TWI248815B - The controlled release formulation of metformin HCl - Google Patents
The controlled release formulation of metformin HCl Download PDFInfo
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- TWI248815B TWI248815B TW92130985A TW92130985A TWI248815B TW I248815 B TWI248815 B TW I248815B TW 92130985 A TW92130985 A TW 92130985A TW 92130985 A TW92130985 A TW 92130985A TW I248815 B TWI248815 B TW I248815B
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- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 229960003105 metformin Drugs 0.000 title abstract description 11
- 239000000203 mixture Substances 0.000 title description 12
- 238000009472 formulation Methods 0.000 title description 10
- 238000013270 controlled release Methods 0.000 title description 7
- 239000002552 dosage form Substances 0.000 claims abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 claims description 13
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 10
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 10
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 6
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 6
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 6
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 6
- 235000019359 magnesium stearate Nutrition 0.000 claims description 5
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 4
- 229960004329 metformin hydrochloride Drugs 0.000 claims description 4
- 239000008188 pellet Substances 0.000 claims description 4
- 239000003086 colorant Substances 0.000 claims 2
- 239000007891 compressed tablet Substances 0.000 claims 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims 2
- 239000003826 tablet Substances 0.000 claims 2
- 241000282320 Panthera leo Species 0.000 claims 1
- 239000002671 adjuvant Substances 0.000 claims 1
- 239000002775 capsule Substances 0.000 claims 1
- 239000011248 coating agent Substances 0.000 claims 1
- 238000000576 coating method Methods 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 229920000609 methyl cellulose Polymers 0.000 claims 1
- 239000001923 methylcellulose Substances 0.000 claims 1
- 235000010981 methylcellulose Nutrition 0.000 claims 1
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 8
- 238000013265 extended release Methods 0.000 abstract description 6
- 239000008280 blood Substances 0.000 abstract description 3
- 210000004369 blood Anatomy 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 14
- 238000013268 sustained release Methods 0.000 description 12
- 239000012730 sustained-release form Substances 0.000 description 12
- 239000003094 microcapsule Substances 0.000 description 10
- 102000004877 Insulin Human genes 0.000 description 7
- 108090001061 Insulin Proteins 0.000 description 7
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- 229940125396 insulin Drugs 0.000 description 7
- 229920000642 polymer Polymers 0.000 description 6
- 239000011159 matrix material Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 229940123208 Biguanide Drugs 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 230000002035 prolonged effect Effects 0.000 description 4
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
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- 238000004519 manufacturing process Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 239000013543 active substance Substances 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 230000003178 anti-diabetic effect Effects 0.000 description 2
- 239000003472 antidiabetic agent Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
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- 229940095884 glucophage Drugs 0.000 description 2
- 230000002218 hypoglycaemic effect Effects 0.000 description 2
- 230000003914 insulin secretion Effects 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 239000011859 microparticle Substances 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- DIIIISSCIXVANO-UHFFFAOYSA-N 1,2-Dimethylhydrazine Chemical compound CNNC DIIIISSCIXVANO-UHFFFAOYSA-N 0.000 description 1
