CN104840480B - Metformin/folic acid/vitamin B12New application of pharmaceutical composition - Google Patents
Metformin/folic acid/vitamin B12New application of pharmaceutical composition Download PDFInfo
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Abstract
The invention relates to a pharmaceutical composition, which is prepared from medicinal dosage of metformin, folic acid and vitamin B12And a pharmaceutically acceptable carrier or excipient, belonging to the field of pharmacy. The pharmaceutical composition can overcome the harmful consequences caused by gastrointestinal adverse reactions when the metformin single drug is applied, has the application of preventing, delaying or treating hyperhomocysteinemia, has better effect than the prior similar pharmaceutical compositions, and provides an economic and practical pharmaceutical composition for diabetic patients. The invention also has the advantage of improving the medication compliance of patients.
Description
Technical Field
The invention relates to a medicine containing metformin, folic acid and vitamin B12The pharmaceutical composition of (1) is used for preparing a medicament suitable for preventing or relieving hyperhomocysteinemia of a type 2diabetes patient. The invention belongs to the field of medicine.
Background
Diabetes mellitus is a common endocrine-metabolic disease characterized by chronic hyperglycemia accompanied by disorders of sugar, fat and protein metabolism caused by insufficient insulin secretion and/or defective action. According to survey, the prevalence rate of diabetes in China is as high as 9.7%, 9240 thousands of people are estimated to be diabetic patients in China [ Yang W, et al.prevalence of diabetes men and women in China. 362: 1090-1101). Diabetes can occur at any age, is easy to cause general nervous, microvascular and macrovascular diseases and the like along with the prolonging of the course of the disease, and can cause chronic and progressive diseases of tissues and organs such as heart, brain, kidney, nerves, eyes and the like.
Metformin (metformin) belongs to biguanide hypoglycemic drugs, and the biguanide hypoglycemic drugs mainly act on tissues outside pancreatic islets, enhance the utilization of peripheral tissues such as muscles to glucose, inhibit or delay the absorption of glucose in gastrointestinal tracts, inhibit gluconeogenesis in livers, increase the number of insulin receptors in target cells and the affinity to insulin, and further have the hypoglycemic effect. In addition, the metformin has the effects of reducing weight and blood fat, and has no effect of reducing blood sugar for normal people. The molecular structural formula of the metformin is as follows:
metformin was approved for marketing in the united states in 1995 with substantial evidence-based medical support and is currently considered the first choice for initiating treatment in diabetic patients. According to the "new consensus on type 2diabetes treatment" published by the american diabetes society of america (ADA) and the european diabetes research institute (EASD) in 2006 and the newly published global treatment guideline for type 2diabetes (global treatment guideline for type 2 diabetes) by the international diabetes union (IDF), it can be established that metformin is the only drug to be used as the basic treatment for type 2diabetes together with lifestyle intervention, and that long-term administration can reduce cardiovascular complications.
However, in decades of clinical applications, the outstanding problem of metformin is still its gastrointestinal side effects: the metformin is mainly absorbed in small intestines after being orally taken, the bioavailability is only 50-60%, the blood concentration reaches the peak value 2 hours after the metformin is orally taken, the medicament is gathered on the intestinal wall and is 10-100 times of the blood plasma concentration, gastrointestinal tract reactions are very obvious, including nausea, vomit, anorexia, metal peculiar smell in mouth, loose stool and diarrhea, and the long-term administration can easily cause the vitamin B in intestines12And folic acid malabsorption. Vitamin B12Is the coenzyme of methionine synthetase, folic acid is the donor of methyl group in body, and the lack of both can obstruct methionine circulation and cause Homocysteine (Hcy) accumulation, resulting in hypercycystemia [ Sato Y, et12default, hyper-homeopathinemia and vascular compositions in tissues with type 2diabetes. 60(12), 1275-. In addition, vitamin B12Deficiency also leads to a dysfunction of DNA synthesis within erythrocytes, causing megaloblastic anemia (pernicious anemia).
