CN104840480A - New use of dimethyldiguanide/folic acid/vitamin B12 pharmaceutical composition - Google Patents
New use of dimethyldiguanide/folic acid/vitamin B12 pharmaceutical composition Download PDFInfo
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Abstract
The invention relates to a pharmaceutical composition containing a pharmaceutical dose of dimethyldiguanide, folic acid, vitamin B12 and a pharmaceutical carrier or an excipient, belonging to the field of pharmacy. According to the pharmaceutical composition, a harmful result caused by adverse reaction of gastrointestinal tracts when dimethyldiguanide is singly used can be overcome; meanwhile, the pharmaceutical composition has the purpose of preventing, delaying or treating hyperhomocysteinemia, the effect is superior to the effects of existing similar pharmaceutical compositions, and the economic and practical pharmaceutical composition is provided for diabetic patients. The pharmaceutical composition further has the advantage that the medication compliance of the patients is improved.
Description
Technical field
The present invention relates to a kind of containing metformin, folic acid, vitamin B
12pharmaceutical composition be applicable to type 2 diabetes mellitus patient prevention in preparation or alleviate the purposes of medicine of hyperhomocysteinemiainjury.The invention belongs to field of medicaments.
Background technology
Diabetes are a kind of common endocrine metabolism diseases, are characterized in that chronic hyperglycemia is with the sugar, fat and the protein metabolism disorder that cause because of hypoinsulinism and/or effect defect.According to investigations, China's diabetes prevalence, up to 9.7%, calculates that national diabetics about has 9,240 ten thousand people [Yang W, et al.Prevalence of diabetes among men and women in China.N Engl J Med.2010; 362:1090-1101].Diabetes can betide any age, along with the course of disease extends, and easy concurrent whole body nerve, blood capillary and macroangiopathy etc., and chronic, the Progressive symmetric erythrokeratodermia pathological changes of the histoorgans such as the heart, brain, kidney, nerve and eye can be caused.
Metformin (metformin) belongs to biguanides hypoglycemic drug, such medicine mainly acts on islets of langerhans and organizes outward, strengthen the peripheral tissues such as muscle to the utilization of glucose, suppression or delay glucose are in gastrointestinal absorption, suppress glyconeogenesis in liver, increase insulin receptor number and the affinity to insulin in target cell, thus produce hypoglycemic activity.In addition, metformin loses weight in addition, lipid-lowering effect, and to normal person without hypoglycemic activity.Metformin molecular structural formula is as follows:
Metformin was got permission in nineteen ninety-five, in U.S.'s listing, to be had solid evidence-based medicine EBM support, is considered to the first-selection of diabetics initial treatment at present." type 2 diabetes mellitus is treated and is newly known together " of jointly issuing according to american diabetes association (ADA) in 2006 and ESAD (EASD) and " the type 2 diabetes mellitus global treatment guide " of IDF (IDF) up-to-date announcement, can to establish metformin be unique and lifestyle modification jointly as the medicine of type 2 diabetes mellitus Primary Care, and long-term taking can reduce cardiovascular complication.
But in the clinical practice of many decades, metformin distinct issues are still its gastrointestinal side effects: metformin is oral rear main at intestinal absorption, bioavailability only has 50% ~ 60%, oral latter 2 hours blood drug level peakings, drug accumulation is at intestinal wall, and be 10 ~ 100 times of plasma concentration, gastrointestinal reaction is fairly obvious, comprise in Nausea and vomiting, loss of appetite, mouth and have metal abnormal flavour, soft stools and diarrhoea, long-term taking easily causes enteral vitamin B
12with the malabsorption of folic acid.Vitamin B
12it is the coenzyme of methionine synthase, folic acid is the donor of methyl in body, both lack then obstruction methionine circulation, cause homocysteine (Homocysteine, be called for short Hcy) accumulation, result causes high Hcy mass formed by blood stasis [Sato Y, et al.Relationship between metformin use, vitamin B
12deficiency, hyper-homocysteinemia and vascular complications in patients with type 2 diabetes.Endocr J.2013; 60 (12): 1275-1280.].In addition, vitamin B
12lack and also cause DNA dyssynthesis in erythrocyte, cause megaloblastic anemia (pernicious anemia).
