CN106420654A

CN106420654A - Metformin hydrochloride enteric-coated tablet medicine composition with reduced untoward effect

Info

Publication number: CN106420654A
Application number: CN201611110951.XA
Authority: CN
Inventors: 颜弘
Original assignee: Individual
Current assignee: Individual
Priority date: 2016-12-06
Filing date: 2016-12-06
Publication date: 2017-02-22

Abstract

The invention relates to a metformin hydrochloride enteric-coated tablet medicine composition with reduced untoward effect, in particular to a medicine composition. The metformin hydrochloride enteric-coated tablet medicine composition comprises a tablet core, a first coating layer and a second coating layer, wherein the first coating layer coats the tablet core; the second coating layer coats the outside of the first coating layer; the active ingredient of the tablet core is metformin hydrochloride. The invention also relates to a method for preparing the medicine composition and pharmaceutic purposes of the medicine composition. The medicine composition provided by the invention has good properties, such as low untoward effect, and can be applicable to patients with contraindication on the metformin hydrochloride.

Description

The Dimethyldiguanide hydrochloride enteric solubility tablet pharmaceutical composition that untoward reaction reduces

Technical field

The invention belongs to pharmaceutical technology field is and in particular to arrive a kind of metformin as the tablet medicine group of active ingredient Compound and preparation method thereof, more particularly to a kind of Dimethyldiguanide hydrochloride enteric solubility tablet medicine group significantly reducing untoward reaction Compound.

Background technology

Metformin (Metformin), clinically commonly uses its hydrochlorate, i.e. metformin hydrochloride, entitled 1, the 1- bis- of chemistry Methyl biguanide hydrochloride, its structural formula is as follows：

Metformin is biguanideses hypoglycemic drug, is that one kind is used for treating non-insulin-depending type (II type) diabetes Common medicine.Because it can substantially reduce the blood glucose of diabeticss, and the danger of the related vascular complication of diabetes can be reduced, subtract Few impaired glucose tolerance patients develop into the incidence rate of diabetes, and side effect is less, up-to-date in IDF in 2005 In the global type 2 diabetes mellitus treatment guidelines promulgated, in the prevention and treatment of diabetes, the effect of metformin is extremely paid attention to. Metformin hypoglycemic medicine mechanism of action includes：1. promote the utilization to glucose for the surrounding tissue cells (muscle etc.)；2. suppress Gluconeogenesis function of liver, therefore reduces glycogen output；8. suppress intestinal wall cellular uptake glucose, different from insulin action, that is, This product no promotes the effect of lipogenesis, and to normal person, no obvious hypoglycemic activity, therefore, does not typically cause hypoglycemia.Diformazan Biguanide can be used for diet-treated only unsatisfied non-insulin-dependent diabetes mellitus people, and especially overweight people, with this class medicine Not only there is hypoglycemic activity it is also possible to there be slimming effect.The sales volume in Europe and the U.S. for the metformin accounts for all respectively The 25% of oral antidiabetic drug and 28%.Over nearly 10 years, medical circle to the pharmacological action of metformin and it in clinical treatment glycosuria Some advantages in disease gradually have new understanding, particularly its effect in terms of improving insulin resistant, are sulphanylureas falls Sugared medicine is unexistent.Because its blood sugar reducing function does not rely on insulin, it is by suppressing the glyconeogenesis of liver and promoting periphery Insulin target tissue utilizes to the picked-up of glucose, to improve the insulin sensitivity of body.Metformin hydrochloride can reduce The hyperglycemia of diabetes patient, but blood glucose will not be made to reduce again when blood glucose is normal again.Therefore, it is used alone metformin not have Hypoglycemic reaction.Therefore, metformin existing oneself become gently, moderate type 2 diabetes mellitus patient, particularly the first-selected of obese patient treat Medicine.There are some researches show, metformin can increase the secretion of glucagon kind polypeptide-1 (GLP-1), GLP-1 can promote 2 type sugar Urinate the insulin secretion of patient's glucose mediation, glucagon suppression is secreted, promote hepatic glycogen synthesis and reduction glycogen defeated Go out, improve B cell function, alleviate hyperinsulinemia.

Hyperglycemia (Hyperglycemia), hyperglycemia (hyperglycaemia) or hyperglycemia (high blood Sugar) it is the condition of illness that wherein excessive glucose (for example, more than 125mg/dL) circulates in blood plasma.Less times greater than normal Chronic hyperglycemia under level can produce multiple severe complications in several years, damages including renal damage, nervous lesion, cardiovascular Evil, retinal damage or foot and leg infringement.Diabetic neuropathy can be the result of prolonged hyperglycemia.

Hyperglycemia can by following cause or with below in connection with：The dysfunction of thyroid, adrenal gland and hypophysis, Pancreatic diseases, severe sepsis and intracranial disease (as encephalitis, the cerebral tumor and meningitiss).Up to the present, chronic hyperglycemia The most common reason of disease is diabetes, and it is popular that described diabetes are widely regarded as extremely urgent health care by a lot of people Disease.In diabetes, hyperglycemia is generally resisted by the insulin under low insulin level (type i diabetes) and/or cellular level Property (type ii diabetes) caused.

A lot of type ii diabetes medicines are designed to reduce blood sugar level.First Line for treating type ii diabetes is first-selected Medicine and the whole world modal anti-diabetic prescription drug is metformin.Contrary with most of diabetes medicament, using two The hypoglycemia of first biguanide is very rare；It also can control body weight and with reduce cardiovascular event and minimizing mortality rate have Close.

Metformin (dimethylbiguanide) belonged to based on containing from Galega officinalis L (Galega officinalis) plant One class biguanide drug (the Bailey＆Turner Metformin.N Engl J of the blood sugar lowering extract research and development of guanidine Med.1996Feb 29；334(9)：574-9；The .Metformin such as Bailey：its botanical background.Practical Diabetes Int.2004；21(3)∶115-7).Metformin is initially in nineteen twenty-one conduct By-product synthesis (Werner E, Bell J.The preparation of methylguanidine, and of β β- Dimethylguanidine by the interaction of dicyanodiamide, and methylammonium and Dimethylammonium chlorides respectively.J Chem Soc, Transactions.1921；121： 1790-5), find that metformin and other biguanideses reduce the blood glucose in animal body.Disclose to diformazan in the 1950's The research of biguanide, the phenformin and buformin hypoglycemic activity in human body.Originally, the larger effect of phenformin and buformin Power causes it widely to use；However, they are ultimately resulted in 20 century 70s most with the relation of lactic acidosis Number country stops using.

Metformin to improve the glucose tolerance of patient by reducing both basal plasma glucose and post-prandial glycemia.Diformazan is double Guanidine single therapy generally by fasting glucose reduce by 20% and by HbA1c level reduce about 1.5% (Bailey＆Turner, Ibid；DeFronzo&Goodman Efficacy of metformin in patients with non-insulin- dependent diabetes mellitus.The Multicenter Metformin Study Group.N Engl J Med.1995 August 31；333(9)：541-9).Metformin has shown and has improved serum lipids, reduces triglyceride, free Fatty acid and LDL- cholesterol and suitably increase HDL- cholesterol (Bailey＆Turner, ibid).

It is assumed that the anti-high-blood-sugar function of metformin is caused by multiple systemic biological chemical interactions, described phase Interaction includes for example suppressing hepatic glucose production, increases insulin sensitivity, improves periphery glucose uptake (by phosphoric acid Change GLUT-4 enhancer), the absorption (Hundal＆ that increases fatty acid oxidation and/or reduce the glucose in the gastrointestinal tract Inzucchi Metformin：New understandings, new uses.Drugs.2003；63(18)：1879-94).? Closely, what researcher was absorbed in that it secretes to glucagon-sample peptide -1 (GLP-1) significantly affects it is clear that determining metformin not Directly act on the L- cell of enteral with induce GLP-1 secretion or strengthen L- cell to some known sercretogogues sensitivity (Mulherin etc., Mechanisms underlying metformin-induced secretion of glucagon- like peptide-1from the intestinal L-cell.Endocrinology 152：4610-19 (2011 12 Month)).These researcheres propose, metformin pass through to be related to muscarine (M3) receptor-independent path independent of intestinal L- cell and The indirect mechanism in Gastrin. release peptide (GRP) path stimulates GLP-1 release, so that the systemic bioavailability of metformin It is crucial for treatment effect.