On the other hand, epidemiological investigations show that the Chinese population has a high Hcy and a high incidence of low folate [ Hao L, et al, high prediction of hypercysteinemia in Chinese adults is associated with low folate, vitamin B-12, and vitamin B-6status. J.Nutr.2007,137: 407-. Elevated plasma Hcy levels are associated with an increased risk of cardiovascular disease, and meta-analysis has shown that: every 5 μmol/L rise in plasma Hcy, there is a 59% increase in stroke risk (OR: 1.59; 95% CI:1.29-1.96), a 60% increase in deep vein thrombosis risk (OR: 1.60; 95% CI:1.15-2.22), and a 32% increase in risk of ischemic heart disease (including coronary heart disease, angina pectoris, arrhythmia, myocardial infarction, and sudden death) (OR: 1.32; 95% CI:1.19-1.45) [ Wald DS, et al. 325: 1202-1206'; evidence-based medical studies have also suggested that folic acid supplementation may reduce the occurrence of cardiovascular and cerebrovascular events [ Voutilain S, et al, serum form and homeostatic and the involvement of cardiovascular events the Kuopio interactive Heart Disease study. am JClin Nutr.2004,80(2): 317-.
Folic acid, vitamin B12All belong to water-soluble B vitamins, are absorbed by intestinal tracts of human bodies, are discharged out of the bodies by urine, are rarely accumulated in the bodies, and are not poisoned. Since water-soluble vitamins are stored only rarely in the body, they must be taken from outside the body frequently to meet the nutritional and metabolic needs of the body. The B vitamins have important functions on metabolism, erythrocyte formation and the maintenance of the functions of the nervous system and the immune system.
In conclusion, the medicine is prepared from metformin, folic acid and vitamin B12The pharmaceutical composition can relieve the side effects (low folic acid, high Hcy blood disease and latent pernicious anemia) caused by the long-term application of the metformin, and is beneficial to reducing the risk of cardiovascular complications of diabetics. Compared with the combined use of the three medicines, the pharmaceutical composition can also obviously reduce the economic burden of the diabetic patients and improve the treatment compliance.
Found by search, the patent "Pre-treatmentA pharmaceutical preparation for preventing or treating metabolic syndrome (patent number: 200510082929.4) relates to a formula of biguanides and B vitamins, but has the purpose of treating metabolic syndrome, which is different from the purpose of the patent; the patent, "metformin folate and its preparation method" (patent No. 200610149044.6) relates to the linkage of folic acid and metformin into a compound by chemical reaction, which is chemically completely impossible, lacks the most basic scientific principles, and the compound does not relate to vitamin B12Unlike this patent; patent containing metformin hydrochloride and vitamin B12The combined medicine of (patent No. 200910310219.0) does not relate to folic acid, and is limited to the treatment of megaloblastic anemia and aplastic anemia, which is completely different from the application of the patent.
Disclosure of Invention
The invention aims to overcome a plurality of adverse effects caused by vitamin loss caused by gastrointestinal side effects existing in long-term oral administration of metformin, and selects a pharmaceutical composition for preventing, delaying or treating hyperpycy blood disease and improving prognosis when the pharmaceutical composition is used for the blood sugar reducing basic treatment of type 2diabetes.
In order to achieve the purpose, the invention adopts the following technical scheme:
a pharmaceutical composition comprising
(1) A pharmaceutically acceptable dose of one of metformin and its active metabolite or salt;
(2) pharmaceutically acceptable dose of vitamin B12；
(3) A pharmaceutically acceptable dose of folic acid;
(4) a pharmaceutically acceptable carrier.
The above "pharmaceutical dosage" refers to an amount of a pharmacological effect that has a synergistic, prophylactic or therapeutic effect.
The invention provides a pharmaceutical preparation, one of the active ingredients is metformin, and the other two active ingredients are folic acid and vitamin B respectively12Wherein folic acid also includes the same class of compounds with similar biological activity, such as leucovorin, 5-methyltetrahydrofolic acid, active metabolites of folic acid and substances which are metabolized and/or folic acid produced in vivo, vitamin B12Also included are the same classes of compounds having similar biological activities, such as cobalamin, methylcobalamin, 5' -deoxyadenosylcobalamin, hydroxocobalamin and substances which metabolize and/or produce such compounds in vivo.
In the present invention, the amount of metformin is 250mg to 1000mg, and more preferably 500mg to 750 mg.
In the invention, the dosage of folic acid is 0.1 mg-0.8 mg; more preferably, the amount is 0.2mg to 0.4 mg.
In the present invention, vitamin B12The amount of (B) is 2.5 to 20. mu.g, more preferably 5 to 10. mu.g.