- 229910052684 Cerium Inorganic materials 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 108010023302 HDL Cholesterol Proteins 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 102000013566 Plasminogen Human genes 0.000 description 1
- 108010051456 Plasminogen Proteins 0.000 description 1
- 241000239226 Scorpiones Species 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 235000009754 Vitis X bourquina Nutrition 0.000 description 1
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- 239000004480 active ingredient Substances 0.000 description 1
- 229920001586 anionic polysaccharide Polymers 0.000 description 1
- 150000004836 anionic polysaccharides Chemical class 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
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- 230000037396 body weight Effects 0.000 description 1
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- GWXLDORMOJMVQZ-UHFFFAOYSA-N cerium Chemical compound [Ce] GWXLDORMOJMVQZ-UHFFFAOYSA-N 0.000 description 1
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- 230000002496 gastric effect Effects 0.000 description 1
- 229960004580 glibenclamide Drugs 0.000 description 1
- 229960001381 glipizide Drugs 0.000 description 1
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 description 1
- 230000004190 glucose uptake Effects 0.000 description 1
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 1
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- 229910052749 magnesium Inorganic materials 0.000 description 1
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- 229910052751 metal Inorganic materials 0.000 description 1
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- 235000020824 obesity Nutrition 0.000 description 1
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- 102000004169 proteins and genes Human genes 0.000 description 1
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- YHULXGUCQZFROV-UHFFFAOYSA-N sulfane;urea Chemical compound S.NC(N)=O YHULXGUCQZFROV-UHFFFAOYSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
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- 230000003442 weekly effect Effects 0.000 description 1
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
1248815 玖、發明說明： 【發明所屬之技術領域】· 糖尿病是一種由於胰島素不足或騰島細胞的代謝缺陷引起的血葡萄 代謝紊亂的一種綜合症。. ” 糖尿病類型： 一、糖尿病第一型：亦稱為胰島素倚賴型，病因是胰臟内製造 的細胞^受破壞，不能製造胰島素，必須依賴注射遺島素=素 一、糖予病第二型'亦稱非胰島素依賴型，是最常見的類型，體内 胰島素分泌正常或相對些微減少，病因是身體對胰島素產 性，胰島素不能發揮功能，而須倚賴口服降血糖磺醯尿素 脈類、甲型糖甘醣抑制劑治療。 ”、雙 二曱气脈(N，N-dimethylimidodicaAonimidic diamide hydrocfe^^ C4H11N5)屬於治療第二型糖尿病的雙胍類口服降華各 糖尿病，近半個世紀以來，二甲雙胍^/床ΙΓίίίίί S3 准二甲雙胍進入臨床使用由 幾年又掀起了使用二甲雙_品的誠。^⑽關和西方各國近 一甲雙脈並不直接影響騰島的分泌，而是通過辦強| 感性’促進周邊組織對葡萄糖的攝取，減少“強 ，，，第二型糖尿病患者空腹和餐後減㊁收= 病胰島素治療血糖控制不佳者。另外，二甲雔、ϋ孓糖尿 獨應用不會引起低血糖，且另有辦加鏃、、容上刺激胰島素分泌，單 對心血管有保護作用。j t用，抑制纖溶酶原啟動抑制物， 於肥胖的的代謝，所以又可以減輕體重，對 從·二^胍5GGmg在空腹下的生體可轉鉍。-甲《_詈 從500〜1500 mg以及85〇~225〇 m 吸 匕^ 一 T雙胍剡里 會影f二甲雙脈吸收及影響其‘，約仏j系。食物 時間將會延長。臨床上，二甲雙胍從小劑量晶;甲最南血中濃度出現 每日2〜3次，逐漸增加劑時服用，每次250mg， 率為5〜30%。 ^里〃敢吊見的田^作用是嚴重胃腸道反應，發生 6 1248815 •【先前技術】 以往之中華民國專利共三件，其公告編號： 505516 —種用於治療糖尿病以及與糖尿病相關之情況之醫藥組合物。與本發明 不同。 v、 又 438587用預防及治療糖尿病之醫藥組成物。與本發明不同。 330933治療糖尿病之喃艾瑞莫菲連及艾瑞莫菲諾德。與本發明不同。 美國專利與本發明不同。其公告編號為： ό，586,438 Antidiabetic fommlation and method抗糖尿病配方及方法。該專利敘述 • 合併Metformin Hydrochloride及Glyburide使用之配方，與本發明不同。 6,559，187 Liquid formulation of metformin 二甲雙胍的溶液劑型。該專^敘述1248815 玖, invention description: [Technical field to which the invention pertains] · Diabetes is a syndrome of blood grape metabolism disorder caused by insulin deficiency or metabolic defects of Tengdao cells. Types of diabetes: First, type 1 diabetes: also known as insulin-dependent type, the cause is that the cells produced in the pancreas are damaged, can not make insulin, must rely on injection of nomadic acid, vegetarian, sugar, second Type 'also known as non-insulin-dependent type, is the most common type, the body's insulin secretion is normal or relatively small, the cause is the body's ability to produce insulin, insulin can not