Unfortunately, the systemic exposure of metformin still has in serious dlactic acid for some PATIENT POPULATION Malicious risk.Lactic acidosis are the possible fatal metabolic complication occurring when the lactate level in blood flow increases.Therefore, Metformin is taboo in the patient with any condition of illness that can increase lactic acidosis risk, and described condition of illness includes nephropathy Disease, lung disease and hepatopathy.According to prescription information, heart failure, particularly unstable or acute congestive heart failure also increases Add the lactic acidosis risk using metformin.Therefore, metformin is still not useable for treating with these contraindications The hyperglycemia of patient.

Additionally, conventional metformin preparation usually produces bad gastrointestinal tract (GI) complication of dose limitation, include suffering from diarrhoea, The untoward reaction such as Nausea and vomiting, dizziness, headache and dyspepsia.Therefore, not unessential generally within a period of time It is based partially on the patient-specific bad GI effect of any gained, patient is applied and is titrated to maximum tolerated dose upwards.Cherish Solve the hope research and development alleviating prolongation delivery formulations of this problem, but this is not fully solved these problems.

Particularly it is known that it is beneficial for making medicine metformin be deferred to little enteric release for solving these problems, such as Described in CN 105101956A (CN201480003932.X).For example this patent documentation has confirmed in embodiment 1： PYY, GLP-1 (active) and the minimizing of GLP-1 (total amount) and glucose and insulin that enteroendocrine cell produces, with diformazan The Plasma absorption non-correlation of biguanide, that is, the metformin exposed amount in blood be not positively correlated with its blood sugar lowering efficiency, for example The diagram of this patent documentation [0427] segment table eighteen data and Figure 14-15 shows, 2000mg metformin IR preparation and 2000mg AUC and Cmax of metformin XR preparation is all considerably higher than 2000mg metformin DR preparation, but as this patent documentation [0445], described in section, AUC reduces but blood sugar lowering effect will not reduce；And as described in this patent documentation [0446] section , " although the systemic exposure of metformin is substantially reduced with regard to metformin DR (for be within 2000mg/ days 45% and It was about 60% for 1000mg/ days, the metformin IR with respect to 2000mg/ days), metformin IR's (2000mg/ days) is complete Portion's hypoglycemic activity is kept ", " additionally, different from metformin IR, the metformin DR of arbitrary dosage and any nausea and vomit Tell unrelated ".In addition, from table eighteen data, metformin have longer half-life (t1/2 of various preparations reach 6 hours with On).It can be seen that, even if in the case that systemic exposure dosage significantly reduces, still through reaching effective blood sugar decreasing effect.So And, this patent documentation teaching people are above-mentioned to be had the technical effect that in the case that medicament is pushed to distal small bowel release active medicine Obtain, on the one hand this can increase medicament manufacture difficulty, reason be small intestinal path longer and in this distance pH change simultaneously Inconspicuous or even have fluctuation, to reach and medicament is pushed to distal small bowel can there is larger difficulty, on the other hand when medicament arrives Reach after distal small bowel may drug release, absorb also not exclusively, will result in medicament continue to be pushed to absorb undesirable big Intestines position, being accurately positioned release and can be subject to different patient, different time gastrointestinal peristalsiss states, enter of particularly above-mentioned this medicament The having a strong impact on of the factors such as food time and amount.

Therefore, this area exist to solve the more preferable and safer compositionss of these tolerations and safety issue with And for delivering the needs of the method for biguanide compound.Additionally, it is desirable to provide one kind can be used for metformin and/or its The more effective therapeutic choice of the metabolic disorder of patient of its biguanideses contraindication.

Content of the invention

It is an object of the invention to provide a kind of new combination of oral medication such as its tablet preparing metformin Method, expects that the tablet of the method preparation has the superperformance of one or more aspects.The present inventor is unexpectedly Find, using the tablet comprising metformin that specific method prepares, there is challenging superior function.The present invention Consequently found that and being accomplished.

For this reason, first aspect present invention provides a kind of pharmaceutical composition in tablet form, it includes label, parcel should First coatings of label, it is wrapped in the second coatings outside this first coatings, the active component in described label is salt Sour metformin.

The pharmaceutical composition of any one according to a first aspect of the present invention, wherein said label includes active ingredient hydrochloric acid diformazan Biguanide, binding agent and lubricant.

The pharmaceutical composition of any one according to a first aspect of the present invention, in wherein said label, binding agent used is selected from： Hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, polyvidone, Polyethylene Glycol (molecular weight 2000～ 8000).In one embodiment, it is preferred to binding agent be selected from：Polyvidone, Macrogol 4000, polyethylene glycol 6000.

The pharmaceutical composition of any one according to a first aspect of the present invention, in wherein said label, binding agent used accounts for hydrochloric acid 2～10% (w/w) of metformin weight, for example, account for 3～6% (w/w) of metformin hydrochloride weight.

The pharmaceutical composition of any one according to a first aspect of the present invention, in wherein said label, lubricant used is selected from： Stearic acid, magnesium stearate, calcium stearate, micropowder silica gel, Pulvis Talci, hydrogenated vegetable oil, sodium lauryl sulphate.Implement at one In scheme, preferred lubricant is selected from：Magnesium stearate, calcium stearate.

The pharmaceutical composition of any one according to a first aspect of the present invention, in wherein said label, lubricant used accounts for hydrochloric acid 0.2～2% (w/w) of metformin weight, for example, account for 0.5～1.5% (w/w) of metformin hydrochloride weight.

The pharmaceutical composition of any one according to a first aspect of the present invention, also includes inorganic salt in wherein said label.Described Inorganic salt be selected from sodium chloride, potassium chloride, sodium bicarbonate, potassium bicarbonate, calcium chloride, sodium sulfate etc., and combinations thereof.Preferably inorganic Salt be selected from sodium chloride, potassium chloride, and combinations thereof.

The pharmaceutical composition of any one according to a first aspect of the present invention, in wherein said label, inorganic salt used accounts for hydrochloric acid 0～20% (w/w) of metformin weight, for example, account for 2～8% (w/w) of metformin hydrochloride weight.

The pharmaceutical composition of any one according to a first aspect of the present invention, also optional in wherein said label comprises to dilute Agent.In one embodiment, described diluent is selected from：Corn starch, Pregelatinized Starch, dextrin, Lactose, Mannitol, crystallite Cellulose etc..In one embodiment, described diluent is selected from：Lactose, Mannitol.

The pharmaceutical composition of any one according to a first aspect of the present invention, in wherein said label, diluent used accounts for hydrochloric acid 0～25% (w/w) of metformin weight, for example, account for 0～10% (w/w) of metformin hydrochloride weight.

The pharmaceutical composition of any one according to a first aspect of the present invention, wraps in the coating material of wherein said first coatings Include filmogen.In one embodiment, described filmogen is ethyl cellulose.

The pharmaceutical composition of any one according to a first aspect of the present invention, in the coating material of wherein said first coatings also Including inorganic salt.For example, described inorganic salt is identical with the inorganic salt in described label.

The pharmaceutical composition of any one according to a first aspect of the present invention, in the coating material of wherein said first coatings, In terms of the ethyl cellulose of every 100 weight portions, amount 20～50 weight portion of inorganic salt, the amount of such as inorganic salt is 20～40 weight Part.

The pharmaceutical composition of any one according to a first aspect of the present invention, in the coating material of wherein said first coatings also The Polyethylene Glycol being 200～600 including molecular weight.

The pharmaceutical composition of any one according to a first aspect of the present invention, in the coating material of wherein said first coatings, In terms of the ethyl cellulose of every 100 weight portions, amount 5～30 weight portion of Polyethylene Glycol, the amount of such as Polyethylene Glycol is 10～20 Weight portion.