One of the active ingredients in the pharmaceutical preparation provided by the invention is metformin, which is clinically used for treating type 2diabetes. The composition has pharmacological effects of increasing anaerobic glycolysis of glucose in muscle, inhibiting or delaying absorption of glucose in intestinal tract, inhibiting hepatic gluconeogenesis, reducing hepatic glucose output, and increasing sensitivity to insulin, and can be used for lowering blood sugar of diabetic patients with normal or lost pancreatic islet function, but not normal people, and simultaneously reducing blood lipid, resisting atherosclerosis, and reducing sensitivity to platelet aggregation agent. The folic acid and the vitamin B in the pharmaceutical preparation provided by the invention12The vitamin B is one of B vitamins, is a nutrient essential to human bodies, has important functions on the metabolism of the living bodies, the formation of red blood cells and the maintenance of the functions of a nervous system and an immune system, and more importantly can reduce the level of plasma homocysteine.
In experimental studies, we have surprisingly found that folic acid alone has a mild hypoglycemic effect, while metformin, folic acid, vitamin B are present in pharmaceutically acceptable doses12The medicinal preparation as the active component has obvious effect of preventing or treating the hyperhomocysteinemia while playing the role of reducing the blood sugar.
The term "pharmaceutically acceptable dose" refers to a dose of a drug that a clinician administers to a diseased individual according to the severity of the disease in the diseased individual for the purpose of effectively controlling or treating the disease. It is to be understood that the invention is not intended to limit the invention to the dosage form which the invention provides, but rather to prefer the invention, that the drug is capable of producing an effective therapeutic effect in the affected individual, generally within the preferred range of dosages. The subject to be affected is an independent living body suffering from a disease, and in the present invention, a living body refers to a human being. It is understood that in the prior art, the human pharmaceutical dosage or range of pharmaceutical dosages can be converted to mammals, e.g., rats, mice, etc.
The dosage form of the pharmaceutical preparation provided by the invention comprises any pharmaceutically acceptable oral dosage form, for example, the pharmaceutical preparation will contain metformin, folic acid and vitamin B12The compound composition can be made into common tablet, double-layer tablet, sustained release tablet, controlled release tablet, dispersible tablet, enteric coated tablet, granule, common capsule, sustained release capsule, controlled release capsule, enteric coated capsule, capsule containing pellet or small tablet, pH dependent capsule containing pellet or small tablet, etc. It should be noted that the composition will contain metformin, folic acid, vitamin B12The composition can be made into sustained release tablets, double-layer tablets, sustained release capsules and enteric capsules.
According to the present invention, the term "pharmaceutically acceptable carrier or excipient" refers to those substances known in the art that can act as fillers or carrier materials in tablets, pills, capsules, and the like. Usually these substances are approved for this purpose and, as pharmaceutical agents, they are inactive. The excipient and the auxiliary material comprise (but are not limited to) starch, microcrystalline cellulose, inorganic salts, hydroxypropyl methylcellulose, ethyl cellulose, polyacrylic resins, carboxyvinyl polymers, soluble/insoluble salts of alginic acid, octadecanol, octadecanoic acid, dextrin, sodium chloride, cysteine, citric acid, sodium sulfite and the like or a composition of a plurality of substances. The pharmaceutical excipients used in the manufacturing process and the methods of preparation are well known and familiar to those skilled in the art.
The compounds of the pharmaceutical compositions provided herein can be administered to the affected individual simultaneously in the same formulation, or separately and sequentially. If the administration is sequential, the delay in administering the second and third active ingredients should not result in a combined effect of the active ingredientsLoss of beneficial effects of (a). If administered simultaneously to an affected individual, the compounds of the composition may be present in admixture in the same pharmaceutical formulation or may be present separately in the same formulation (combination package). If they are present independently in the same formulation, the pharmaceutical compositions may alternatively be presented in the form of a "combination kit". A "combination kit" is a box-like container containing one or more dosage forms of a pharmaceutical combination and instructions for its use, in the present invention metformin, folic acid, vitamin B12Respectively making into combined kit of the same preparations.
The invention has the advantages that: the invention provides a pharmaceutical dosage containing metformin, folic acid and vitamin B12The new use of the pharmaceutical composition. Metformin, folic acid and vitamin B12The combined effect of the two active substances is not the simple addition of the respective effects of the active substances, but the combined effect can prevent and treat the hyperhomocysteinemia on the basis of better controlling the blood sugar of the type 2 diabetic patients, and obviously reduce a plurality of adverse effects caused by the gastrointestinal side effects of the metformin. That is, metformin and folic acid, vitamin B12The combination achieves synergistic effect, so the compound is more suitable for antidiabetic.
