TW201705943A - Long-term sustained release pharmaceutical composition and preparation method thereof providing features of simple manufacturing process, short processing time and low preparation costs to reduce patients' medical burdens - Google Patents
Long-term sustained release pharmaceutical composition and preparation method thereof providing features of simple manufacturing process, short processing time and low preparation costs to reduce patients' medical burdens Download PDFInfo
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本發明係關係一種製備方法，尤指一種長效緩釋醫藥組成物之製備方法；本發明更關係一種藉由前述製備方法所製備之長效緩釋醫藥組成物。The present invention relates to a preparation method, in particular to a preparation method of a long-acting sustained-release pharmaceutical composition; the invention further relates to a long-acting sustained-release pharmaceutical composition prepared by the aforementioned preparation method.
口服錠劑係最廣泛被使用之藥物劑型，既有技術利用一控制釋放予以控製藥物主成分自口服錠劑溶離出來之速率，以增進療效、減少藥物副作用並增加病人服藥順從性。Michael E. Altonet al . Aulton’s pharmaceutics：the design and manufacture of medicine 3rd edition揭露既有技術製備口服錠劑之控制釋放包含三種方法，第一種方法為基質系統(matrix system)，第二種方法為薄膜控制系統(membrane-controlled system)，第三種方法為滲透壓系統(osmotic pump system)。Oral lozenges are the most widely used pharmaceutical dosage forms. Both techniques use a controlled release to control the rate at which the main component of the drug is eluted from the oral lozenge to improve efficacy, reduce side effects, and increase patient compliance. Michael E. Alton et al . Aulton's pharmaceutics: the design and manufacture of medicine 3rd edition discloses that the controlled release of the prior art preparation of oral lozenges comprises three methods, the first method being a matrix system and the second method being The membrane-controlled system, the third method is the osmotic pump system.
基質系統可分為二大類，第一類為親水性基質錠，其係將藥物主成分分散於一親水性之基質中；第二類為疏水性基質錠，其係將藥物主成分分散於疏水性之基質。親水性基質錠係將水分與基質接觸形成一凝膠層(gel)以控制藥品之溶離速率，其優點為技術成熟，製造設備簡單、賦形劑安全且成本便宜、可承戴高劑量之藥物主成分、基質之可溶蝕(erodible)性可避免不溶性聚合物***出現於***物中，造成使用者疑惑與困擾之問題。The matrix system can be divided into two categories. The first type is a hydrophilic matrix ingot which disperses the main component of the drug in a hydrophilic matrix. The second type is a hydrophobic matrix ingot which disperses the main component of the drug in hydrophobic form. The matrix of sex. The hydrophilic matrix ingot forms a gel layer by contacting moisture with a substrate to control the dissolution rate of the drug, and has the advantages of mature technology, simple manufacturing equipment, safe and inexpensive excipients, and high-dose drugs. The erodibility of the main component and the matrix prevents the insoluble polymer excretion from appearing in the excrement, causing problems for the user to be confused and troubled.
膜衣控制系統主要分成錠劑膜衣及粒子膜衣二大類，該二大類皆係利用錠劑或粒子外圍之聚合物膜衣來控制藥品之溶離速率，粒子膜衣於製備技術上較錠劑膜衣困難。錠劑膜衣控制系統之缺點為倘若聚合物膜衣製造不良，將導致劑量傾瀉(dose dumping)之問題。The film coating control system is mainly divided into two types of tablet film coating and particle film coating. The two types mainly use the polymer film coating on the periphery of the tablet or the particle to control the dissolution rate of the drug. The particle film coating is better than the tablet in the preparation technology. The film coat is difficult. A disadvantage of the tablet film control system is that if the polymer film coat is poorly manufactured, it will cause problems with dose dumping.
滲透壓控制系統係利用滲透壓機制，使水分經由一半透膜進入該口服錠劑內，並將藥物主成分經由雷射孔擠出，滲透壓控制系統之優點為藥品之釋放快慢將不受胃腸道酸鹼值之影響，其缺點為雷射穿孔之設備昂貴、製程時間長，且半透膜膜衣倘若製造不良將導致藥物劑量傾瀉之危險。The osmotic pressure control system uses an osmotic pressure mechanism to allow water to enter the oral lozenge via a half-permeable membrane and to extrude the main component of the drug through the laser orifice. The advantage of the osmotic pressure control system is that the release rate of the drug will not be affected by the gastrointestinal tract. The shortcomings of the acidity and alkalinity are that the equipment for laser perforation is expensive, the processing time is long, and if the semipermeable membrane film is badly manufactured, the risk of drug dosage is poured.