The pharmaceutical composition of any one according to a first aspect of the present invention, the coating material of wherein said first coatings be by It is configured to the coating solution of solid concentration 2～10% (w/v) for being coated to described label.In an embodiment party In case, the coating material of described first coatings be configured to the coating solution of solid concentration 3～8% (w/v) for Described label is coated.In one embodiment, prepare described coating solution solvent be 30～90% ethanol molten Liquid, e.g. 50～85% ethanol solution.

The pharmaceutical composition of any one according to a first aspect of the present invention, the coating material weight of wherein said first coatings It is 1～10% (w/w) of label weight, such as 2～6% (w/w).Herein, coating material weight refers to constitute coating material The weight of solid matter, does not include wherein preparing the solvent of coating solution.This percent is also commonly referred to coating weight gain.

The pharmaceutical composition of any one according to a first aspect of the present invention, wraps in the coating material of wherein said second coatings Include filmogen, this filmogen is that Hydroxypropyl methyl cellulose phtalate (is commonly abbreviated as HPMCP, also known as adjacent benzene two Formic acid Hypromellose ester), Hydroxypropyl Methyl Cellulose Phthalate (being commonly abbreviated as HPMCAS), acrylic acid and methyl-prop Olefin(e) acid ester copolymer (Eudragit of such as L or S type), and combinations thereof.In one embodiment, described filmogen is hydroxyl Third methylcellulose phthalic acid ester and Hydroxypropyl Methyl Cellulose Phthalate combination.In one embodiment, Described filmogen is both Hydroxypropyl methyl cellulose phtalate and Hydroxypropyl Methyl Cellulose Phthalate with weight ratio 1：The combination of 0.5～1 ratio.In one embodiment, described filmogen be Hydroxypropyl methyl cellulose phtalate and Both Hydroxypropyl Methyl Cellulose Phthalate compare 1 with weight：The combination of 0.6～0.9 ratio.

The pharmaceutical composition of any one according to a first aspect of the present invention, in the coating material of wherein said second coatings also Including plasticizer, described plasticizer is selected from：Glycerol, propylene glycol, PEG, cochin oil, Oleum Ricini, Semen Maydis oil, liquid paraffin, Monoacetin, triacetin (glyceryl triacetate), dibutyl sebacate, dibutyl phthalate, phthalic acid Diethylester, triethyl citrate etc. and combinations thereof.In one embodiment, described plasticizer is triethyl citrate.One In individual embodiment, the consumption of plasticizer is the 20～35% of filmogen consumption, such as 25～35%.

The pharmaceutical composition of any one according to a first aspect of the present invention, in the coating material of wherein said second coatings also Optional is included selected from following antiplastering aid：Pulvis Talci, magnesium stearate, silicon dioxide etc. and combinations thereof.In an embodiment In, described antiplastering aid is Pulvis Talci.In one embodiment, the consumption of antiplastering aid is the 20～35% of filmogen consumption, Such as 25～35%.

The pharmaceutical composition of any one according to a first aspect of the present invention, in the coating material of wherein said second coatings also Optional inclusion sodium lauryl sulphate.In one embodiment, the consumption of sodium lauryl sulphate is filmogen consumption 2～3.5%, such as 2.5～3.5%.

The pharmaceutical composition of any one according to a first aspect of the present invention, the coating material of wherein said second coatings be by It is configured to the coating solution of solid concentration 3～15% (w/v) for being coated to described label.In an embodiment party In case, the coating material of described second coatings be configured to the coating solution of solid concentration 5～10% (w/v) for Described label is coated.In one embodiment, the solvent preparing described coating solution is water.

The pharmaceutical composition of any one according to a first aspect of the present invention, the coating material weight of wherein said second coatings It is 1～10% (w/w) of label weight, such as 2～6% (w/w).Herein, coating material weight refers to constitute coating material The weight of solid matter, does not include the solvent such as water wherein preparing coating solution.This percent is also commonly referred to coating weight gain.

The pharmaceutical composition of any one according to a first aspect of the present invention, when it shines stripping quantity algoscopy and measures, it is in acid In 2 little stripping quantities constantly be less than labelled amount 5% (e.g., less than labelled amount 4%, e.g., less than the 3% of labelled amount)； PH value be 5.0 ± 0.1 water in 2 little stripping quantities constantly be less than labelled amount 10% (e.g., less than labelled amount 8%, E.g., less than labelled amount 5%)；In buffer 1 little stripping quantity constantly be less than labelled amount 40% (for example in labelled amount 25～40% in the range of), be 20～80% (such as 45～60%) of labelled amount in the stripping quantities of 2 hours, molten at 4 hours Output is more than 80% (being greater than the 85% of labelled amount) of labelled amount；Described stripping quantity algoscopy is as follows：

Rule according to the first method method 2 of Chinese Pharmacopoeia four general rules of version in 2015 " 0931 dissolution and drug release determination method " Model measures；

With 0.1mol/L hydrochloric acid solution 900ml as dissolution medium, rotating speed is 100 turns per minute, operates, through 2 hours in accordance with the law When, take solution 20ml to filter, discard just filtrate 10ml, take subsequent filtrate as need testing solution (1)；

In in addition parallel test, to adjust the water 900ml for 5.0 ± 0.1 for the pH value with 0.1mol/L hydrochloric acid solution it is Dissolution medium, rotating speed is 100 turns per minute, operates in accordance with the law, through 2 little constantly take solution 20ml to filter, discard just filtrate 10ml, Take subsequent filtrate as need testing solution (2)；

Then above-mentioned be dissolution medium with 0.1mol/L hydrochloric acid solution operation, basket emersion liquid level will be turned immediately, with will Turn basket immersion phosphate buffer (pH6.8) and (take 0.1mol/L hydrochloric acid solution and 0.2mol/L sodium radio-phosphate,P-32 solution, by 3:1 mixing Uniformly, use 2mol/L hydrochloric acid solution or 2mol/L sodium hydroxide solution to adjust pH value to 6.8 ± 0.05 if necessary) 900ml molten Go out in medium, rotating speed is constant, continue operate in accordance with the law, through 1 hour, 2 hours, 4 little constantly, take solution 10ml respectively, and immediately mend Fill mutually synthermal, same volume dissolution medium, filtration, precision measures subsequent filtrate in right amount, and with water, quantitatively dilution is made if necessary In every 1ml, the solution containing about metformin hydrochloride 5 μ g, respectively obtains the need testing solution of three sampling time points, as examination Product solution (3)；

Separately take metformin hydrochloride reference substance, accurately weighed, it is dissolved in water and quantitative dilution is made in every 1ml containing about 25 μ g Solution, as reference substance solution (2), it is used for calculating the concentration of the metformin hydrochloride in need testing solution (2)；

Separately take metformin hydrochloride reference substance, accurately weighed, plus 0.1mol/L hydrochloric acid solution dissolves and quantitative dilution is made Solution containing about 25 μ g in every 1ml, as reference substance solution (1), the hydrochloride that it is used for calculating in need testing solution (1) is double The concentration of guanidine；

Separately take metformin hydrochloride reference substance, accurately weighed, it is dissolved in water and quantitative dilution is made in every 1ml containing about 5 μ g Solution, as reference substance solution (3), it is used for calculating the concentration of the metformin hydrochloride in need testing solution (3)；

Take need testing solution (1), (2), (3) and reference substance solution (1), (2), (3), according to Chinese Pharmacopoeia version in 2015 four The specification of general rule " 0401 ultraviolet visible spectrophotometry ", difference mensuration absorbance at the wavelength of 233nm, calculate every respectively Piece in acid 2 little stripping quantities constantly, in pH5.0 medium 2 little stripping quantities constantly and in buffer little 1 When, 2 hours, 4 little stripping quantities constantly.

Have now surprisingly been found that, it is specific that above-mentioned label composition, the first coatings composition and the second coatings form Combination, the stripping curve of the tablet expression characteristicses preparing, and this kind of tablet assumes significantly more biology effect The biology effect for example being characterized with GLP-1 and/or PYY.