function, but must rely on oral hypoglycemic sulfonium urea veins, Treatment with aglycoside inhibitor. ", N, N-dimethylimidodica Aonimidic diamide hydrocfe ^ C4H11N5) belongs to the treatment of type 2 diabetes, biguanides, oral hypothermia, diabetes, nearly half a century, metformin ^/bed ΙΓ 3 二甲 胍 胍 胍 胍 胍 胍 胍 胍 胍 胍 胍 胍 S S S S S S S 胍 胍 胍 胍 S 胍 胍 胍 胍^(10) Guan and the nearly one pair of veins in Western countries do not directly affect the secretion of Tengdao, but through the strong | sensible 'promoting peripheral tissue glucose uptake, reducing "strong,, type 2 diabetes patients fasting and meals After the reduction of 2 = disease insulin treatment of poor glycemic control. In addition, dimethyl hydrazine, diarrhea and urine alone will not cause hypoglycemia, and there is another treatment, stimulating insulin secretion, single cardiovascular Protective effect. Jt, inhibits the activation of plasminogen, inhibits the metabolism of obesity, so it can reduce the body weight, and can transfer to the body under the fasting of 5GGmg from the 二. 500~1500 mg and 85〇~225〇m 匕^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ The concentration of the most southern blood appears 2 to 3 times a day, and the dosage is gradually increased when taking the agent, 250mg each time, the rate is 5~30%. ^The brain of the scorpion is a serious gastrointestinal reaction, which occurs 6 1248815 • [Prior Art] In the past, the Republic of China patents total three , Announcement No.: 505516 - A pharmaceutical composition for treating diabetes and diabetes-related conditions. It is different from the present invention. v, 438587 is a pharmaceutical composition for preventing and treating diabetes. It is different from the present invention. 330933 for treating diabetes The invention is different from the present invention. The US patent is different from the present invention. The publication number is: ό, 586, 438 Antidiabetic fommlation and method Anti-diabetic formula and method. The formulation used by Metformin Hydrochloride and Glyburide is different from the present invention. 6,559,187 Liquid formulation of metformin solution dosage form.
Metformin Hydrochloride之溶液劑易吞服，增加生體可用率，與本發明 不同。 6,524,618 Directly compressible extended-release matrix formulation for metformin hydr〇ch_de二甲雙胍的直壓延長釋放基質錠之配方。該專利敘述改 良壓錠前粉劑之流動及壓錠性，已達成延長釋放的效果，與本發明 同。 ,. ό，517,870 Oral fonnulation comprising biguanide and an organic acid 包含雙胍類及The solution of Metformin Hydrochloride is easily swallowed, increasing the availability of the organism, which is different from the present invention. 6,524,618 Directly compressible extended-release matrix formulation for metformin hydr〇ch_de a direct pressure extended release matrix ingot of metformin. This patent describes the effect of prolonged release by improving the flow and tableting properties of the powder before the tableting, and is the same as the present invention. , ό, 517, 870 Oral fonnulation includes biguanide and an organic acid
一各有機酸的口服配方。該專利敘述添加矯味劑改善苦味，如槔撥 油等精油，與本發明不同。 T 6,506,410 Sustained release microparticle and method for preparing the same 緩釋微 粒及相關製造方法。該專利敘述油劑或乳劑都含有生物分解性聚合^ 物，與本發明不同。 " 6,491，950 Controlled release pharmaceutical composition 控釋的藥劑組成。該專利 敘述以咼溶點的油、酯、聚合物纖維素的的藥劑組成物，可延釋約％ 小時，與本發明不同。 '' 6,458,387 Sustained release microspheres緩釋的微圓粒。該專利敘述由蛋白質、水 溶聚合物、陰離子多糖化物、金屬陽離子等組成直徑1〇〇〇埃大小的‘ 粒，與本發明不同。 .· 6,447,750 Medicinal aerosol formulation醫學氣霧配方該專利敘述。斑本發明不 同。 〃 6,117,455 Sustained-release microcapsule of amorphous water- soluble pharmaceutical active agent水溶性藥劑活性機制緩釋微膠囊。該專利 敘述含有無定形水可溶解藥物的乳劑，與本發明不同。 6,099,862 Oral dosage form for the controlled release of a biguanide and sulfonylurea 雙胍類及磺醯尿素的口服控釋劑型。該專利敘述*metf〇rmin、 ’ glipizide、介面活性劑、膜衣包覆劑與塑〗匕劑所組成，與本發明不同。 5,665,394及5,594,091 之Matrix for sustained-release preparation 緩釋基質劑的製 ‘備。該專利敘述由聚酯類聚合物製備基質緩釋劑，與本發明不同。· 5,476,663 Prolonged release micrpcapsule 延釋微膠囊。該專利敘述以water-in-〇il 乳劑作成微膠囊形式，與本發明不同。 , 1248815 5.330.767 Sustained release microcapsule 緩釋微膠囊。