注意力不足過動症(attention deficiency hyperactivity disorder, ADHD)係大腦刺激不足或發育不夠成熟所致，其主要的臨床症狀包含缺乏持續專注力、缺乏衝動控制能力以及過度的活動等，其盛行率約為3%至7%。甲基芬尼特鹽酸鹽(methylphenidate HCl)係治療注意力不足過動症之藥物，該藥物包含藥效約四小時之短效型藥劑以及藥效約十二小時之長效型藥劑。市售之短效型藥劑包含利他能錠® (Ritalin® tablet)，利他能錠® 之藥物釋放速度快，其所產生之副作用亦較明顯，患者通常一天需服用二次至三次，由於患者必須一天服用多次，因此患者服用利他能錠® 較難以保有隱私性，且患者血中濃度將因多次服用而呈現忽高忽低之變化。市售之長效型藥劑包含專思達® 長效錠(Concerta® extended release tablet)，其係一種兼顧速效劑量及緩釋劑量之長效型藥劑，患者通常一天只需服用一次，因此其副作用較不明顯且患者較容易保有隱私性。Attention deficiency hyperactivity disorder (ADHD) is caused by insufficient brain stimulation or insufficient development. The main clinical symptoms include lack of continuous concentration, lack of impulsive control, and excessive activity. It is 3% to 7%. Methylphenidate HCl is a drug for the treatment of attention deficit hyperactivity disorder. The drug contains a short-acting drug with a potency of about four hours and a long-acting drug with a potency of about twelve hours. Commercially available short-acting agent comprises an ingot Ritalin ® (Ritalin ® tablet), Ritalin ® lozenges of fast rate of release of drug, the side effects they produce than obvious, patients often need to take secondary to three times a day, as the patient must one day take many times, so patients taking Ritalin ® tablets are more difficult to maintain privacy, and the blood concentration due to multiple doses and showed the peaks and valleys of the changes in the patient. The commercial long-acting agents include long-term special Star ® tablets (Concerta ® extended release tablet), its Department of a balanced long-acting slow-release drug dosage and dose of fast-acting, patient taken once a typical day, so its side effects Less obvious and patients are more likely to maintain privacy.
美國專利號US 6919373 B1揭露專思達® 長效錠之製備方法乃是藉由滲透壓控制系統，在一裸錠外面包覆一半透膜膜衣以及一速放主成分膜衣層，以該專思達® 長效錠之總劑量百分比為基準，其中甲基芬尼特鹽酸鹽在速放主成分膜衣層中所佔之重量百分比為22.2%。為了使專思達® 長效錠劑之主成分在患者血中濃度有一段較長時間呈現上升型態，滲透壓控制系統將該專思達® 長效錠劑製備為一包含一第一成分層、一第二成分層及一第三推擠層之三層錠劑。該三層錠劑之製備另需一特殊之縱向壓錠(longitudinally compressed tablet)設備以使該三層錠劑形成雙凸圓柱形，此外，該三層錠劑之製備亦需要使用流體床濕式造粒法以製備每一層。因此，專思達® 錠劑之製備相較於一般滲透壓控制系統更加地耗時且需投入更高的成本，進而增加患者之醫藥負擔。U.S. Patent No. US 6919373 B1 discloses a method designed Star ® depot preparation of an ingot by osmotic pressure control system but, outside of a bare spindle half-permeable membrane coated film coated immediate release and a main component of the film coating layer, to the Star ® designed total dose of long-acting starter percentage basis, wherein A Jifennite hydrochloride immediate release coating layer in the film main component a weight percentage of 22.2%. In order to specifically Sida depot ® lozenges main component of the blood concentrations in the patient for a longer period upward patterns, specifically the osmotic pressure control system Star ® depot preparation is a lozenge comprising a first component a three-layer tablet of a layer, a second component layer and a third push layer. The preparation of the three-layer tablet further requires a special longitudinal tablet device to form the three-layer tablet into a biconvex cylindrical shape. In addition, the preparation of the three-layer tablet requires a fluid bed wet process. Granulation to prepare each layer. Thus, the preparation of tablets specifically Star ® osmotic pressure compared to the general control system more time consuming and require higher investment costs, thereby increasing the burden of medical patients.