The pharmaceutical composition of any one according to a first aspect of the present invention, it is to be prepared by a method comprising the following steps Arrive：

(1) prepare label：Binding agent is made into the solution that concentration is 3～6%, double to hydrochloride using binder solution Guanidine or itself and optional inorganic salt and diluent mixing gained mixture wet granular, are dried, and add mix lubricant uniformly, pressure Piece, obtains final product label；

The coating of (2) first coatings：The coating material of the first coatings is configured to coating solution, by this coating solution to institute State label to be coated；

The coating of (3) second coatings：The coating material of the second coatings is configured to coating solution, by this coating solution to step Suddenly (2) gained coated tablet is coated, and obtains final product.

The pharmaceutical composition of any one according to a first aspect of the present invention, the solvent being wherein used for preparing binder solution is water Or the ethanol solution that concentration is 30～80%.

Further, second aspect present invention provides medicine group described in preparation first aspect present invention any embodiment The method of compound, it comprises the steps：

The method of any one according to a second aspect of the present invention, the solvent being wherein used for preparing binder solution is water or dense Spend the ethanol solution for 30～80%.

Or, second aspect present invention provides a kind of method preparing the pharmaceutical composition in tablet form, this medicine Compositionss include label, the first coatings wrapping up this label, are wrapped in the second coatings outside this first coatings, described Active component in label is metformin hydrochloride；The method comprises the steps：

The method of any one according to a second aspect of the present invention, wherein said label include active ingredient hydrochloric acid metformin, Binding agent and lubricant.

The method of any one according to a second aspect of the present invention, in wherein said label, binding agent used is selected from：Hydroxypropyl Cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, polyvidone, Polyethylene Glycol (molecular weight 2000～8000).One In individual embodiment, preferred binding agent is selected from：Polyvidone, Macrogol 4000, polyethylene glycol 6000.

The method of any one according to a second aspect of the present invention, in wherein said label, binding agent used accounts for hydrochloride pair 2～10% (w/w) of guanidine weight, for example, account for 3～6% (w/w) of metformin hydrochloride weight.

The method of any one according to a second aspect of the present invention, in wherein said label, lubricant used is selected from：Stearic acid, Magnesium stearate, calcium stearate, micropowder silica gel, Pulvis Talci, hydrogenated vegetable oil, sodium lauryl sulphate.In one embodiment, Preferably lubricant is selected from：Magnesium stearate, calcium stearate.

The method of any one according to a second aspect of the present invention, in wherein said label, lubricant used accounts for hydrochloride pair 0.2～2% (w/w) of guanidine weight, for example, account for 0.5～1.5% (w/w) of metformin hydrochloride weight.

The method of any one according to a second aspect of the present invention, also includes inorganic salt in wherein said label.Described inorganic salt Selected from sodium chloride, potassium chloride, sodium bicarbonate, potassium bicarbonate, calcium chloride, sodium sulfate etc., and combinations thereof.Preferably inorganic salt is selected from Sodium chloride, potassium chloride, and combinations thereof.

The method of any one according to a second aspect of the present invention, in wherein said label, inorganic salt used accounts for hydrochloride pair 0～20% (w/w) of guanidine weight, for example, account for 2～8% (w/w) of metformin hydrochloride weight.

The method of any one according to a second aspect of the present invention, also optional in wherein said label comprises diluent.One In individual embodiment, described diluent is selected from：Corn starch, Pregelatinized Starch, dextrin, Lactose, Mannitol, Microcrystalline Cellulose Deng.In one embodiment, described diluent is selected from：Lactose, Mannitol.

The method of any one according to a second aspect of the present invention, in wherein said label, diluent used accounts for hydrochloride pair 0～25% (w/w) of guanidine weight, for example, account for 0～10% (w/w) of metformin hydrochloride weight.

The method of any one according to a second aspect of the present invention, the coating material of wherein said first coatings includes film forming Material.In one embodiment, described filmogen is ethyl cellulose.

The method of any one according to a second aspect of the present invention, is also included in the coating material of wherein said first coatings no Machine salt.For example, described inorganic salt is identical with the inorganic salt in described label.

The method of any one according to a second aspect of the present invention, in the coating material of wherein said first coatings, with every 100 The ethyl cellulose meter of weight portion, amount 20～50 weight portion of inorganic salt, the amount of such as inorganic salt is 20～40 weight portions.

The method of any one according to a second aspect of the present invention, also includes in the coating material of wherein said first coatings point Son measures the Polyethylene Glycol for 200～600.

The method of any one according to a second aspect of the present invention, in the coating material of wherein said first coatings, with every 100 The ethyl cellulose meter of weight portion, amount 5～30 weight portion of Polyethylene Glycol, the amount of such as Polyethylene Glycol is 10～20 weight portions.

The method of any one according to a second aspect of the present invention, the coating material of wherein said first coatings is to be prepared The coating solution becoming solid concentration 2～10% (w/v) is for being coated to described label.In one embodiment, The coating material of described first coatings is the coating solution being configured to solid concentration 3～8% (w/v) for described Label is coated.In one embodiment, the solvent preparing described coating solution is 30～90% ethanol solution, for example It is 50～85% ethanol solution.

The method of any one according to a second aspect of the present invention, the coating material weight of wherein said first coatings is label 1～10% (w/w) of weight, such as 2～6% (w/w).Herein, coating material weight refers to constitute the solidss of coating material The weight of matter, does not include the solvent such as water wherein preparing coating solution.This percent is also commonly referred to coating weight gain.

The method of any one according to a second aspect of the present invention, the coating material of wherein said second coatings includes film forming Material, this filmogen is that Hydroxypropyl methyl cellulose phtalate (is commonly abbreviated as HPMCP, also known as phthalic acid hydroxyl Third methylcellulose ester), Hydroxypropyl Methyl Cellulose Phthalate (being commonly abbreviated as HPMCAS), acrylic acid and methacrylate Copolymer (Eudragit of such as L or S type), and combinations thereof.In one embodiment, described filmogen is that hydroxypropyl first is fine The plain phthalic acid ester of dimension and Hydroxypropyl Methyl Cellulose Phthalate combination.In one embodiment, described one-tenth Membrane material is that both Hydroxypropyl methyl cellulose phtalate and Hydroxypropyl Methyl Cellulose Phthalate compare 1 with weight：0.5～ The combination of 1 ratio.In one embodiment, described filmogen is Hydroxypropyl methyl cellulose phtalate and acetic acid hydroxypropyl Both methylcellulose succinates compare 1 with weight：The combination of 0.6～0.9 ratio.

The method of any one according to a second aspect of the present invention, also includes in the coating material of wherein said second coatings increasing Mould agent, described plasticizer is selected from：Glycerol, propylene glycol, PEG, cochin oil, Oleum Ricini, Semen Maydis oil, liquid paraffin, glycerol list Acetate, triacetin (glyceryl triacetate), dibutyl sebacate, dibutyl phthalate, diethyl phthalate, Triethyl citrate etc. and combinations thereof.In one embodiment, described plasticizer is triethyl citrate.In an embodiment party In case, the consumption of plasticizer is the 20～35% of filmogen consumption, such as 25～35%.

The method of any one according to a second aspect of the present invention, also optional in the coating material of wherein said second coatings Including selected from following antiplastering aid：Pulvis Talci, magnesium stearate, silicon dioxide etc. and combinations thereof.In one embodiment, described Antiplastering aid is Pulvis Talci.In one embodiment, the consumption of antiplastering aid is the 20～35% of filmogen consumption, such as 25～ 35%.

The method of any one according to a second aspect of the present invention, also optional in the coating material of wherein said second coatings Including sodium lauryl sulphate.In one embodiment, the consumption of sodium lauryl sulphate be filmogen consumption 2～ 3.5%, such as 2.5～3.5%.

The method of any one according to a second aspect of the present invention, the coating material of wherein said second coatings is to be prepared The coating solution becoming solid concentration 3～15% (w/v) is for being coated to described label.In one embodiment, The coating material of described second coatings is the coating solution being configured to solid concentration 5～10% (w/v) for institute State what label was coated.In one embodiment, the solvent preparing described coating solution is water.