On the other hand, Epidemiological study display Chinese population height Hcy mass formed by blood stasis, higher [the Hao L of low folic acid incidence rate, et al.High prevalence of hyperhomocysteinemia in Chinese adults is associated with low folate, vitamin B-12, and vitamin B-6status.J.Nutr.2007,137:407 – 413].Plasma Hcy level raises to be increased relevant with the occurrence risk of cardiovascular disease, has meta-analysis to show: Plasma Hcy often raises 5 μm of ol/L, and risk of stroke increases by 59% (OR:1.59, 95%CI:1.29-1.96), deep venous thrombosis risk increases by 60% (OR:1.60, 95%CI:1.15-2.22), ischemic heart desease (comprising coronary heart diseases and angina pectoris, arrhythmia, heart infarction and sudden death) risk increases by 32% (OR:1.32, 95%CI:1.19-1.45) [Wald DS, et al.Homocysteine and cardiovascular disease:evidence on causality from a meta-analysis.BMJ.2002, 325:1202-1206], generation [the Voutilainen S that Study of evidence based medicine also points out Supplement of folic acid may reduce cardiocerebrovasculaevents events, et al.Serum folate and homocysteine and the incidence of acute coronary events:the Kuopio Ischaemic Heart Disease Risk Factor Study.Am J Clin Nutr.2004, 80 (2): 317-323] [Wang X, et al.Efficacy of folic acid supplementation in stroke prevention:a meta analysis.Lancet, 2007, 369:1876-1882].
Folic acid, vitamin B
12all belong to water-soluble B vitamin, absorb through human body intestinal canal, excreted by urine, seldom accumulate in vivo, also can not therefore occur poisoning.Because water soluble vitamins storage is in vivo little, so constantly from external picked-up, body nutrition and metabolism needs could be met.Vitamin B group is formed metabolism, erythrocyte, keeps nervous system and function of immune system to have important function.
In sum, by metformin, folic acid, vitamin B
12the pharmaceutical composition formed both can alleviate the side effect (low folic acid, high Hcy mass formed by blood stasis, potential pernicious anemia) that metformin prolonged application causes, and was conducive to again the risk reducing diabetics generation cardiovascular complication.Compare above-mentioned three kinds of Drug combinations, pharmaceutical composition of the present invention also significantly can alleviate the financial burden of diabetics, improves curative compliance.
Find through retrieval, patent " pharmaceutical preparation of prevention or treatment metabolism syndrome " (patent No.: the prescription 200510082929.4) relating to biguanides and vitamin B group, but purposes is treatment metabolism syndrome, different from the purposes of this patent; Patent " folacin dimethylbiguanide and preparation method thereof the " (patent No.: 200610149044.6) relate to that to be connected by the method for chemical reaction with metformin by folic acid be a compound, this is being chemically completely impossible, lack the most basic the principles of science, and this compound does not relate to vitamin B
12, different from this patent; Patent " hydrochloric metformin and vitamin B
12composition of medicine " (patent No.: 200910310219.0) do not relate to folic acid, and be only limitted to treatment megaloblastic anemia and aplastic anemia, completely different from this patent purposes.
Summary of the invention
The present invention be intended to overcome that Long-term Oral metformin exists, cause vitamin to be lost and derivative many adverse consequencess by gastrointestinal side effect, select a kind of pharmaceutical composition, for preventing while the Primary Care of type 2 diabetes mellitus blood sugar lowering, delaying or treat high Hcy mass formed by blood stasis, improve prognosis.
For achieving the above object, the present invention is by the following technical solutions:
A kind of pharmaceutical composition, comprises
(1) metformin of pharmaceutical dosage and the one of active metabolite or salt apoplexy due to endogenous wind thereof;
(2) vitamin B of pharmaceutical dosage
12;
(3) folic acid of pharmaceutical dosage;
(4) acceptable carrier on pharmaceutics.