因此，開發出一種製備時間短且成本低之長效緩釋醫藥組成物之製備方法，以減輕患者負擔係本領域亟待解決之問題。Therefore, a preparation method of a long-acting sustained-release pharmaceutical composition having a short preparation time and a low cost has been developed to alleviate the burden on patients, which is an urgent problem to be solved in the field.
有鑑於現有技術的缺失，本發明之目的在於利用將活性成分於裸錠及主成分膜衣層之劑量調整以獲得一長效緩釋醫藥組成物，以供病患服用。為達到上述之目的，本發明提供一種長效緩釋醫藥組成物之製備方法，其步驟包含： 將活性成分與親水性聚合物以及賦形劑進行打錠，以形成一裸錠； 將疏水性聚合物(hydrophobic polymer)以及賦形劑混合，以形成一控釋膜衣層，其中控釋膜衣層佔該裸錠之總重量大於0 wt%至10 wt%； 將活性成分以及賦形劑混合，以形成一主成分膜衣層； 將控釋膜衣層包覆裸錠後，再將該主成分膜衣層包覆已包覆裸錠之控釋膜衣層，以形成長效緩釋醫藥組成物；其中裸錠之活性成分佔長效緩釋醫藥組成物之整體活性成分之總重量之75 wt%至92 wt%；其中主成分膜衣層之活性成分佔長效緩釋醫藥組成物之整體活性成分之總重量之8 wt%至25 wt%。In view of the absence of the prior art, the object of the present invention is to adjust the dosage of the active ingredient in the bare ingot and the main component film coating layer to obtain a long-acting sustained-release pharmaceutical composition for administration to a patient. In order to achieve the above object, the present invention provides a method for preparing a long-acting sustained-release pharmaceutical composition, the method comprising the steps of: ingoting an active ingredient with a hydrophilic polymer and an excipient to form a bare ingot; Hydrophobic polymer and excipients are mixed to form a controlled release film coating layer, wherein the controlled release film coating layer accounts for more than 0 wt% to 10 wt% of the total weight of the bare ingot; the active ingredient and the excipient Mixing to form a main component film coating layer; after coating the controlled release film coating layer with the bare ingot, the main component film coating layer is coated with the controlled release film coating layer of the bare ingot to form a long-term slowing The pharmaceutical composition; wherein the active ingredient of the bare ingot accounts for 75 wt% to 92 wt% of the total weight of the total active ingredient of the long-acting sustained-release pharmaceutical composition; wherein the active ingredient of the main component film layer constitutes a long-acting sustained-release medicine From 8 wt% to 25 wt% of the total weight of the total active ingredient of the composition.
較佳的，本發明所述之製備方法更包含： 利用一膜衣材料以製備一保護層膜衣，並將所述之保護層膜衣包覆已包覆控釋膜衣層及裸錠之主成分膜衣層。Preferably, the preparation method of the present invention further comprises: using a film coating material to prepare a protective layer film coating, and coating the protective layer film coating on the coated controlled release film coating layer and the bare ingot. The main component film layer.
較佳的，所述之活性成分係甲基芬尼特鹽酸鹽。Preferably, the active ingredient is methylfenitate hydrochloride.
更佳的，所述之活性成分在裸錠中，活性成分佔長效緩釋醫藥組成物之整體活性成分之總重量之78 wt%至89 wt%；所述之主成分膜衣層之活性成分佔長效緩釋醫藥組成物之整體活性成分之總重量之11 wt%至22 wt%。More preferably, the active ingredient is in the bare ingot, and the active ingredient accounts for 78 wt% to 89 wt% of the total weight of the whole active ingredient of the long-acting sustained-release pharmaceutical composition; the activity of the main component film coating layer The composition comprises from 11 wt% to 22 wt% of the total weight of the total active ingredient of the long-acting sustained release pharmaceutical composition.
較佳的，所述之親水性聚合物佔裸錠之總重量之10 wt%至40 wt%，且該親水性聚合物係甲基纖維素(methyl cellulose)、水溶性聚乙烯氧化物(water-soluble polyethylene oxide)、羥丙基纖維素(hydroxypropyl cellulose)、聚乙烯吡咯啶酮(polyvinyl pyrrolidone)、羥丙基甲基纖維素(hydroxypropyl methyl cellulose)或其混合。Preferably, the hydrophilic polymer comprises 10 wt% to 40 wt% of the total weight of the bare ingot, and the hydrophilic polymer is methyl cellulose, water soluble polyethylene oxide (water) -soluble polyethylene oxide), hydroxypropyl cellulose, polyvinyl pyrrolidone, hydroxypropyl methyl cellulose or a mixture thereof.