The present invention is further described with reference to the following detailed description, which is not intended to be limiting, but rather is intended to cover all equivalent art-recognized alternatives falling within the scope of the invention.
Detailed Description
The preparation process and the amount of the substances or the materials used in the preparation in the following pharmaceutical preparation examples are not limited to the words, and all the preparation methods containing the pharmaceutical composition provided by the present invention belong to the protection scope of the present invention, and the specific experimental methods can refer to the general reference books of pharmaceutical preparations, such as "pharmaceutical adjuvant application and preparation", "pharmacy" and "biopharmacy" and "pharmacokinetics".
Example 1Preparation of compound metformin/folic acid/vitamin B12Tablet (1000 tablets)
The preparation method comprises the following steps: sieving all the auxiliary materials with a 80-mesh sieve, and crushing the metformin hydrochloride raw material medicine and sieving with a 100-mesh sieve for later use. Taking 0.4g folic acid and 5mg vitamin B12Mixing uniformly according to an equivalent increasing method, mixing with carboxymethyl starch sodium and microcrystalline cellulose, sieving with a 80-mesh sieve, mixing with 500g of metformin hydrochloride, adding starch and low-substituted hydroxypropyl cellulose, mixing uniformly, preparing into a soft material by using 5% povidone K30-95% ethanol solution, granulating with a 20-mesh sieve, drying at 60 ℃ for about 2h, granulating with a 20-mesh sieve, controlling the water content of the granules to be 2-3%, mixing the dried granules with magnesium stearate uniformly, detecting the content of the semi-finished product, and pressing into 1000 tablets by using a tablet press. The prepared tablet is packaged by an aluminum plastic blister and is stored in dark. Each tablet of the prepared compound tablet contains 500mg of metformin hydrochloride, 0.4mg of folic acid and vitamin B125μg。
Example 2Preparation of compound metformin/folic acid/vitamin B12Double-layer sustained-release tablet (1000 tablets)
The formula is as follows:
the metformin sustained-release layer:
folic acid/vitamin B12Layer (b):
the preparation method comprises the following steps: (1) the metformin sustained-release layer: uniformly mixing the metformin hydrochloride, the hydroxypropyl methylcellulose and the octadecanol which are crushed and sieved by a sieve of 80 meshes according to the prescription amount, adding 5 percent ethyl cellulose alcohol solution to prepare a soft material, granulating by a sieve of 20 meshes, drying for 2 hours at 60 ℃, grading by the sieve of 20 meshes, then adding the magnesium stearate, and detecting. (2) Folic acid vitamin B12Layer (b): taking 0.4g folic acid and 10mg vitamin B12Mixing according to equivalent increasing method, adding microcrystalline cellulose, mixing, sieving with 80 mesh sieve, and adding starch respectivelyMixing the carboxymethyl starch sodium and the low-substituted hydroxypropyl cellulose uniformly, preparing a soft material by using 5% of povidone, granulating by using a 20-mesh sieve, drying at 60 ℃ for about 2 hours, and finishing the granules by using the 20-mesh sieve, wherein the water content of the granules is controlled to be 2-3%. And (5) detecting the semi-finished product, and determining the moisture and the content. (3) The preparation method of the double-layer tablet comprises the following steps: mixing the prepared metformin and folic acid B12The granules are respectively filled into a feed hopper and pressed into 1000 special-shaped tablets by a double-layer tablet press. The prepared tablet needs to be protected from light and is packaged by an aluminum plastic blister. The prepared sustained release tablet contains 500mg of metformin hydrochloride, 0.4mg of folic acid and vitamin B1210μg。
Example 3Preparation of compound metformin/folic acid/vitamin B12Sustained release tablets (1000 tablets)
Metformin hydrochloride sustained-release layer:
folic acid/vitamin B12A quick-release coating layer:
the preparation method comprises the following steps:
a slow release layer: uniformly mixing the metformin hydrochloride, lactose and glyceryl behenate which are crushed and sieved by a 100-mesh sieve according to the prescription amount, adding hydroxypropyl methylcellulose, mixing, adding 10% povidone K30 ethanol solution to prepare a soft material, granulating by a 18-mesh sieve, drying at 60 ℃ for 2 hours, granulating by a 18-mesh sieve, adding magnesium stearate, detecting, and tabletting.