Above-mentioned " pharmaceutical dosage " refers to the amount of pharmacological action with collaborative, prevention or response to treatment.
Pharmaceutical preparation provided by the invention, one of its active component is metformin, and another two active ingredients are folic acid, vitamin B respectively
12, its Folic Acid also comprises the similar compound with similar biological activity, as formyl tetrahydrofolic acid, 5-methyltetrahydrofolate, folic acid active metabolite and can metabolism and/or generate the material of folic acid, vitamin B in vivo
12also the similar compound with similar biological activity is comprised, as cobalamine, mecobalamin element, 5 '-deoxyadenosyl cobalamin, hydroxocobalamine and can metabolism and/or generate the material of this compounds in vivo.
In the present invention, the consumption of metformin is 250mg ~ 1000mg, and being more preferably consumption is 500mg ~ 750mg.
In the present invention, the consumption of folic acid is 0.1mg ~ 0.8mg; Being more preferably consumption is 0.2mg ~ 0.4mg.
In the present invention, vitamin B
12consumption be 2.5 μ g ~ 20 μ g, being more preferably consumption is 5 μ g ~ 10 μ g.
One of active component in pharmaceutical preparation provided by the invention is metformin, is used for the treatment of type 2 diabetes mellitus clinically.This medical instrument have increase intramuscular glucose anerobic glycolysis, suppression or delay glucose intestinal absorption, suppress liver glycogen heteroplasia to reduce glycogen to export, increase pharmacological actions such as the sensitivity of insulin; hypoglycemic activity is had per capita to the diabetes that islet function normally or is lost; but to normal person without hypoglycemic activity; meanwhile, this medicine reduces blood fat, atherosclerosis, attenuating in addition to effects such as platelet aggregating agent sensitivity.Folic acid in pharmaceutical preparation provided by the invention, vitamin B
12are all one of vitamin B group, vitamin B group is the nutrient of needed by human, and formed life entity metabolism, erythrocyte, keep nervous system and function of immune system to have important function, what is more important can reduce Plasma Homocysteine.
In experimentation, we are surprised to find, and folic acid is alone slight hypoglycemic activity, and with the metformin of pharmaceutical dosage, folic acid, vitamin B
12for the pharmaceutical preparation of active component has remarkable result to prevention or treatment hyperhomocysteinemiainjury while performance hypoglycemic activity.
Term " pharmaceutical dosage " refers to that clinician grants the dosage of medicine to diseased individuals according to diseased individuals coincident with severity degree of condition in order to reach effectively control or disease therapy object.Be to be understood that medicine pharmaceutical dosage provided by the invention is not limitation of the present invention, but to preferably of the present invention, under normal circumstances, in this dosage preferable range, this medicine can produce effective therapeutic effect to diseased individuals.Diseased individuals refers to the self-existent life entity suffering from disease, and in the present invention, life entity is the mankind espespecially.Should be appreciated that in prior art, human pharmaceutical use dosage or pharmaceutical dosage scope can with mammal, as rat, mice etc. are converted.
Medicament form of pharmaceutical preparation provided by the invention comprises any peroral dosage form of pharmaceutically acceptable, such as will containing metformin, folic acid, vitamin B
12the compositions of compound makes the dosage forms such as conventional tablet, bilayer tablet, slow releasing tablet, controlled release tablet, dispersible tablet, enteric coated tablet, granule, conventional capsule, slow releasing capsule, controlled release capsule, enteric coated capsule, capsule containing micropill or small pieces, pH dependent form capsule containing micropill or small pieces.Should it is emphasized that will containing metformin, folic acid, vitamin B
12compositions make slow releasing tablet, bilayer tablet, slow releasing capsule and enteric coated capsule.