該專利敘述以W/0/W 乳劑 調整黏度到lOOOOcps製成微膠囊形式，與本發明不同。 5,304,377 Prolonged release preparation and polymers thereof 延釋製備物及其所用 之聚合物該專利敘述用乳酸聚合物製成延釋的乳劑，與未發^不同。’ 5.330.767 Sustained release microcapsule緩釋微膠囊。以乳酸及相關纖維素類聚合 物之W/0/W乳劑製成延釋的乳劑，與本發明不同。 ” ^ 5,055,3〇6 Sustained-release formulations 緩釋劑型的配方該專利。敘述以Eurdragit 包衣活性成分，與本發明不同。 4,834,985 Controlled release pharmaceutical composition 控釋的藥劑組成。該專利 敘述以乳劑為主，與本發明不同。· ”、” 4,711,782 Prolonged release microcapsules and their production 延釋微膠嚢及產 品。該專利敘述以cycl〇dextrin及纖維素為主，與本發明。 1248815 【發明内容】 方，僅有美國專利6,524,618提及。該*國專利與本發明^An oral formulation of each organic acid. This patent describes the addition of a flavoring agent to improve bitterness, such as essential oils such as eucalyptus oil, which is different from the present invention. T 6,506,410 Sustained release microparticle and method for preparing the same sustained release microparticles and related manufacturing methods. This patent states that oils or emulsions contain biodegradable polymers, which are different from the present invention. " 6,491,950 Controlled release pharmaceutical composition Controlled release of pharmaceutical composition. This patent describes a pharmaceutical composition of an oil, an ester or a polymer cellulose having a cerium melting point which can be extended for about % hours, which is different from the present invention. '' 6,458,387 Sustained release microspheres sustained release micro-round pellets. This patent describes a "particle" having a diameter of 1 angstrom by protein, a water-soluble polymer, an anionic polysaccharide, a metal cation or the like, which is different from the present invention. . . 6, 447, 750 Medicinal aerosol formulation medical aerosol formulation described in this patent. The spotted invention is different. 〃 6,117,455 Sustained-release microcapsule of amorphous water-soluble pharmaceutical active agent This patent describes an emulsion containing an amorphous water-soluble drug, which is different from the present invention. 6,099,862 Oral dosage form for the controlled release of a biguanide and sulfonylurea. Oral controlled release dosage form of biguanide and sulfonamide. This patent is composed of *metf〇rmin, 'glipizide, an interface active agent, a film coater and a plasticizer, and is different from the present invention. Matrix for sustained-release preparation of 5,665,394 and 5,594,091 Preparation of sustained-release matrix agents. This patent describes the preparation of a matrix sustained release agent from a polyester based polymer, which is different from the present invention. · 5,476,663 Prolonged release micrpcapsule extended release microcapsules. This patent describes the use of a water-in-〇il emulsion as a microcapsule, which is different from the present invention. , 1248815 5.330.767 Sustained release microcapsule sustained release microcapsules. This patent describes the preparation of microcapsules in a W/0/W emulsion adjusted viscosity to 1000 cps, which is different from the present invention. 5,304,377 Prolonged release preparation and polymers thereof The extended release preparation and the polymer used therefor. This patent describes the use of a lactic acid polymer to make a delayed release emulsion, which is different from the prior art. ' 5.330.767 Sustained release microcapsule sustained release microcapsules. A delayed release emulsion made of a W/0/W emulsion of lactic acid and a related cellulosic polymer is different from the present invention. ^ 5,055,3〇6 Sustained-release formulations This patent is formulated to coat the active ingredient with Eurdragit, which is different from the present invention. 4,834,985 Controlled release pharmaceutical composition Controlled release pharmaceutical composition. , "," 4,711,782 Prolonged release microcapsules and their production extended release microcapsules and products. This patent describes cycl〇dextrin and cellulose, and the present invention. 1248815 [Summary content] Mention is made in U.S. Patent No. 6,524,618.
