TWI248815B - The controlled release formulation of metformin HCl - Google Patents

Abstract

The invention of extended-release dosage form of metformin HCl has been demonstrated with better therapeutically effect via clinic study on Chinese volunteer. It can control blood sugar for a long period of time and steady concentration on diabetes patients.

Description

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.

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

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 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%

Microcrystalline Cellulose 13% HPC 1.5% HPMC 2208 31.5%

Magnesium 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. 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 12.8

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 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 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 %

Microcrystalline Cellulose 15.5 % HPMC 2910 1.5 % HPMC 2208 lOOOcps 33.5 %

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 %

Microcrystalline 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

Claims (1)

1248815 Pick up, apply for patent scope: 1. HC lion's doctor _, its y is 1000 centimeter J tong methyl cellulose or hydroxypropyl cellulose, its viscosity is 100% ± 3%. —, 96^±4% at pH 4·5, 2· : ^, 1 * Μ at pH 6.8 3. The pharmaceutical composition according to item i of the patent application, which contains ·· · (a) 48 To 53% by weight of metformin hydrochloride; jb) 15.0 to 33.0% by weight of hydroxypropylmethylcellulose; (c) 1.0 to 3.0% by weight of hydroxypropylcellulose; (d) l〇.〇 to 2 〇. 〇 by weight of microcrystalline cellulose; (e) 0.5 to 2.0% by weight of magnesium stearate; (ί) 1·1 to 0.2% by weight of the coloring agent. A pharmaceutical composition according to item 1, which may be a sigma-administered dosage form. The pharmaceutical composition according to item 3 of the patent application, which comprises: (4) 52% by weight of metformin hydrochloride; 32% by weight of hydroxypropylmethylcellulose (HPMC 2208); (6) 14 weight percent of hydroxy group Propylcellulose (HPC); (d) 13% by weight of microcrystalline cellulose; *0).1.5% by weight of magnesium stearate; (ί) 1·1 by weight of a coloring agent. 7 医药 The pharmaceutical composition of claim 5, which may be an oral administration form. • The pharmaceutical composition of claim 1, which may be in the form of pellets, wherein the pellets are extruded into tablets or filled into capsules. • The pharmaceutical group of the patent application section: item 7, wherein the pellet is coated with a pharmaceutically acceptable coating adjuvant.医药 The pharmaceutical composition of claim 1 of the patent scope may be a type of tablet that is directly compressed. 11. The pharmaceutical composition of claim 3, which may be in the form of a directly compressed tablet. • A pharmaceutical composition according to claim 5 of the patent application, which may be in the form of a directly compressed tablet. 14