According to the present invention, term " pharmaceutically suitable carrier or excipient " refers at those materials known in the art, can serve as filler or support material in tablet, pill, capsule etc.Usually these materials get the Green Light for this object, and as pharmaceutical agents, they are non-activities.Described excipient and accessory package are containing the compositions of one or more materials of the solubility/insoluble salt, octadecanol, stearic acid, dextrin, sodium chloride, cysteine, citric acid and sodium sulfite etc. of (but being not limited to) starch, microcrystalline Cellulose, inorganic salts, hydroxypropyl emthylcellulose, ethyl cellulose, polyacrylic resin class, polycarboxy ethene, alginic acid.Pharmaceutic adjuvant used in manufacturing process and preparation method are all as well known to those skilled in the art and familiar.
Compound in pharmaceutical composition provided by the invention can grant diseased individuals in identical preparation simultaneously, also in succession grants diseased individuals discriminably.If in succession grant diseased individuals, then the loss of the beneficial effect that second, the 3rd delay that active component is granted should not cause active ingredient combination to bring.If grant diseased individuals simultaneously, the compound in compositions can mix and is present in same pharmaceutical dosage forms, also independently can exist with same dosage form (packaged in combination).If independently exist with same dosage form, then pharmaceutical composition can flexible existing with " Combined drug box " form." Combined drug box " is a kind of case type container, the drug regimen of one or more dosage forms built-in and operation instructions thereof, is metformin, folic acid, vitamin B in the present invention
12make the Combined drug box of same preparation respectively.
Advantage of the present invention: the invention provides the metformin containing pharmaceutical dosage, folic acid, vitamin B
12the novelty teabag of pharmaceutical composition.Metformin and folic acid, vitamin B
12combined effect be not the simple addition of each self-applying of each active substance, but the basis obtaining better control type 2 diabetes mellitus patient blood glucose can prevent and treat hyperhomocysteinemiainjury, significantly reduce many adverse consequencess that metformin gastrointestinal side-effect brings.That is, metformin and folic acid, vitamin B
12drug combination achieves synergy, is therefore antidiabetic medicine preferably.
Below in conjunction with detailed description of the invention, the present invention will be further described, not limitation of the invention, and the equivalent replacement of all any this areas of carrying out according to content of the present invention, all belongs to protection scope of the present invention.
Detailed description of the invention
The formulation process of following pharmaceutical preparation embodiment and the consumption of preparation material used or preparation material used are not limited to character express; all formulation methods containing pharmaceutical composition provided by the invention; all belong to protection scope of the present invention; concrete experimental technique can reference drug preparation quick-reference book, as " pharmaceutical necessities applications and preparation ", " pharmaceutics ", " Biopharmaceutics and Pharmacokinetics " etc.
embodiment 1prepare compound metformin/folic acid/vitamin B
12sheet (1000 amounts)
Preparation method: whole supplementary material is crossed 80 mesh sieves, metformin hydrochloride crude drug pulverized 100 mesh sieves, for subsequent use.Get 0.4g folic acid, 5mg vitamin B
12, according to equal increments method mix homogeneously, mixed 80 mesh sieves with carboxymethylstach sodium, microcrystalline Cellulose, mix with 500g metformin hydrochloride again, add starch, low-substituted hydroxypropyl cellulose mix homogeneously, make soft material with 5% PVP K30-95% alcoholic solution, 20 mesh sieves are granulated, 60 DEG C of drying about 2h, 20 mesh sieve granulate, the water content controlling granule is 2-3%, dried granule is mixed homogeneously with magnesium stearate, semi-finished product detect, and measure content, are pressed into 1000 with tablet machine.The tablet made needs aluminium-plastic bubble plate packing, keeps in Dark Place.The hydrochloric metformin 500mg of every sheet, folic acid 0.4mg, vitamin B in the compound tablet made
125 μ g.