^nstolMye^^ 〇LUC〇PIMGE XR( MetformE L^M 錠恥。以Sodmm CMC、HPMC、MC、及Mag· Stearate所組成的配方。 ° 在口聚 i 中釋放’錠劑的惰性(非有效)成分，可能保持完 本發明之優點為 L f”匕欠内部”階段合併到，，外部，，的離散粒子(discrete Particl啦 2. 3. 錠劑的惰性成分於排泄物消失。 ϋ明性試驗之f床試驗，確證本發明於國人的生體有效 I： x-r"auc〇- ^ - 驗『確周64人次的隨機雙盲平行臨床療效評估試 大醫院進行===尿病治療，較一般傳統劑型佳。本研究於台北臺 4. 1248815 【實施方式】 實施例一 試製 MetforminHC1 錠 每鍵理論重：1〇〇〇 mg 重量差異：950〜1050 mg 硬度：5〜12 kg 配方：^nstolMye^^ 〇LUC〇PIMGE XR (MetformE L^M Insult. Formulated with Sodmm CMC, HPMC, MC, and Mag·Stearate. ° Released in the mouth of the 'inert' (inactive) The composition, which may maintain the advantages of the present invention, is an integral part of the Lf"匕inside" phase, and the external, discrete particles (discrete Particl 2. 3. The inert component of the tablet disappears in the excrement. The f-bed test confirms that the present invention is effective in the human body of the Chinese I: x-r"auc〇- ^ - test "several double-blind parallel clinical efficacy evaluation of 64 people in the weekly trial test === urinary treatment, This study is better than the traditional dosage form. This study was conducted at Taipei Station 4. 1248815 [Embodiment] Example 1 Trial production of Metformin HC1 ingots Theoretical weight: 1〇〇〇mg Weight difference: 950~1050 mg Hardness: 5~12 kg Formulation:
Metformin HC1 52.5%Metformin HC1 52.5%
Microcrystalline Cellulose 13% HPC 1.5% HPMC 2208 31.5%Microcrystalline Cellulose 13% HPC 1.5% HPMC 2208 31.5%
Magnesium stearate 1.5% 混合調製： 1) 取 Microcrystalline cellulose、HPC 及 HPMC 22〇8 以 Standard mesh Νο·80 過篩0 2) 稱取 Metformin HC1 以 Standard mesh No· 40 過篩。 3) 將混合後之粉末置於快速混合製粒機，預混合i分鐘，再加入Ajcohd (95%) 800 g作成濕顆粒。 4) 將濕顆粒置於乾燥箱中乾燥之，溫度為30°C±5°C。 6) 將乾燥完的顆粒以Standard mesh No. 16整粒之，整粒完，加入Magnesium · stearate 75 g，混合 5 分鐘。 7) 最終混合後的顆粒送至壓錠室壓錠。 本實施例之溶離試驗，依USP 25 pH 4.5 Phosphate Buffer之測試結果如下； 時間(小時） 1 2 4 6 8 溶離率(％) 30.6 46.4 65 75.7 86.8 將本發明與美國必治妥施貴寶股份有限公司之GLUCOPHAGE XR進行國人 之生體可用試驗。結果如下： . 1248815Magnesium stearate 1.5% Mixed Modulation: 1) Microcrystalline cellulose, HPC and HPMC 22〇8 were sieved with Standard mesh Νο·80 0 2) Metformin HC1 was weighed and sieved with Standard mesh No. 40. 3) The mixed powder was placed in a rapid mixing granulator, premixed for 1 minute, and then Ajcohd (95%) 800 g was added to make wet granules. 4) Dry the wet granules in a dry box at a temperature of 30 °C ± 5 °C. 6) The dried granules are granulated as Standard Mesh No. 16. After granulating, add Magnesium · stearate 75 g and mix for 5 minutes. 7) The finally mixed granules are sent to the tablet presser. The dissolution test of this example, according to the USP 25 pH 4.5 Phosphate Buffer test results are as follows; time (hours) 1 2 4 6 8 dissolution rate (%) 30.6 46.4 65 75.7 86.8 The present invention and the US must-have Squibb Co., Ltd. The GLUCOPHAGE XR is a test for the human body. The results are as follows: . 1248815