A quick release layer: taking the feed amount of folic acid (folic acid is fed in an excess amount of 30 percent) and vitamin B12(vitamin B)12Adding excessive material according to 35 percent) into 570g of purified water, uniformly stirring, adding 30g of Opadry film coating premix, stirring for 45min after the Opadry film coating premix is completely dissolved, and passing the coating solution through a colloid mill. Placing the pressed metformin hydrochloride sustained release tablet in a high-efficiency coating machine, introducing constant-temperature filtering hot air for preheating, controlling the material temperature at 38-45 deg.C, and openingStarting a spray gun, adjusting the spraying speed, controlling the spraying pressure to 0.15-0.2 MPa, spraying coating liquid on 1/3 positions on the rotating tablet core, wherein the coating liquid is vertical to the material, the rotating speed of a coating pan is maintained at 8-12 r/min, the flow of the spray gun is controlled at 2-5ml/min, and the prepared vitamin B is contained12And spraying the folic acid coating solution completely, stopping coating to obtain coated tablet, and packaging with aluminum-plastic bubble cap. The prepared sustained release tablet contains 500mg of metformin hydrochloride, 0.4mg of folic acid and vitamin B1210μg。
Example 4Metformin/folic acid/vitamin B12Effect of the composition on rat blood sugar and blood homocysteine
The method comprises the following steps: 80 SD rats with weight of 200-230 g and half of male and female are adaptively raised for one week, 10 SD rats are randomly extracted to serve as blank control groups, the rest 70 SD rats are respectively given 30mg/kg Streptozotocin (STZ) for single intraperitoneal injection, after 14 days, blood sampling is carried out on tail veins of the rats to measure blood sugar level, the blood sugar level is more than 11.1mmoL/L, the model is determined to be successful in diabetes modeling, and the SD rats are randomly divided into 5 groups, namely a model control group, a metformin group, a folic acid group, folic acid and vitamin B12Group metformin + folic acid + vitamin B12Group, the last 4 groups were administered metformin 100mg/kg, folic acid 80. mu.g/kg, folic acid + vitamin B daily12(80 mug +2 mug)/kg, metformin + folic acid + vitamin B12(100mg + 80. mu.g + 2. mu.g)/kg, and the blank group and the model group were fed with the same amount of physiological saline 2 times a day for 8 weeks. After 8 weeks l 0% chloral hydrate was intraperitoneally injected to anesthetized animals, and blood glucose, plasma homocysteine (Hcy), etc. were measured from abdominal aorta. The dead rats were removed, the results and statistics of each group are shown in Table 1, and the data are measured as means. + -. standard deviation
And (4) showing.
As a result: see table below. (1) The hypoglycemic effect is achieved by administering the medicine to the diabetic rats for 8 weeks, and then metformin, folic acid and vitamin B are added12Metformin/folic acid/vitamin B12The FPG of rats in the composition group is reduced, wherein the FPG is most obvious in an experimental group containing metformin, and the basic hypoglycemic drug position of the metformin is suggested(ii) a We have unexpectedly found that the folic acid group, folic acid + vitamin B12The group also has the effect of reducing blood sugar, and the folic acid is considered to have the effect of slightly reducing the blood sugar by combining the previous research results. (2) Compared with the model group, the Hcy reducing effect of the metformin group is increased, but the metformin group contains folic acid or folic acid plus vitamin B12All showed significant plasma Hcy lowering effect consistent with the expected effect, and this effect was based on folic acid, vitamin B12And (4) synergy. Combining the above results, we believe that metformin is associated with folic acid and vitamin B12The composition has synergistic effects of lowering blood sugar and relieving Hcy blood disease.
TABLE 1 metformin/folic acid/vitamin B12Action of composition on blood sugar and Hcy of rat
Note: comparison with model group<0.05，**P<0.01; compared with the group of metformin, the composition,△P<0.05，△△P<0.01；
in comparison with the folic acid group,#P<0.05，#P<0.01. FPG-fasting plasma glucose, Hcy-plasma homocysteine.
Claims (1)
1. A pharmaceutical composition for treating type 2diabetes and preventing or relieving hyperhomocysteinemia comprises the following components:
1) a pharmaceutically acceptable dose of metformin or a pharmaceutically acceptable salt thereof;
2) a pharmaceutically acceptable dose of folic acid;
3) pharmaceutically acceptable dose of vitamin B12(ii) a And
4) a pharmaceutically acceptable carrier or excipient which,
wherein, the content of the metformin is 1000mg, the content of the folic acid is 0.8mg, and the method is characterized in that: vitamin B12The content of (2) is 20. mu.g.
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