更佳的，所述之親水性聚合物佔裸錠之總重量之15 wt%至35 wt%，且親水性聚合物係羥丙基纖維素、羥丙基甲基纖維素或其混合。More preferably, the hydrophilic polymer comprises from 15 wt% to 35 wt% of the total weight of the bare ingot, and the hydrophilic polymer is hydroxypropylcellulose, hydroxypropylmethylcellulose or a mixture thereof.
較佳的，所述之疏水性聚合物佔乾燥後控釋膜衣層之總重量之55 wt%至85 wt%，且該疏水性聚合物係乙基纖維素(ethyl cellulose)、丙烯酸共聚物(acrylic copolymer)、聚乙烯乙酯(polyvinyl acetate)或其混合。Preferably, the hydrophobic polymer accounts for 55 wt% to 85 wt% of the total weight of the controlled release film layer after drying, and the hydrophobic polymer is ethyl cellulose or acrylic copolymer. (acrylic copolymer), polyvinyl acetate or a mixture thereof.
更佳的，所述之疏水性聚合物佔乾燥後控釋膜衣層之總重量之60 wt%至80 wt%，且該疏水性聚合物係乙基纖維素。More preferably, the hydrophobic polymer comprises from 60% by weight to 80% by weight based on the total weight of the controlled release film layer after drying, and the hydrophobic polymer is ethyl cellulose.
較佳的，所述之控釋膜衣層之賦形劑更包含一成孔劑，該成孔劑係佔乾燥後控釋膜衣層總重量之2 wt%至20 wt%，該成孔劑係羥丙基纖維素、羥丙基甲基纖維素、聚乙烯醇/聚乙二醇接枝共聚物(polyvinyl alcohol-polyethylene glycol graft copolymer)或其混合。Preferably, the excipient of the controlled release film layer further comprises a pore former, and the pore former comprises 2 wt% to 20 wt% of the total weight of the controlled release film layer after drying. The agent is hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymer or a mixture thereof.
更佳的，所述之成孔劑係佔乾燥後之控釋膜衣層總重量之5 wt%至15 wt%之聚乙烯醇/聚乙二醇接枝共聚物。More preferably, the porogen is from 5 wt% to 15 wt% of the polyvinyl alcohol/polyethylene glycol graft copolymer based on the total weight of the controlled release film layer after drying.
較佳的，所述之主成分膜衣層之賦形劑包含一黏合劑，所述之黏合劑與活性成分之重量比例為0.7至1.3：1，且該黏合劑係羥丙基纖維素或羥丙基甲基纖維素。Preferably, the excipient of the main component film coating layer comprises a binder, the weight ratio of the binder to the active ingredient is 0.7 to 1.3:1, and the binder is hydroxypropyl cellulose or Hydroxypropylmethylcellulose.
更佳的，所述之黏合劑與活性成分之重量比例為0.8至1.2：1，且該黏合劑係羥丙基纖維素。More preferably, the weight ratio of the binder to the active ingredient is from 0.8 to 1.2:1, and the binder is hydroxypropylcellulose.
較佳的，所述之主成分膜衣層之賦形劑包含一黏合改善劑，所述之黏合改善劑與活性成分之重量比例為大於0至0.7：1，且該黏合改善劑係微結晶性纖維素(microcrystalline cellulose)、乳糖(lactose)或糊精(dextrin)。Preferably, the excipient of the main component film coating layer comprises a adhesion improving agent, the weight ratio of the adhesion improving agent to the active ingredient is more than 0 to 0.7:1, and the adhesion improving agent is microcrystalline. Microcrystalline cellulose, lactose or dextrin.
更佳的，所述之黏合改善劑與活性成分之重量比例為0.3至0.7：1，且該黏合改善劑係微結晶性纖維素。More preferably, the weight ratio of the adhesion improving agent to the active ingredient is from 0.3 to 0.7:1, and the adhesion improving agent is microcrystalline cellulose.
較佳的，在製備保護層膜衣之步驟中，所述之保護層膜衣係在主成分膜衣層相對於控釋膜衣層之一側，並使主成分膜衣層位於保護層膜衣與控釋膜衣層之間。Preferably, in the step of preparing the protective layer film coat, the protective layer film coat is on the side of the main component film coat layer relative to the controlled release film coat layer, and the main component film coat layer is located on the protective layer film. Between the coat and the controlled release film coat.