The method of any one according to a second aspect of the present invention, the coating material weight of wherein said second coatings is label 1～10% (w/w) of weight, such as 2～6% (w/w).Herein, coating material weight refers to constitute the solidss of coating material The weight of matter, does not include the solvent such as water wherein preparing coating solution.This percent is also commonly referred to coating weight gain.

The method of any one according to a second aspect of the present invention, surveys when its obtained pharmaceutical composition shines stripping quantity algoscopy Regularly, this pharmaceutical composition in acid 2 little stripping quantities constantly be less than labelled amount 5% (e.g., less than labelled amount 4%, E.g., less than labelled amount 3%)；It is less than the 10% of labelled amount in 2 little stripping quantities constantly in the water for 5.0 ± 0.1 for the pH value (e.g., less than labelled amount 8%, e.g., less than the 5% of labelled amount)；Buffer is less than in 1 little stripping quantity constantly and indicates 40% (for example in the range of the 25～40% of labelled amount) of amount, the stripping quantities of 2 hours be labelled amount 20～80% (for example 45～60%), the stripping quantity at 4 hours is more than 80% (being greater than the 85% of labelled amount) of labelled amount；Described dissolution measures Determine method as follows：

Further, third aspect present invention provides metformin hydrochloride and is used for treating diabetes or in system in preparation It is ready for use on treatment hyperglycemia or the purposes in the pharmaceutical composition that preparation loses weight, wherein said medicine for induction Compositionss are as described in first aspect present invention any embodiment.

Purposes described in any embodiment according to a third aspect of the present invention, wherein said diabetes are type 2 diabetes mellitus, example As obese type type 2 diabetes mellitus.

Purposes described in any embodiment according to a third aspect of the present invention, wherein said pharmaceutical composition is used for and islets of langerhans Element shares, and to increase the hypoglycemic activity of insulin, and/or reduces insulin dosage, and/or prevents hypoglycemia from occurring.

Purposes described in any embodiment according to a third aspect of the present invention, wherein said diabetes are 1 type or 2 type glycosurias Disease.

Purposes described in any embodiment according to a third aspect of the present invention, wherein said pharmaceutical composition is used for treating sugar Urine disease simultaneously reduces the risk being used caused adverse events by metformin.

Purposes described in any embodiment according to a third aspect of the present invention, wherein said adverse events are lactic acidosis Or selected from following gastrointestinal complication：Nausea, diarrhoea, dyspepsia, vomiting.

Purposes described in any embodiment according to a third aspect of the present invention, wherein said pharmaceutical composition is used for treating sugar Urine disease simultaneously avoids the contraindication relevant with metformin.

Purposes described in any embodiment according to a third aspect of the present invention, the wherein said taboo relevant with metformin Disease is selected from：Anoxia condition of illness, phosphagen system are impaired, metformin clearance rate is impaired or a combination thereof.

Purposes described in any embodiment according to a third aspect of the present invention, wherein said metformin clearance rate is impaired Contraindication is selected from：Moderate renal impairment, severe renal impairment or end-stage renal disease or a combination thereof.

Purposes described in any embodiment according to a third aspect of the present invention, wherein said hyperglycemia is chronic hyperglycemia Disease.

Purposes described in any embodiment according to a third aspect of the present invention, wherein said hyperglycemia is chronic hyperglycemia Disease is caused by type ii diabetes.

Although the concrete steps of its description are in some details or language in the step of the above-mentioned preparation method of the present invention Step described in preparation example with following detailed description part in description is otherwise varied, however, people in the art Member can summarize approach described above step completely according to the detailed disclosure of full text of the present invention.

Any embodiment of the either side of the present invention, can be combined with present invention other any embodiment, As long as they are not in contradiction.Additionally, in any embodiment of either side of the present invention, arbitrary technical characteristic can be fitted For this technical characteristic in present invention other any embodiment, as long as they are not in contradiction.

The invention will be further described below.

All documents recited in the present invention, their full content is incorporated herein by, and if these are civilian When implication expressed by offering is inconsistent with the present invention, it is defined by the statement of the present invention.Additionally, the present invention use various terms and Phrase has well known to a person skilled in the art general sense, nonetheless, the present invention remain desirable at this to these terms and Phrase is described in more detail and explains, the term referring to and phrase if any inconsistent with common art-recognized meanings, with institute of the present invention table The implication stated is defined.

It should be noted that " the first coatings " or " the second coatings " that the present invention refers to, refer to a kind of only clothing Layer.It is well known that in medicament art for coating, wrapping up a kind of clothing layer and be typically required material is given either continuously or intermittently entered Row coating, particularly in the case of batch (-type) coating, a kind of such clothing layer can be made up of multilamellar, that is, spraying one layer of coating Liquid is simultaneously dried at once, then continues to spray one layer of coating solution and be at once dried, and so coating is until such one repeatedly Kind of clothing layer reaches intended effect, for example desired thickness it is desirable to weightening etc..In the present invention, such as not specifically mentioned, made PVP is PVP K30.

The coating operations of the present invention can adopt well known to a person skilled in the art coating equipment in sugar production line is coated, for example with The coating equipment in sugar production line of the principles such as pan coating device, rotation coating device, fluidized coating device is coated, in view of the property of coated tablet Majority can be determined by coating property, therefore select what type of coating equipment in sugar production line generally to have no effect on present invention essence.At one In embodiment, can be coated using following typical coating pan device：Take plain chip to put in coating pan, open compression empty Gas, starts seed-coating machine, so that coating pan is slowly rotated, and when preheating label is to about 40 DEG C, opens spray gun, coating solution is sprayed onto and turns On dynamic label, spraying is dried with the hot blast relaxing simultaneously, finishes to coating solution spraying, and continuing blowing hot-air makes coating solvent Volatilization is dry.

Metformin hydrochloride is a kind of blood sugar lowering, and in terms of pharmacological action, it has the blood improving type 2 diabetes mellitus patient Sugared tolerance, reduces the effect of basis and post-prandial glycemia.The mechanism of action of metformin hydrochloride is different from other types of oral Anti- blood glucose medicine, it can reduce the generation of glycogen, reduces intestinal to sugared absorption, and can be by increasing picked-up and the utilization of periphery sugar And improve the sensitivity of insulin, and unlike sulfonylureas, metformin hydrochloride will not to type 2 diabetes mellitus patient or The patient of euglycemia produces hypoglycemia (except special circumstances see points for attention).After metformin hydrochloride treatment, islets of langerhans The secretion of element keeps constant, and reduces Fasting insulin level and daily plasma insulin level.Toxicological study：Genetoxic： This product Salmonella reversion test, mouse lymphocyte gene mutation test, Chromosome Aberration In Human Lymphocytes test and mouse microkernel test Result is feminine gender.Genotoxicity：Male rat and female rats give metformin hydrochloride, and dosage is up to 600mg/kg/ day (being equivalent to clinical recommend maximum daily dose 3 times of people by body surface area conversion), has no the impact to fertility.Rat and rabbit Give metformin hydrochloride, dosage is up to and 600mg/kg/ day (is equivalent to the maximum daily dose of the clinical recommendation of people by body surface area conversion 2 times and 6 times) when, no teratogenesis.Age of sucking, the result of study of rat showed, metformin hydrochloride can be secreted into milk, And can reach the level in blood plasma.Carcinogenecity：Rat gives at 104 weeks metformin hydrochloride 900mg/kg/ day and mice gives salt Sour 91 weeks metformin 1500mg/kg/ days (being equivalent to clinical recommend maximum daily dose 4 times of people by body surface area conversion), Carcinogenesis are had no with animal.But in the female rats of 900mg/kg/ day, there is the increasing that optimum interstitial metropolypuses occur Plus.

