, 총 8시간 동안 연속적으로 용출시험하였다. 아미트리프틸린의 방출량은 UVspectrophotometer (HP8453, Hewlett Packard)를 이용하여 측정하였다. 측정된 결과는 도 4에 그래프로 나타낸 바와 같다.The granules prepared in Example 1 and commercially available amitriptyline tablets (Enafon Tablet, Panin Pharmaceutical Co., Ltd.) were taken as amitriptyline in an amount corresponding to 50 mg for 1 hour in a pH 1.2 eluate and an hour in a pH 4.5 eluate. Elution test was carried out continuously for 6 hours in a pH 6.8 eluate for a total of 8 hours. The release amount of amitriptyline was measured using a UVspectrophotometer (HP8453, Hewlett Packard). The measured result is as graphed in FIG.
도 4에 도시된 결과로부터, 본 발명의 실시예에서 제조된 과립제는 시판되고 있는 정제보다 약물을 서서히 지속적으로 컴퓨터 시뮬레이션에 일치하게끔 방출하는 것을 알 수 있으며, 따라서 생체내 적용시 지속적인 흡수를 나타내는 것을 기대할 수 있다.From the results shown in Figure 4, it can be seen that the granules prepared in the examples of the present invention release the drug slowly and consistently in accordance with computer simulations than commercially available tablets, and thus exhibit continuous absorption upon in vivo application. You can expect
실험예 3 : 약물의 혈중농도시험Experimental Example 3 Blood Concentration Test of Drugs
실험대상은 4인의 건강한 성인 남자로 하였다. 시험제제로는 상기 실시예 1에 따라 제조된 본 발명의 과립을 충진한 경질캅셀제를 시험하였고, 대조제제로는 시판 중에 있는 동일 함량의 아미트리프틸린 일반정제 (에나폰정, 환인제약)를 사용하였다. 각각의 제제를 1인당 아미트린프틸린 50 mg 해당량씩 경구투여하여 약물의 혈중농도를 측정하고 비교하여 보았다.The test subjects were four healthy adult males. As a test formulation, the hard capsules filled with the granules of the present invention prepared according to Example 1 were tested, and as a control formulation, amitriphthyline general tablets (Enafon tablet, hwanin Pharmaceutical Co., Ltd.) of commercially available amounts were used. It was. Each formulation was orally administered in an amount of 50 mg of amitrinphthylrin per person, and the blood levels of the drugs were measured and compared.
실험결과, 본 발명의 실시예 1에 따라 제조된 과립제의 경우 일반정제에 비해 혈중농도가 지속적으로 유지됨이 관찰되었다 (도 5). 하기 표 2에 나타난 약물동력학 파라미터 중 생체이용율에 직접적인 영향을 미치는 곡선하면적 (AUC)의 경우 약 260%의 증가를 나타내어 1일 1회 복용이 가능한 과립제로 적합함을 알 수 있었다.As a result of the experiment, it was observed that in the case of the granules prepared according to Example 1 of the present invention, blood concentration was continuously maintained as compared to general tablets (FIG. 5). The area under the curve (AUC), which directly affects bioavailability among the pharmacokinetic parameters shown in Table 2, was increased by about 260%, indicating that the granule can be taken once daily.
실험예 4 : 비교용출시험Experimental Example 4: Comparative Dissolution Test
본 발명의 실시예 1에 따라 제조된 과립과, 아미트리프틸린의 일반제제 (상품명: 아나폰정) 및 아미트리프틸린의 서방성제제 (상품명: 사로텐 리타드)에 대하여 pH 1.2와 pH 6.8에서 비교용출시험을 실시하고 그 결과를 각각 도 6c, 6a 및 6b에 나타내었다.PH 1.2 and pH 6.8 for the granules prepared according to Example 1 of the present invention and for the general preparation of amitriptyline (trade name: Anaphon Tablet) and the sustained release preparation of amitriphthyline (trade name: Sarotene Ritad). The comparative dissolution test was performed at and the results are shown in FIGS. 6C, 6A and 6B, respectively.