Table 1. 口服GLUCOPHAGE； X.R.受試者之藥動學參數Table 1. Oral GLUCOPHAGE; X.R. Subject Pharmacokinetic Parameters
Subject No. AUCo— r .ss (hrxug/ml) Cmax.ss (ug/ml) Cmin.ss (ug/ml) Cave.ss (ug/ml) Fluctuation MRTss (hr.) Tmax.ss (hr) Ti/2 (hr) 1 4.32 0.330 0.0689 0.180 1.45 9.20 6.00 26.9 2 5.31 0.478 0.131 0.221 1.57 8.86 5.00 25.2 3 6.45 0.494 0.126 0.269 1.37 9.26 4.00 28.0 4 5.02 0.495 0.0975 0.209 1.90 9.27 6.00 24.4 5 4.74 0.414 0.112 0.198 1.53 9.30 5.00 26.2 6 4.15 0.379 0.109 0.173 1.56 9.51 5.00 27.9 7 5.41 0.405 0.109 0.226 1.31 9.78 5.00 23.0 8 4.01 0.346 0.0921 0.167 1.52 8.58 5.00 26.1 9 4.17 0.348 0.106 • 0.174 1.39 9.07 4.00 24.2 ' 10 3.83 0.318 0.0707 0.159 1.55 9.06 4.00 24.0 11 5.55 0.404 0.120 0.231 1.23 9.78 5.00 24.5 12 3.51 0.260 0.0558 0.146 1.40 9.35 4.00 27.2 13 4.32 0.408 0.0739 0.180 1.86 8.95 5.00 23.6 14 3.67 0.242 0.0842 0.153 1.03 10.8 7.00 31.2 15 5.01 0.368 0.0835 0.209 1.36 9.30 5.00 26.3 16 7.84 0.462 0.141 0.327 0.983 11.9 8.00 15.9 Mean 4.83 0.384 0.0988 0.201 1.44 9.50 5.19 25.3 SD 1.13 0.076 0.0246 0.047 0.24 0.81 1.11 3.2 CV 23.3 19.9 24.9 23.4 17.0 8.53 21.4 12.8Subject No. AUCo- r .ss (hrxug/ml) Cmax.ss (ug/ml) Cmin.ss (ug/ml) Cave.ss (ug/ml) Fluctuation MRTss (hr.) Tmax.ss (hr) Ti /2 (hr) 1 4.32 0.330 0.0689 0.180 1.45 9.20 6.00 26.9 2 5.31 0.478 0.131 0.221 1.57 8.86 5.00 25.2 3 6.45 0.494 0.126 0.269 1.37 9.26 4.00 28.0 4 5.02 0.495 0.0975 0.209 1.90 9.27 6.00 24.4 5 4.74 0.414 0.112 0.198 1.53 9.30 5.00 26.2 6 4.15 0.379 0.109 0.173 1.56 9.51 5.00 27.9 7 5.41 0.405 0.109 0.226 1.31 9.78 5.00 23.0 8 4.01 0.346 0.0921 0.167 1.52 8.58 5.00 26.1 9 4.17 0.348 0.106 • 0.174 1.39 9.07 4.00 24.2 ' 10 3.83 0.318 0.0707 0.159 1.55 9.06 4.00 24.0 11 5.55 0.404 0.120 0.231 1.23 9.78 5.00 24.5 12 3.51 0.260 0.0558 0.146 1.40 9.35 4.00 27.2 13 4.32 0.408 0.0739 0.180 1.86 8.95 5.00 23.6 14 3.67 0.242 0.0842 0.153 1.03 10.8 7.00 31.2 15 5.01 0.368 0.0835 0.209 1.36 9.30 5.00 26.3 16 7.84 0.462 0.141 0.327 0.983 11.9 8.00 15.9 Mean 4.83 0.384 0.0988 0.201 1.44 9.50 5.19 25.3 SD 1.13 0.076 0.0246 0.047 0.24 0.81 1.11 3.2 CV 23.3 19.9 24.9 23.4 17.0 8.53 21.4 12.8
Table 2. 口服本發明(GlucomineX.R.)受試者之藥動學參數Table 2. Oral pharmacokinetic parameters of subjects in the present invention (Glucomine X.R.)