In terms of the pharmacokineticss of metformin, oral administration of metformin is mainly in intestinal absorption.Oral under fasted conditions The absolute bioavailability that 0.5 gram of metformin is 50～60%.Take food simultaneously and slightly reduce the infiltration rate of medicine and absorb journey Degree.Domestic oral this product pharmacokinetic trial result shows, reaches the blood peak concentration of drug time for 2 hours, average blood plasma after being administered orally Medicine removes the half-life about 4 hours.Metformin is hardly combined with plasma protein, according to conventional clinical dosage and administration side Case is administered orally this product, can reach Cpss in 24～48 hours., mainly through renal excretion, after oral this product, 24 is little for this product When interior renal excretion 90%.

In terms of the clinical trial of metformin, a prospective randomized study (UKPDS) confirms to strengthen glycemic control For type 2 diabetes mellitus, patient has far-reaching significance.The diabeticss of the obesity that diet-treated only is failed to respond to any medical treatment use two First biguanide is treated, and interpretation of result shows：Significantly reduce the risk that diabetic complication occurs, melbine group patient (29.8 Event/1000 patient) compare, p=0.0023 with group of keeping on a diet merely (43.3 event/1000 patient)；With combine Sulphanylureas group and alone insulin group (40.1 event/1000 patient) compare, p=0.0034.Significantly reduce and glycosuria The related mortality rate of disease, melbine group 7.5 event/1000 patient, group 12.7 of keeping on a diet merely event/1000 are suffered from Person, p=0.017.Significantly reduce general mortality rate, melbine group 13.5 event/1000 patient, with group of keeping on a diet merely 20.6 event/1000 patients compare (p=0.011)；With combine sulphanylureas group and alone insulin group 18.9 event/1000 Position patient compares (p=0.021).Significantly reduce the risk that myocardial infarction occurs, melbine group 11 event/1000 are suffered from Person, keep on a diet merely group 18 event/1000 patients (p=0.01).For metformin as second line treatment medicine, joint Sulfonylurea drugs use, and the meaning for clinical effectiveness there is no conclusion.For type 1 diabetes patient, some patient is random Accept metformin joint insulin therapy, but the clinical efficacy for this drug combination there is no formal final conclusion.

Present invention has been found that can advantageously improve the curative properties of metformin hydrochloride using inventive formulation.

Brief description

Fig. 1：Describe the schematic depiction of T value.

Specific embodiment

Further illustrate the present invention below by specific embodiment/experimental example, it should be understood, however, that, these enforcements Example and experimental example are only used for specifically describing in more detail and are used, and are not to be construed as limiting in any form this Bright.

The present invention to used in test to material and test method carry out generality and/or specific describe.Though It is so to realize many materials that the object of the invention used and operational approach is it is known in the art that the still present invention still here Describe in detail as far as possible.It will be apparent to those skilled in the art that hereinafter, if not specified, material therefor of the present invention and Operational approach is well known in the art.

When the present invention hereafter prepares tablet, the amount comprising metformin hydrochloride in every is 500mg.List system below During agent prescription, if not otherwise indicated, be to be illustrated with the every amount comprising metformin hydrochloride for 500mg, the every batch of inventory be to Few 10000.When listing the amount of coating composition, for convenience, can be so that the ratio of weight portion illustrates without absolute magnitude Illustrate.

[stripping quantity algoscopy]

Following stripping quantity algoscopy is used for measuring the stripping quantity of Metformin Hydrochloride Tablets agent：

Take need testing solution (1), (2), (3) and reference substance solution (1), (2), (3), according to Chinese Pharmacopoeia version in 2015 four The specification of general rule " 0401 ultraviolet visible spectrophotometry ", difference mensuration absorbance at the wavelength of 233nm, calculate every respectively Piece in acid 2 little stripping quantities constantly, in pH5.0 medium 2 little stripping quantities constantly and in buffer little 1 When, 2 hours, 4 little stripping quantities constantly.If preparation has its particularity, can correspondingly change dissolution sample time etc. will Element.

The general approach below preparing coated tablet comprises the steps：

(1) prepare label：Binding agent is made into the solution that concentration is 3～6%, and (solvent is water or concentration is 30～80% Ethanol solution), using binder solution to metformin hydrochloride or its mix with diluent mixing gained with optional inorganic salt Compound wet granular, is dried, and adds mix lubricant uniformly, and tabletting obtains final product label；

Embodiment part：Prepare metformin hydrochloride coated tablet

Embodiment 1：Prepare metformin hydrochloride coated tablet

Label：

Metformin hydrochloride	500mg,
		Polyvidone	20mg,
Sodium chloride	25mg,
		Magnesium stearate	5mg；

Preparation：Binding agent water is made into the solution that concentration is 4%, to metformin hydrochloride and is removed using binder solution The mixture wet granular of the other adjuvants outside lubricant, is dried, and adds mix lubricant uniformly, and tabletting obtains final product label.

First coatings：

Ethyl cellulose	100 weight portions,
		Sodium chloride	30 weight portions,
PEG400	15 weight portions,
		75% ethanol solution	In right amount, prepare the coating solution containing solid content 5%；
Coating weight gain	3.5% (with respect to label)

Coating：According to listed by prescription, above coating material is configured to the coating solution of the first coatings, by this coating solution pair Label is coated.

Second coatings：

Coating：According to listed by prescription, above coating material is configured to the coating solution of the second coatings, by this coating solution pair To be coated is coated.

The Metformin Hydrochloride Tablets of parcel two-layered coating are obtained by above formula and preparation method.

Embodiment 2：Prepare metformin hydrochloride coated tablet

Label：

Metformin hydrochloride	500mg,
		PEG4000	25mg,
Potassium chloride	30mg,
		Calcium stearate	5mg；

Preparation：Binding agent water is made into the solution that concentration is 3%, to metformin hydrochloride and is removed using binder solution The mixture wet granular of the other adjuvants outside lubricant, is dried, and adds mix lubricant uniformly, and tabletting obtains final product label.

First coatings：

Ethyl cellulose	100 weight portions,
		Potassium chloride	35 weight portions,
PEG200	18 weight portions,
		65% ethanol solution	In right amount, prepare the coating solution containing solid content 4%；
Coating weight gain	3% (with respect to label)

Second coatings：

HPMCP	100 weight portions,
		HPMCAS	70 weight portions,
Triethyl citrate	50 weight portions,
		Pulvis Talci	45 weight portions,
Water	In right amount, prepare the coating solution containing solid content 8%；
		Coating weight gain	4% (with respect to label)

Embodiment 3：Prepare metformin hydrochloride coated tablet

Label：

Metformin hydrochloride	500mg,
		Polyvidone	17mg,
Sodium chloride	45mg,
		Magnesium stearate	8mg；

Preparation：Binding agent water is made into the solution that concentration is 6%, to metformin hydrochloride and is removed using binder solution The mixture wet granular of the other adjuvants outside lubricant, is dried, and adds mix lubricant uniformly, and tabletting obtains final product label.

First coatings：

Ethyl cellulose	100 weight portions,
		Sodium chloride	20 weight portions,
PEG600	10 weight portions,
		50% ethanol solution	In right amount, prepare the coating solution containing solid content 3%；
Coating weight gain	2% (with respect to label)

Second coatings：

HPMCP	100 weight portions,
		HPMCAS	60 weight portions,
Triethyl citrate	40 weight portions,
		Pulvis Talci	55 weight portions,
Water	In right amount, prepare the coating solution containing solid content 5%；
		Coating weight gain	6% (with respect to label)

Embodiment 4：Prepare metformin hydrochloride coated tablet

Label：

First coatings：

Ethyl cellulose	100 weight portions,
		Potassium chloride	40 weight portions,
PEG350	20 weight portions,
		85% ethanol solution	In right amount, prepare the coating solution containing solid content 8%；
Coating weight gain	6% (with respect to label)

Second coatings：

HPMCP	100 weight portions,
		HPMCAS	90 weight portions,
Triethyl citrate	65 weight portions,
		Pulvis Talci	48 weight portions,
Water	In right amount, prepare the coating solution containing solid content 10%；
		Coating weight gain	2% (with respect to label)

Embodiment 5：Prepare metformin hydrochloride coated tablet

Label：

Metformin hydrochloride	500mg,
		Polyvidone	25mg,
Sodium chloride	30mg,
		Magnesium stearate	6mg；
Lactose	40mg；

Preparation：Binding agent water is made into the solution that concentration is 5%, to metformin hydrochloride and is removed using binder solution The mixture wet granular of the other adjuvants outside lubricant, is dried, and adds mix lubricant uniformly, and tabletting obtains final product label.