embodiment 2prepare compound metformin/folic acid/vitamin B
12double-layer sustained release tablets (1000 amounts)
Formula:
Metformin slow release layer:
Folic acid/vitamin B
12layer:
Preparation method: (1) metformin slow release layer: pulverizing, the metformin hydrochloride crossing 80 mesh sieves, hypromellose and octadecanol are pressed recipe quantity mix homogeneously, add 5% ethyl cellulose alcoholic solution soft material, granulate with 20 mesh sieves, in 60 DEG C of dryings 2 hours, with 20 mesh sieve granulate, then add magnesium stearate, detect.(2) folic acid vitamin B
12layer: get 0.4g folic acid, 10mg vitamin B
12mix according to equal increments method, add microcrystalline Cellulose mixing again, cross 80 mesh sieves, add starch, carboxymethylstach sodium and low-substituted hydroxypropyl cellulose respectively, Homogeneous phase mixing, make soft material with 5% polyvidone, 20 mesh sieves are granulated, 60 DEG C of drying about 2h, 20 mesh sieve granulate, the water content controlling granule is 2-3%.Semi-finished product detect, and measure moisture and content.(3) double-layer tablet preparation method: by the above-mentioned metformin for preparing and folic acid B
12granule is respectively charged in feed hopper, is pressed into special-shaped tablets 1000 with double-layer tablet tablet machine.The tablet made needs lucifuge, and uses aluminium-plastic bubble plate packing.The hydrochloric metformin 500mg of every sheet, folic acid 0.4mg, vitamin B in the slow releasing tablet made
1210 μ g.
embodiment 3prepare compound metformin/folic acid/vitamin B
12slow releasing tablet (1000 amounts)
Diabecron sustained-release layer:
Folic acid/vitamin B
12rapid release coatings:
Preparation method:
Slow release layer: will pulverize, cross the metformin hydrochloride of 100 mesh sieves with lactose, Glyceryl Behenate with mix homogeneously by recipe quantity, add hypromellose mixing again, add 10% PVP K30 alcoholic solution soft material, granulate with 18 mesh sieves, in 60 DEG C of dryings 2 hours, with 18 mesh sieve granulate, then add magnesium stearate, detect, tabletting.
Release layer: get inventory folic acid (folic acid is according to 30% Excess quantities), vitamin B
12(vitamin B
12according to 35% Excess quantities) add 570g purified water and stir, then add Opadry film coating pre-mix dose 30g and stir, continue to stir 45min after Opadry film coating pre-mix dose dissolves completely, coating solution is crossed colloid mill.The diabecron sustained-release tablet that pressure makes is put in high-efficiency coating machine, pass into temperature filtration hot-air pre-heating, control temperature of charge at 38-45 DEG C, open spray gun, adjustable spraying speed, control atomisation pressure to 0.15 ~ 0.2MPa, on the label rotated, coating solution is sprayed perpendicular to material in 1/3 place, coating pan rotating speed maintains 8 ~ 12r/min, and gun traffic controls at 2-5ml/min, contains vitamin B by what prepare
12, folic acid coating solution all sprayed stopping coating, obtain coated tablet, and use aluminium-plastic bubble plate packing.The hydrochloric metformin 500mg of every sheet, folic acid 0.4mg, vitamin B in the slow releasing tablet made
1210 μ g.
embodiment 4metformin/folic acid/vitamin B
12compositions is on the impact of rat blood sugar and homocysteine
Method: SD rat 80, body weight 200 ~ 230g, male and female half and half, adaptability randomly draws 10 as blank group after raising l week, all the other 70 give streptozotocin (STZ) 30mg/kg single intraperitoneal injection respectively, and after 14d, rat tail vein blood sampling measures blood sugar level, are greater than 11.1mmoL/L and are defined as Glycemia Decline success, be divided into 5 groups at random, i.e. model control group, metformin group, folic acid group, folic acid+vitamin B
12group, metformin+folic acid+vitamin B
12group, latter 4 groups give metformin 100mg/kg, folic acid 80 μ g/kg, folic acid+vitamin B respectively every day
12(80 μ g+2 μ g)/kg, metformin+folic acid+vitamin B
12(100mg+80 μ g+2 μ g)/kg, blank group and model group give normal saline, each group all by fill with for 2 times every day hello, medication or processing time are 8 weeks.L0% chloral hydrate intraperitoneal injection of anesthesia animal after 8 weeks, abdominal aortic blood surveys blood glucose, homocysteine in plasma (Hcy) etc.Removing midway rat cadavers, often group records result and statistics in table 1, and measurement data is with mean ± standard deviation
represent.