較佳的，在製備保護層膜衣之步驟中，所述之保護層膜衣係佔長效緩釋醫藥組成物總重量之3 wt%至5 wt%，且該保護層膜衣材料包含，但不限於羥丙基甲基纖維素或聚乙烯醇(polyvinyl alcohol)。Preferably, in the step of preparing the protective layer film coat, the protective layer film coat comprises 3 wt% to 5 wt% of the total weight of the long-acting sustained release pharmaceutical composition, and the protective layer film coating material comprises However, it is not limited to hydroxypropylmethylcellulose or polyvinyl alcohol.
本發明更提供一種經由前述製備方法所得之長效緩釋醫藥組成物，所述之長效緩釋醫藥組成物由內至外依序包含裸錠、控釋膜衣層以及主成分膜衣層；其中裸錠以及主成分膜衣層分別包含一活性成分；且在裸錠中，該活性成分佔長效緩釋醫藥組成物之整體活性成分之總重量之75 wt%至92 wt%；在主成分膜衣層中，該活性成分佔長效緩釋醫藥組成物之整體活性成分之總重量之8 wt%至25 wt%。The present invention further provides a long-acting sustained-release pharmaceutical composition obtained by the aforementioned preparation method, wherein the long-acting sustained-release pharmaceutical composition comprises a bare ingot, a controlled release film coating layer and a main component film coating layer from the inside to the outside. Wherein the bare ingot and the main component film coating layer respectively comprise an active ingredient; and in the bare ingot, the active ingredient comprises from 75 wt% to 92 wt% of the total weight of the total active ingredient of the long-acting sustained release pharmaceutical composition; In the main component film coating layer, the active ingredient accounts for 8 wt% to 25 wt% of the total weight of the entire active ingredient of the long-acting sustained-release pharmaceutical composition.
較佳的，所述之裸錠之活性成分佔長效緩釋醫藥組成物之整體活性成分之總重量之78 wt%至89 wt%；主成分膜衣層之活性成分佔該長效緩釋醫藥組成物之整體活性成分之總重量之11 wt%至22 wt%。Preferably, the active ingredient of the bare ingot accounts for 78 wt% to 89 wt% of the total weight of the whole active ingredient of the long-acting sustained-release pharmaceutical composition; the active ingredient of the main component film layer accounts for the long-acting sustained release 11 wt% to 22 wt% of the total weight of the active ingredients of the pharmaceutical composition.
較佳的，所述之長效緩釋醫藥組成物更包含一保護層膜衣，保護層膜衣係在主成分膜衣層相對於控釋膜衣層之一側，並使主成分膜衣層位於保護層膜衣與控釋膜衣層之間。Preferably, the long-acting sustained-release pharmaceutical composition further comprises a protective layer film coat, the protective layer film coat is on the side of the main component film coat layer relative to the controlled release film coat layer, and the main component film coat The layer is between the protective layer film coat and the controlled release film coat layer.
較佳的，所述之保護層膜衣佔長效緩釋醫藥組成物總重量之3 wt%至5 wt%，且該保護層膜衣包含羥丙基甲基纖維素或聚乙烯醇。Preferably, the protective layer film coat comprises from 3 wt% to 5 wt% of the total weight of the long-acting sustained release pharmaceutical composition, and the protective layer film coat comprises hydroxypropylmethylcellulose or polyvinyl alcohol.
因此，本發明之製備方法相較於現有技術不需使用設備成本高且製程時間長之滲透壓控制系統以及雷射穿孔技術之製備方法，進以達成製程簡單、製程時間短以及製備成本低之功效。此外，本發明藉由裸錠中之親水性聚合物與體內之水分接觸所形成之凝膠層，使裸錠中之活性成分達到緩釋之效果。再者，本發明所述之長效緩釋醫藥組成物之活性成分係以特定比例設置於裸錠以及主成分膜衣層，當長效緩釋醫藥組成物服用入人體後，主成分膜衣層之活性成分會快速釋放，再藉由控釋膜衣層及裸錠以控制活性成分之釋放速度，使該長效緩釋醫藥組成物達到長效緩釋之效果。Therefore, the preparation method of the present invention does not require the use of an osmotic pressure control system with high equipment cost and long process time and a preparation method of the laser perforation technology, thereby achieving a simple process, a short process time, and a low preparation cost. efficacy. In addition, the present invention achieves a sustained release effect of the active ingredient in the bare ingot by the gel layer formed by the contact of the hydrophilic polymer in the bare ingot with the moisture in the body. Furthermore, the active ingredient of the long-acting sustained-release pharmaceutical composition according to the present invention is set in a specific ratio in the bare ingot and the main component film coating layer, and when the long-acting sustained-release pharmaceutical composition is taken into the human body, the main component film coating The active ingredient of the layer is quickly released, and the controlled release film layer and the bare ingot are used to control the release rate of the active ingredient, so that the long-acting sustained-release pharmaceutical composition achieves a long-term sustained release effect.