Subject No. AUCo^ r .ss (hrxug/ml) Cmax.ss (ug/ml) Cmin.ss (ug/ml) Cave.ss (ug/ml) Fluctuation MRTss (hr.) Tmax.ss (hr) Ti/2 (hr) 1 4.45 0.373 0.0744 0.185 1.61 9.16 6.00 26.7 2 6.54 0.456 0.133 0.272 1.19 10.2 5.00 29.8 3 6.05 0.508 0.121 0.252 1.53 8.94 6.00 27.3 4 5.41 0.470 0.121 0.225 1.55 9.47 5.00 27.6 5 5.20 0.518 0.0990 0.216 1.94 9.04 5.00 30.9 6 · 6.49 0.615 0.125 0.271 1.81 9.36 5.00 28.0 7 5.87 0.403 0.108 0.244 1.21 9.94 6.00 22.8 8 4.34 0.356 0.0922 0.181 1.46 9.39 5.00 25.8 9 4.37 0.417 0.0748 0.182 1.88 9.04 4.00 26.9 10 4.25 0.375 0.0935 0.177 1.59 8.85 5.00 24.4 11 1.9*9 0.117 0.0785 0.0828 0.465 10.1 0 28.1 12 4.61 0.409 0.0668 0.192 1.78 8.87 4.00 29.1 13 5.67 0.510 0.0810 0.236 1.82 9.15 5.00 24.9 14 6.08 0.484 0.118 0.253 1.44 9.88 6.00 23.8 15 6.31 0.465 Ό.132 0.263 1.27 9.28 4.00 23.5 16 6.44 0.474 0.135 0.268 1.26 9.66 6.00 26.8 Mean 5.25 0.434 0.103 0.219 1.49 9.40 4.81 26.7 SD 1.21 0.108 0.024 0.050 0.37 0.44 1.47 2.3 CV 23.0 24.8 22.9 23.0 24.6 4.69 30.6 8.72 π 1248815 服本發明相對口服GLUCOPHAGE X.R之生體可用試驗Subject No. AUCo^ r .ss (hrxug/ml) Cmax.ss (ug/ml) Cmin.ss (ug/ml) Cave.ss (ug/ml) Fluctuation MRTss (hr.) Tmax.ss (hr) Ti /2 (hr) 1 4.45 0.373 0.0744 0.185 1.61 9.16 6.00 26.7 2 6.54 0.456 0.133 0.272 1.19 10.2 5.00 29.8 3 6.05 0.508 0.121 0.252 1.53 8.94 6.00 27.3 4 5.41 0.470 0.121 0.225 1.55 9.47 5.00 27.6 5 5.20 0.518 0.0990 0.216 1.94 9.04 5.00 30.9 6 · 6.49 0.615 0.125 0.271 1.81 9.36 5.00 28.0 7 5.87 0.403 0.108 0.244 1.21 9.94 6.00 22.8 8 4.34 0.356 0.0922 0.181 1.46 9.39 5.00 25.8 9 4.37 0.417 0.0748 0.182 1.88 9.04 4.00 26.9 10 4.25 0.375 0.0935 0.177 1.59 8.85 5.00 24.4 11 1.9*9 0.117 0.0785 0.0828 0.465 10.1 0 28.1 12 4.61 0.409 0.0668 0.192 1.78 8.87 4.00 29.1 13 5.67 0.510 0.0810 0.236 1.82 9.15 5.00 24.9 14 6.08 0.484 0.118 0.253 1.44 9.88 6.00 23.8 15 6.31 0.465 Ό.132 0.263 1.27 9.28 4.00 23.5 16 6.44 0.474 0.135 0.268 1.26 9.66 6.00 26.8 Mean 5.25 0.434 0.103 0.219 1.49 9.40 4.81 26.7 SD 1.21 0.108 0.024 0.050 0.37 0.44 1.47 2.3 CV 23.0 24.8 22.9 2 3.0 24.6 4.69 30.6 8.72 π 1248815 The bioavailability test of the present invention relative to oral GLUCOPHAGE X.R