First coatings：

Ethyl cellulose	100 weight portions,
		Sodium chloride	35 weight portions,
PEG350	15 weight portions,
		70% ethanol solution	In right amount, prepare the coating solution containing solid content 5%；
Coating weight gain	3% (with respect to label)

Second coatings：

HPMCP	100 weight portions,
		HPMCAS	70 weight portions,
Triethyl citrate	50 weight portions,
		Pulvis Talci	60 weight portions,
Sodium lauryl sulphate	4 weight portions,
		Water	In right amount, prepare the coating solution containing solid content 7%；
Coating weight gain	5% (with respect to label)

Embodiment 6：Prepare metformin hydrochloride coated tablet

Label：

Metformin hydrochloride	500mg,
		PEG6000	20mg,
Sodium chloride/potassium chloride (2/1)	35mg,
		Calcium stearate	5mg；
Mannitol	50mg；

First coatings：

Ethyl cellulose	100 weight portions,
		Potassium chloride	25 weight portions,
PEG600	18 weight portions,
		60% ethanol solution	In right amount, prepare the coating solution containing solid content 4%；
Coating weight gain	5% (with respect to label)

Second coatings：

HPMCP	100 weight portions,
		HPMCAS	80 weight portions,
Triethyl citrate	55 weight portions,
		Pulvis Talci	45 weight portions,
Sodium lauryl sulphate	6 weight portions,
		Water	In right amount, prepare the coating solution containing solid content 8%；
Coating weight gain	3% (with respect to label)

Embodiment 7：Prepare metformin hydrochloride coated tablet

Respectively refer to embodiment 2-6, different is only the formula that the wherein first coatings use embodiment 1 instead, obtains 5 kinds of pieces Agent.

Embodiment 8：Prepare metformin hydrochloride coated tablet

Respectively refer to embodiment 2-6, different is only the formula that the wherein second coatings use embodiment 1 instead, obtains 5 kinds of pieces Agent.

Embodiment 9：Prepare metformin hydrochloride coated tablet

Respectively refer to embodiment 2-6, different is only the formula that wherein label uses embodiment 1 instead, obtain 5 kinds of tablets.

Embodiment 10：The Metformin Hydrochloride Tablets of reference are provided

Metformin IR：The Metformin Hydrochloride Tablets buied from American market commercial sources, manufacturer AUROBINDO PHARMA LTD company, U.S. FDA approved date Jan 14,2005, U.S. FDA application number 077095, specification 500mg/ piece, piece Core includes adjuvant polyvidone and magnesium stearate, film coating (clothing material is Hypromellose and Polyethylene Glycol), and the present embodiment carries For this commercially available Metformin Hydrochloride Tablets ordinary tablet and CN 105101956 A (CN201480003932.X) description it [0347] the metformin IR piece that-[0348] and [0423] are mentioned is that releasing piece is identical product to metformin hydrochloride immediately, It can be described as metformin IR in the present invention.

Metformin XR：The diabecron sustained-release tablet buied from American market commercial sources, manufacturer Bristol- Myers Squibb company, trade nameCommodity article No. NDC 0087-6063-13, its package insert Can find from U.S. FDA official website, network address is http://www.chemdatas.com/FDA/OBResultC1.aspx？ Kword=Metformin＆KType=RX, present invention specification provided herein is 500mg/ piece, and it can be described as in the present invention Metformin XR, the adjuvant of this slow releasing tablet 500mg specification is sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose Element (using as diluent, manufacturer is not added with this diluent in 750mg specification metformin XR piece) and magnesium stearate, according to this The package insert of the official approval of metformin XR is recorded, and this slow releasing tablet includes a kind of double-hydrophilic polymeric matrix system, Metformin hydrochloride and drug release control polymer to combine to form " interior " phase, and then it is incorporated into second as another kind of particle Plant " outward " phase of polymer, gastrointestinal fluid enters in tablet upon administration, causes each polymer hydration and expands, medicine passes through Gel skeleton spreads thus slowly discharging from medicament, and this diffusion release does not substantially rely on pH's.It is true that this reality This commercially available metformin XR piece applying example offer is carried with CN 105101956 A (CN201480003932.X) description [0423] The metformin XR piece arriving is identical product, and it can be described as metformin XR in the present invention.

Metformin DR：Wrap up 2% (with respect to label weight) sealing in commercially available gained metformin IR tablet surface again Coating and 3.8% (with respect to label weight) enteric coating obtain, and concrete preparation method is with reference to CN 105101956 A (CN201480003932.X) description its [0347], wherein initial metformin IR piece includes active component, polyvidone, hard Fatty acid magnesium, Hypromellose and Polyethylene Glycol, sealing coating portion includes hydroxypropyl methylcellulose, glyceryl triacetate, Pulvis Talci (three's weight compares 5：1.5：1.5, this is also ratio commonly used in the art), enteric coating includes methacrylic acid copolymer (L30D-55), poly- (methacrylate -co- methylmethacylate -co- methacrylic acid) 7: 3: 1 (FS30D), Laurel Base sodium sulfate, polysorbate80, glyceryl monostearate and triethyl citrate, this weight is than for 5：5：0.3： 0.3：2：2.5, this is also ratio commonly used in the art.

Test example 1：Tablet stripping quantity

With reference to stripping quantity algoscopy of the present invention, stripping quantity mensure is carried out to correlation tablet according to the present invention.Result：

2 hours in acid：

(tablet of the two kinds of clothing layers of inclusion being finally obtained, if especially not dated herein for the whole tablet of embodiment 1～9 Embodiment 1～9 tablet coating number, each means the final tablet of two kinds of clothing layers of bag) in the medium the stripping quantity of 2 hours all little In 1%, all in the range of 0～0.5%, particularly most respectively less than 0.2%,

Embodiment 1～9 all only wrap the tablet of the first coatings in the medium the stripping quantity of 2 hours all 75～85% In the range of,

The stripping quantity of 2 hours is all higher than 95%, all in 97～101% scopes to the whole label of embodiment 1～9 in the medium It is interior,

The metformin IR stripping quantity 97.7% of 2 hours in the medium,

The metformin XR stripping quantity 21% of 2 hours in the medium,

The metformin DR stripping quantity 0.7% of 2 hours in the medium；

2 hours in pH5.0 medium：

The stripping quantity of 2 hours is respectively less than 5% to the whole tablet of embodiment 1～9 in the medium, all in the range of 0～3%, Particularly most respectively less than 2%,

Embodiment 1～9 all only wrap the tablet of the first coatings in the medium the stripping quantity of 2 hours all 65～72% In the range of,

The stripping quantity of 2 hours is all higher than 95%, all in 97～100% scopes to the whole label of embodiment 1～9 in the medium It is interior,

The metformin IR stripping quantity 98.4% of 2 hours in the medium,

The metformin XR stripping quantity 19% of 2 hours in the medium,

The metformin DR stripping quantity 5.8% of 2 hours in the medium；

1,2,4 hours in pH6.8 medium：

The whole tablet of embodiment 1～9 in the medium, 1 hour stripping quantity all in the range of 25～40%, dissolution in 2 hours All in the range of 45～60%, stripping quantity is all higher than 85% to amount within 4 hours,

The tablet that embodiment 1～9 all only wraps the first coatings (does not carry out 0.1mol/L hydrochloric acid Jie in the medium in advance Matter processes but is placed directly within pH6.8 medium for 2 hours) 1 hour stripping quantity be all in the range of 20～30%, 2 hours stripping quantities All in the range of 45～55%, 4 hours stripping quantities equal>85%,

Metformin XR in the medium 1 hour stripping quantity 8% (28%, before have in acid during 2 hours about 20% molten Go out, about 8% dissolution during buffer 1 hour, similarly hereinafter), 2 hours stripping quantities 21% (41%), 4 hours stripping quantities 46% (66%),

Metformin DR 1 hour stripping quantity 93% in the medium, 2 hours stripping quantities>95%, 4 hours stripping quantities> 97%.