下列實施例用於示範說明本發明。所述之實施例不以任何方式意欲限制本發明之範圍，但用於指示如何實施本發明的材料及方法。The following examples are intended to illustrate the invention. The examples are not intended to limit the scope of the invention in any way, but are intended to indicate how to practice the materials and methods of the invention.
製備例：長效緩釋醫藥組成物之製備方法Preparation example: preparation method of long-acting sustained-release medicine composition
稱取甲基芬尼特鹽酸鹽、羥丙基甲基纖維素、羥丙基纖維素、微結晶性纖維素、乳糖以及硬脂酸鎂(magnesium stearate)利用40目(mesh)篩網進行過篩、混合均勻以及打錠，以形成一裸錠。前述打錠之方法係依據Michael E. Altonet al . Aulton’s pharmaceutics：the design and manufacture of medicine 3rd edition page 448所述之方法所製錠劑。Methylfenitate hydrochloride, hydroxypropylmethylcellulose, hydroxypropylcellulose, microcrystalline cellulose, lactose, and magnesium stearate were weighed using a 40 mesh screen. Sieve, mix well and ingot to form a bare ingot. The foregoing method of tableting is based on the method described by Michael E. Alton et al . Aulton's pharmaceutics: the design and manufacture of medicine 3rd edition page 448.
將Aquacoat® ECD-30 (購自於美國FMC公司)及檸檬酸三乙酯(triethyl citrate)，混合攪拌30分鐘，以形成一疏水性聚合物分散液。之後再稱取孔洞形成劑Kollicoat® IR (購自於德國BASF公司)，並將之完全溶於水中，再與疏水性聚合物分散液混合，並進行攪拌10分鐘，以形成一控釋膜衣液。Aquacoat ® ECD-30 (available from FMC, USA) and triethyl citrate were mixed and stirred for 30 minutes to form a hydrophobic polymer dispersion. Then weighed the pore former Kollicoat ® IR (purchased from BASF, Germany) and completely dissolved in water, mixed with the hydrophobic polymer dispersion, and stirred for 10 minutes to form a controlled release film coat. liquid.
將甲基芬尼特鹽酸鹽及羥丙基纖維素完全溶於一酸鹼值(pH值)為3.0磷酸溶液(phosphoric acid solution)中，以形成一混合溶液。再稱取微結晶性纖維素加入混合溶液中進行攪拌，以形成一主成分層膜衣液。Methylfenitate hydrochloride and hydroxypropylcellulose were completely dissolved in a pH acid value of 3.0 phosphoric acid solution to form a mixed solution. Further, microcrystalline cellulose is weighed and added to the mixed solution to be stirred to form a main component layer coating liquid.
將羥丙基甲基纖維素或聚乙烯醇與賦形劑分散於水中，以形成一保護層膜衣液。Hydroxypropyl methylcellulose or polyvinyl alcohol is dispersed in water with an excipient to form a protective film coating liquid.
將控釋膜衣液包覆裸錠，再將主成分層膜衣液包覆已包覆裸錠之控釋膜衣層，最後再將保護層膜衣液包覆已包覆控釋膜衣層及裸錠之主成分膜衣層，以形成長效緩釋醫藥組成物(即該長效緩釋醫藥組成物由內至外依序為裸錠、控釋膜衣層、主成分膜衣層以及保護膜衣層)。The controlled release film coating liquid is coated with the bare ingot, and the main component layer coating liquid is coated with the controlled release film coating layer of the bare ingot, and finally the protective layer coating liquid is coated with the coated controlled release film coating. The main component film layer of the layer and the bare ingot to form a long-acting sustained-release pharmaceutical composition (that is, the long-acting sustained-release pharmaceutical composition is a bare ingot, a controlled release film coating layer, and a main component film coating from the inside to the outside. Layer and protective film coating).