Subject No. AUCo— r .ss (hrxug/ml) Glucomine XR AUCo— r .ss (hrxug/ml) GLUCOPHAGE XR Relative Bioavailability (Glucomine XR/ GLUCOPHAGE XR) 1 4.45 4.32 * 1.03 2 6.54 5.31 1.23 3 6.05 6.45 ， 0.938 4 5.41 5.02 1.08 5 5.20 4.74 1.10 6 6.49 4.15 1.56 7 5.87 5.41 1.09 8 4.34 4.01 1.08 9 4.37 *4.17 • 1.05 10 4.25 3.83 1.11 11 # 1.99 5.55 0.359 12 4.61 3.51 卜 1.31 13 5.67 4.32 1.31 14 6.08 3.67 1.66 15 6.31 5.01 1.26 16 6.44 7.84 0.821 口服本發明之AUCo— r .ss較口服GLUCOPHAGE XR之AUCo— r .ss相對生 體可用率平均值高出112%。 將本發明與一般傳統劑型進行16周64人次之隨機雙盲平行臨床療效評估試驗， 對於HbAlc、Cholesterol、HDL、LDL、Triglyceride的改變及療效，本發明皆比 一般傳統劑型佳。 實施例二 •配方：Subject No. AUCo- r .ss (hrxug/ml) Glucomine XR AUCo- r .ss (hrxug/ml) GLUCOPHAGE XR Relative Bioavailability (Glucomine XR/ GLUCOPHAGE XR) 1 4.45 4.32 * 1.03 2 6.54 5.31 1.23 3 6.05 6.45 , 0.938 4 5.41 5.02 1.08 5 5.20 4.74 1.10 6 6.49 4.15 1.56 7 5.87 5.41 1.09 8 4.34 4.01 1.08 9 4.37 *4.17 • 1.05 10 4.25 3.83 1.11 11 # 1.99 5.55 0.359 12 4.61 3.51 Bu 1.31 13 5.67 4.32 1.31 14 6.08 3.67 1.66 15 6.31 5.01 1.26 16 6.44 7.84 0.821 Oral The AUCo-r.ss of the present invention is 112% higher than the average AUCo-r.ss relative to the bioavailability of oral GLUCOPHAGE XR. The present invention and the conventional conventional dosage form were subjected to a randomized double-blind parallel clinical efficacy evaluation test of 64 weeks and 64 times. The present invention is better than the conventional conventional dosage forms for the changes and effects of HbAlc, Cholesterol, HDL, LDL, Triglyceride. Example 2 • Formulation:
Metformin HC1 48.0 %Metformin HC1 48.0 %
Microcrystalline Cellulose 15.5 % HPMC 2910 1.5 % HPMC 2208 lOOOcps 33.5 %Microcrystalline Cellulose 15.5 % HPMC 2910 1.5 % HPMC 2208 lOOOcps 33.5 %
Magnesium stearate 1.5 % 本實施例之溶離試驗依USP 25 pH 4.5 Phosphate Buffer之測試結果如下: 時間(小時） 1 .2 4 6 8 溶離率(％)· 30.9 43.3 62.6 75.2 86.1 12 1248815 實施例三 配方：Magnesium stearate 1.5 % The dissolution test of this example according to USP 25 pH 4.5 Phosphate Buffer is as follows: Time (hours) 1. 2 4 6 8 Dissolution rate (%) · 30.9 43.3 62.6 75.2 86.1 12 1248815 Example 3 Formulation:
Metformin HC1 54.0 %Metformin HC1 54.0 %
Microcrystalline Cellulose 24.0 % HPMC 2910 1.5 % HPMC 2208 lOOOOOcps 19.0 % * Magnesium stearate 1.5 % 本實施例之溶離試驗依USP 25，pH 4·5 Phosphate Buffer之測試結果如下: 時間(小時） 1 2 4 6 8 溶離率(％) 27.5 42.7 52.7 60.7 81.7 13Microcrystalline Cellulose 24.0% HPMC 2910 1.5% HPMC 2208 lOOOOOcps 19.0 % * Magnesium stearate 1.5 % The dissolution test of this example according to USP 25, pH 4·5 Phosphate Buffer is as follows: Time (hours) 1 2 4 6 8 Dissolution rate (%) 27.5 42.7 52.7 60.7 81.7 13
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