Result: see the following form.(1) hypoglycemic activity is given with diabetes rat Drug therapy after 8 weeks, metformin, folic acid, folic acid+vitamin B
12, metformin/folic acid/vitamin B
12compositions group rat FPG all has reduction, wherein remarkable with the experimental group containing metformin, the basic antidiabetic drug status of prompting metformin; We surprisingly find, folic acid group, folic acid+vitamin B
12group also has hypoglycemic activity, and in conjunction with result of study previously, we think that folic acid has slight blood sugar reducing function.(2) fall Hcy effect to compare with model group, metformin group blood Hcy raises to some extent, but containing folic acid or folic acid+vitamin B
12group all show significant Plasma Hcy reducing effect, consistent with intended effect, and this work is main in order to folic acid, vitamin B
12collaborative.Based on the above results, we think metformin and folic acid and vitamin B
12share the effect that there is collaborative blood sugar lowering, alleviate high Hcy mass formed by blood stasis.
Table 1 metformin/folic acid/vitamin B
12compositions is to the effect of rat blood sugar, Hcy
Note: compare with model group, * P<0.05, * * P<0.01; Compare with metformin group,
△p<0.05,
△ △p<0.01;
Compare with folic acid group,
#p<0.05,
#p<0.01.FPG-fasting glucose, Hcy-homocysteine in plasma.
Claims (6)
1. a pharmaceutical composition, constituent is:
1) metformin of pharmaceutical dosage or its officinal salt;
2) folic acid of pharmaceutical dosage;
3) vitamin B of pharmaceutical dosage
12; And
4) pharmaceutically suitable carrier or excipient.
2. compositions according to claim 1, is characterized in that: the content of described metformin is 250 ~ 1000mg, preferably 500 ~ 750mg; The content of described folic acid is 0.2 ~ 0.8mg, preferably 0.2 ~ 0.4mg, described vitamin B
12content be 2.5 ~ 20 μ g, preferably 5 ~ 10 μ g.
3. the pharmaceutical dosage form of the compositions of claim 1 to 2 described in any one comprises conventional tablet, bilayer tablet, multilayer tablet, slow releasing tablet, single chamber controlled release tablet, two rooms controlled release tablet, pore type controlled release tablet, sublingual lozenge, oral cavity quick disintegrating slice, dispersible tablet, enteric coatel tablets, granule, pill, enteric coated capsule, delayed-release tablet, regularly/position releasing piece, conventional capsule, slow releasing capsule, controlled release capsule, the capsule containing micropill or small pieces, the pH dependent form capsule containing micropill or small pieces, preferred slow releasing tablet or capsule.
4. compositions according to claim 1, is characterized in that: metformin, folic acid and vitamin B
12three kinds of active component are present in same preparation.
5. compositions according to claim 1, is characterized in that: metformin, folic acid and vitamin B
12make preparation respectively, be present in packaged in combination.
6. the purposes that the compositions in claim 1 to 5 described in any one is treated type 2 diabetes mellitus, prevention in preparation or alleviated in the medicine of hyperhomocysteinemiainjury.
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Effective date of registration: 20230605 Address after: 518057 the 1st and 2nd floors of No.2 building, phase III of biological incubator, No.16, Gaoxin Zhongyi Road, central high tech Zone, Nanshan District, Shenzhen City, Guangdong Province Patentee after: SHENZHEN AUSA PHARMACEUTICAL Co.,Ltd. Patentee after: SHENZHEN AUSA PHARMED Co.,Ltd. Patentee after: Beijng Aosa Medical Research Center, Inc. Address before: 518057 No. 16, Gaoxin Zhongyi Road, Nanshan District, Shenzhen, Guangdong Patentee before: SHENZHEN AUSA PHARMACEUTICAL Co.,Ltd. Patentee before: Beijng Aosa Medical Research Center, Inc. |