溶離試驗Dissolution test 之方法Method
將12克(g)氯化鈉(sodium chloride)溶解於適量之水中，並加入42毫升(ml)鹽酸，最後加水至總體積6公升(liter)，以形成一pH值為1.2之溶離媒液。12 g (g) of sodium chloride was dissolved in an appropriate amount of water, and 42 ml (ml) of hydrochloric acid was added, and finally water was added to a total volume of 6 liters to form a dissolution medium having a pH of 1.2. .
8.5毫升5%磷酸溶液加水至6公升，以形成一pH值為3.0之溶離媒液。8.5 ml of 5% phosphoric acid solution was added to 6 liters of water to form a dissolution medium having a pH of 3.0.
將35.88克三水醋酸鈉(sodium acetate trihydrate)與2.06毫升冰醋酸(glacial acetic acid)溶於適量之水中，待完全溶解後再加入水至總體積為6公升，以形成一pH值為5.5之溶離媒液。35.88 g of sodium acetate trihydrate and 2.06 ml of glacial acetic acid were dissolved in an appropriate amount of water, and after completely dissolved, water was added to a total volume of 6 liters to form a pH of 5.5. Dissolve the vehicle.
對照組：Control group:
將6錠且每錠劑量為36毫克之市售之專思達® 長效錠(Concerta® extended release tablet)分別放入於500毫升，pH值為1.2、3.0及5.5之溶離媒液中，並利用高效液相層析儀(high performance liquid chromatography, HPLC)於波長220奈米(nm)測定專思達® 長效錠於第1小時、第3小時、第6小時、第8小時以及第10小時之吸光度，再將吸光度轉換成溶離百分比(%)。The six spindles designed Sida depot ® (Concerta ® extended release tablet) and each spindle 36 mg dose of the commercially available were placed in 500 ml, pH = 1.2,3.0 and 5.5 of the solution from the liquid medium, and Star ® specifically measured at a wavelength of 220 nm Long ingot (nm) by high performance liquid chromatograph (high performance liquid chromatography, HPLC) in the first hour, 3 hours and 6 hours at 8 hours and 10 The absorbance of the hour is converted to the percentage of dissolution (%).
實驗組：將6錠且本發明製備例所得之每錠活性成分劑量為36毫克之長效緩釋醫藥組成物，分別放入於500毫升，pH值為1.2、pH值為3.0及pH值為5.5之溶離媒液中，並利用高效液相層析儀於波長220奈米測定長效緩釋醫藥組成物於第1小時、第3小時、第6小時、第8小時以及第10小時之吸光度，再將吸光度轉換成溶離百分比。Experimental group: a long-acting sustained-release pharmaceutical composition of 6 tablets in an amount of 36 mg per active ingredient obtained in the preparation of the present invention, respectively, placed in 500 ml, pH 1.2, pH 3.0 and pH value The absorbance of the long-acting sustained-release pharmaceutical composition at the first hour, the third hour, the sixth hour, the eighth hour, and the tenth hour was measured by a high performance liquid chromatography at a wavelength of 220 nm in a solution of 5.5. And then convert the absorbance into a percentage of dissolution.
專思達® 長效錠以及長效緩釋醫藥組成物之溶離試驗之相似度比對值(f2 值)係依據美國藥典第38版(General chapters：＜1090＞ Assessment of drug product performance-bioavailability, bioequivalence, and dissolution-dissolution andin vitro product performance)之規定，f2 值之推算係依下列公式求得，公式：f2 =50 × LOG {[1 + 1 / n×Σ(Rt-Tt)^2]^-0.5 × 100}，所述之公式中之Rt及Tt分別代表對照組及實驗組在抽樣時間點(t)之6個錠劑之平均溶離百分比(%)。所述之公式中之n表示抽樣點次數，n值至少為3，85%以上僅取一點計算。倘若f2 值大於或等於50，代表此兩產品之溶離程度相似。Solution composition of the ingot and the special Star ® long-acting release pharmaceutical depot from the similarity test ratio value (f 2 value) of the system according to U.S. Pharmacopeia 38 (General chapters: <1090> Assessment of drug product performance-bioavailability , bioequivalence, and dissolution-dissolution and in vitro product performance), the calculation of the f 2 value is obtained by the following formula: formula: f 2 = 50 × LOG {[1 + 1 / n × Σ (Rt-Tt) ^2]^-0.5 × 100}, Rt and Tt in the above formula represent the average percent dissolution (%) of the six lozenges of the control group and the experimental group at the sampling time point (t), respectively. In the formula, n represents the number of sampling points, and the value of n is at least 3, and 85% or more is calculated only by one point. If the f 2 value is greater than or equal to 50, it means that the degree of dissolution of the two products is similar.