도 6a에 나타난 바와 같이 아미트리프틸린의 일반제제인 아나폰정은 pH 1.2 및 pH 6.8에서 모두, 1시간도 채 경과되기 전에 제제 중의 약물이 100 % 방출되어 버림을 확인할 수 있었다. 아미트리프틸린의 서방성제제인 사로텐 리타드(도 6b)는 pH 1.2에서는 비교적 바람직한 용출양상을 보였으나 pH 6.8에서는 용출속도가 크게 감소되어 약물의 흡수속도 및 흡수량이 환자의 상태 등에 따라 크게 변화될 수 있음을 확인할 수 있었다.As shown in Figure 6a, Anapon tablets, a general formulation of amitriptyline, at both pH 1.2 and pH 6.8, it was confirmed that 100% of the drug was released in the formulation before 1 hour elapsed. Sarotene retard (FIG. 6B), which is a sustained release of amitriptyline, showed a relatively favorable dissolution pattern at pH 1.2, but the dissolution rate was greatly decreased at pH 6.8, and the rate of absorption and the amount of absorption of the drug were greatly changed according to the condition of the patient. Could be confirmed.
이에 반하여 본 발명의 과립(도 6c)은 pH에 무관하게 일정한 용출양상을 보임을 확인할 수 있었다. 따라서 본 발명의 과립은 복용방법, 타약물과의 상호관계(제산제 또는 위산분비조절제), 복용시 물의 양, 환자의 건강상태 등에 크게 영향받지 않고 재현성 있는 흡수를 보일 것으로 기대된다.On the contrary, it could be seen that the granules of the present invention (FIG. 6C) showed a constant dissolution pattern regardless of pH. Therefore, the granules of the present invention are expected to exhibit reproducible absorption without being greatly influenced by the method of administration, the interaction with other drugs (antacid or gastric acid secretion agent), the amount of water when taken, and the health of the patient.
실험예 5 : 혼합과립제와의 비교제조Experimental Example 5 Comparative Preparation with Mixed Granules
기존의 속방성 과립과 서방성 과립을 혼합한 과립의 경우, 과립의 제조공정이 2배로 증가하고 제조후 함량 측정을 통한 혼합비 계산, 용출율 측정을 통한 혼합비 계산 등의 번거로움 및 재현성 저하가 관찰되었었으며 제조수율도 체과 및 두 과립제의 혼합시 나타나는 손실로 인해 80% 정도에 그치는 결과를 보여주었다.In the case of the granules in which the immediate-release granules and the sustained-release granules were mixed, the manufacturing process of the granules was doubled, and the cumbersome and reproducible deterioration such as the mixing ratio calculation through the content measurement after the preparation and the mixing ratio calculation through the dissolution rate measurement were observed. In addition, the production yield was only about 80% due to the loss of the sieve and the mixing of the two granules.
실시예 1에 따라 과립제를 제조하는 경우, 동일 배치 (batch)상에서 연속적으로 전 공정이 마치게 되어 공정이 단축되고 함량 및 용출을 맞추기 위한 혼합비 설정의 번거로움이 없을 뿐만 아니라 제조수율도 95%에 이르는 것으로 나타났다.In the case of preparing the granules according to Example 1, the whole process is continuously completed on the same batch, which shortens the process, hassle-free setting of the mixing ratio for adjusting the content and dissolution, and the production yield reaches 95%. Appeared.
이로써 알 수 있듯이 본 발명의 과립제 제조방법은 기존의 지속성 과립제 제조방법에 비해 공정이 간단하고 수율이 높은 이점을 지니고 있음을 알 수있다.As it can be seen that the granules manufacturing method of the present invention can be seen that the process is simple and has a high yield compared to the conventional continuous granules manufacturing method.
본 발명에서 사용한 펠렛제조방법은 메트릭스 제어와 막 제어 방식을 동시 응용하여 1종의 과립을 제조하므로 제법이 간단하고, 따라서 제조수율도 높다. 개개의 과립이 모두 동일한 용출 양상을 나타내면서 용출이 조절되기 때문에 재현성 또한 우수하다. 더우기 pH에 따른 용출변화가 미세하여 인체 위장관의 pH변화에 따른 용출변화도 거의 없어 매우 바람직하다.Pellet production method used in the present invention is a simple method of producing a granule by applying a matrix control and a film control method at the same time, so the production yield is also high. Reproducibility is also excellent because the dissolution is controlled while the individual granules all exhibit the same dissolution pattern. Moreover, since the dissolution change according to pH is minute, there is almost no dissolution change due to the pH change of the human gastrointestinal tract.
Claims (16)
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| KR1019990039518A KR100341664B1 (en) | 1999-09-15 | 1999-09-15 | Amitriptyline granule as a controlled release system and the preparation method thereof |
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| KR1019990039518A KR100341664B1 (en) | 1999-09-15 | 1999-09-15 | Amitriptyline granule as a controlled release system and the preparation method thereof |
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