實施例Example 11 ：溶離試驗: Dissolution test
對照組：使用專思達® 長效錠作為對照組實驗Control group: the use of special long-term Star ® lozenges as control experiments
實驗組：本實施例係以甲基芬尼特鹽酸鹽做為活性成分，該甲基芬尼特鹽酸鹽係以長效型醫藥組成物之活性成分之總重量百分比為基準，在裸錠中，甲基芬尼特鹽酸鹽佔整體活性成分之重量百分比為77.8 wt%；在主成分膜衣層中，甲基芬尼特鹽酸鹽佔整體活性成分之重量百分比為22.2 wt%，且裸錠、控釋膜衣層以及主成分膜衣層所包含之成分分別如表1至表3所示。 表1 裸錠之成分
控釋膜衣層所包含之成分如表2所示： 表2 控釋膜衣層之成分
主成分膜衣層所包含之成分如表3所示： 表3 主成分膜衣層之成分
將對照組之專思達®
長效錠以及實驗組之長效緩釋醫藥組成物分別放入於pH值為1.2、pH值為3.0及pH值為5.5之溶離媒液中進行溶離試驗，其結果分別如圖1至圖3以及分別如表4至表6所示。結果顯示，在pH值為1.2、pH值為3.0及pH值為5.5之溶離媒液中，對照組之溶離程度以及實驗組之溶離程度相近，其f2
值分別為68.8、62.9以及53.5。 表4 在pH值為1.2之溶離媒液中，對照組以及實驗組之溶離程度
經由本實施例之試驗結果顯示，依據本發明所製備之長效緩釋醫藥組成物之溶離效果與市售之專思達® 長效錠之溶離效果相似。The test results via a display of the present embodiment, based on dissolution of long-acting release pharmaceutical compositions of the present invention is prepared from commercially available Solubility of Star ® depot exclusively from an ingot of similar effect.
實施例Example 22 ：溶離試驗: Dissolution test
對照組：使用專思達® 長效錠作為對照組實驗Control group: the use of special long-term Star ® lozenges as control experiments
實驗組：裸錠、控釋膜衣層以及主成分膜衣層所包含之成分分別如表7至表9所示，相較於實施例1之裸錠成分，本實施例利用二氧化矽以及檸檬酸取代實施例1之羥丙基纖維素，且以長效型醫藥組成物之整體活性成分之總重量百分比為基準，在裸錠中，甲基芬尼特鹽酸鹽佔整體活性成分之重量百分比為88.9 wt%；在主成分膜衣層中，甲基芬尼特鹽酸鹽佔整體活性成分之重量百分比為11.1 wt%。 表7 裸錠之成分
將對照組以及實驗組分別放入於pH值為1.2、pH值為3.0及pH值為5.5之溶離媒液中進行溶離試驗，其結果分別如表10至表12所示。結果顯示，在pH值為1.2、pH值為3.0及pH值為5.5之溶離媒液中，對照組之溶離程度以及實驗組之溶離程度相近，其f2
值分別為56.2、51.7以及50.4。 表10 在pH值為1.2之溶離媒液中，對照組以及實驗組之溶離程度
經由本實施例之試驗結果顯示，依據本發明所製備之長效緩釋醫藥組成物之溶離效果與市售之專思達® 長效錠之溶離效果相似。The test results via a display of the present embodiment, based on dissolution of long-acting release pharmaceutical compositions of the present invention is prepared from commercially available Solubility of Star ® depot exclusively from an ingot of similar effect.
(無)(no)
圖1係本發明之實驗組以及對照組於pH值為1.2之溶離媒液之溶離曲線圖。 圖2係本發明之實驗組以及對照組於pH值為3.0之溶離媒液之溶離曲線圖。 圖3係本發明之實驗組以及對照組於pH值為5.5之溶離媒液之溶離曲線圖。Figure 1 is a graph showing the dissolution profile of the experimental group and the control group of the present invention at a pH of 1.2. Fig. 2 is a graph showing the dissolution profile of the experimental group and the control group of the present invention at a pH of 3.0. Figure 3 is a graph showing the dissolution profile of the experimental group of the present invention and the control group at a pH of 5.5.
(無)(no)
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