It has been found that for the Tablets only wrapping up the first coatings, when it is exposed in different pH medium, pH value More low then stripping quantity is bigger, and this trend its mechanism for the present inventor is unclear, but may for tablet properties Have certain/unique impact of some aspects.In addition, in buffer salt, the tablet dissolving out capability of parcel two-layer and one layer of parcel Zero difference.Can also see, the dissolution data of metformin DR and the data described in CN 105101956 A are substantially to kiss Close.

In above test example 1, the present invention is also simultaneous for domestic Dimethyldiguanide hydrochloride enteric solubility tablet, and (specification is every 0.5g, Chinese medicines quasi-word H20073157, it can be described as metformin LL in the present invention) and carrying out stripping quantity mensure, result shows Its stripping quantity under various conditions is basically identical with metformin DR, and for example its 2 hours stripping quantity in hydrochloric acid medium is less than 1%, reach 91% within 1 hour in buffering salt medium.Because tablet typically requires more than 2 hours in dividing a word with a hyphen at the end of a line in whole small intestinal, Generally may require that 3～5 hours, therefore metformin DR or metformin LL mainly just dissolves almost in small intestinal front half section ?.

Complementary testing 1：With reference to embodiment of the present invention 1-6, different is only by the citron triethylenetetraminehexaacetic acid in its second coatings Vinegar is changed to triacetin (glyceryl triacetate), dibutyl sebacate, dibutyl phthalate or diethyl phthalate When, the various tablet of gained 1 hour stripping quantity in hydrochloric acid medium is just all higher than 15% and 2 hours stripping quantities have been above 25%, The various tablet of gained 1 hour stripping quantity in pH5.0 medium is just all higher than 25% and 2 hours stripping quantities have been above 35%, to the greatest extent Pipe triacetin (glyceryl triacetate), dibutyl sebacate, dibutyl phthalate or diethyl phthalate they It is in chemical constitution and functionally all similar with triethyl citrate used by the present invention, but when preparing Tablets But present with huge difference, and show that outermost layer can not be effectively antiacid when using these four esters；Additionally, according to this Complementary testing 1, above citron triethylenetetraminehexaacetic acid vinegar etc. is typically as the plasticizer of tablet coating, but its species selects but to piece Agent dissolution assumes impact, and this is that prior art at all cannot be expected.

Complementary testing 2：With reference to embodiment of the present invention 1-6, different only will be inorganic used by its first coatings The PEG of model wherein used is cancelled without or all replaced with to salt, or by PEG used in the first coatings cancel without Or all replace with the inorganic salt of type wherein used, or PEG used in the first coatings is replaced with equivalent HPMC (although the technical staff of medicament coating fields is generally expected to HPMC and can obtain and PEG same performance), or by first In coatings, inorganic salt used replaces with the calcium chloride of equivalent, and the various tablet of gained is 2 little in hydrochloric acid medium and pH5.0 medium Constantly stripping quantity is respectively less than 3%, but after they are transferred in buffer salt from hydrochloric acid medium, all assumes ratio embodiment 1-6 Tablet substantially quickly discharges, these tablets in this buffer salt 1 hour stripping quantity all in the range of 65～75%, 2 hours molten Output is all higher than 90%.This shows in the first coatings only in inorganic salt of the present invention with PEG in situation about being applied in combination The performance that Tablets reach controllable release in buffer salt can be given down.

Complementary testing 3：With reference to embodiment of the present invention 1-6, different be only by the inorganic salt in its label cancel without or The inorganic salt different from the inorganic salt in the first coatings that person uses equivalent instead (that is, uses chlorine instead in label when using sodium chloride Change potassium, in label, when using potassium chloride, use sodium chloride instead), or the hydroxypropyl binding agent in its label being replaced with equivalent Base cellulose, hydroxypropyl methyl cellulose or sodium carboxymethyl cellulose, the various tablet of gained is in hydrochloric acid medium and pH5.0 medium In 2 little constantly stripping quantities be respectively less than 2%, but after they are transferred in buffer salt from hydrochloric acid medium, all present than enforcement The significantly slower release of example 1-6 tablet, these tablets in this buffer salt 1 hour stripping quantity all in the range of 8～13%, 2 is little When stripping quantity all in the range of 17～28%, stripping quantity is all in the range of 44～58% within 4 hours；It can be seen that, the piece of Tablets Core only when the specific inorganic salt of the present invention and special adhesive are applied in combination, could give Tablets in buffer salt Dissolved corrosion during 1～4 hour.This prescription changes imparting tablet its corresponding embodiment 1-6 tablet in dissolving out capability On significant difference, and these dissolving out capability (rate of release) in buffer salt of tablet of changing prescriptions and metformin XR Similar.

Test example 2：Medicine vivo potency

CN 105101956 A embodiment embodiment 1 particularly therein and embodiment 2 are instructed, active component metformin Blood drug level in body-internal-circulation can not directly reflect the hypoglycemic activity of medicine, and from blood active GLP-1 concentration, total GLP-1 concentration and PYY concentration can more intuitively reflect medicine hypoglycemic activity.For example, show in the publication, metformin DR has less active medicine blood drug level AUC than metformin IR, but two kinds of medicaments are in active GLP-1 concentration increments (with respect to its baseline, similarly hereinafter), total GLP-1 concentration increments and PYY concentration increments aspect but have no obvious difference, and the two Blood sugar decreasing effect is substantially suitable, thus showing, GLP-1 and PYY increment essentially identical can reach essentially identical hypoglycemic In the case of effect, DR preparation enter whole body in medication amount lower than IR preparation thus DR preparation has lower untoward reaction Incidence rate and the sensitivity lower to contraindication.

For verifying Tablets performance, the method with reference to CN 105101956 A embodiment 1 and embodiment 2 is tried Test, specific as follows.

(1) reagent：

The embodiment of the present invention 1 gained include two-layered coating tablet (being labeled as EX1),

The embodiment of the present invention 2 gained include two-layered coating tablet (being labeled as EX2),

Metformin IR (being labeled as IR),

Metformin XR (being labeled as XR),

Metformin DR (is labeled as DR).

(2) experimenter：22～27 years old men's health volunteers, and no metformin contraindication, 30 people, mean random is divided into 5 groups, each group tests above-mentioned 5 kinds of medicaments respectively.

(3) medication and test：Each experimenter is in test day 8:00、12:00、18:Enter equal amount meals 00 3 times, in 8:00 The simultaneously every group of experimenter that have meal takes the medicament 2 (being metformin 1000mg) that this group specifies, first 2 hours respectively at medication Before (being represented by -2h), medication at that time (0h), (1h, after by that analogy), 2h 1 hour after medication, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 14h, 16h, 20h, 24h, 30h, 40h extracting vein blood, measure each time point blood sample in Determination of Metformin Plasma Concentration, Active GLP-1 concentration, total GLP-1 concentration, PYY concentration, and averaging of income result is that y-axis makees smooth figure with time x-axis, as Various time effect figures.

For both GLP-1 and PYY basic value in terms of the average of this test group -2h and 0h test value, in time effect In figure, during 0h to 40h, GLP-1 and PYY curve down to basic value above section area as under GLP-1 and PYY curve Area (AUC).

In time effect in figure, for each group of Determination of Metformin Plasma Concentration curve, in this curve drug level peak value Half at draw a horizontal linear, calculate blood drug level be higher than this straight line duration, represented with T, in dosage identical In the case of, this T is longer to represent that the time span of blood medicine onset is bigger, shows that expected therapeutic effect can be more preferably (if certain agent Amount is not enough or dosage too high if can be by suitable adjustment dosage so that this straight line be in therapeutic window as far as possible)； Because the half-life t1/2 of metformin is longer, the XR preparation of therefore whether the IR preparation of quick release or slow release is all There is no sharp peak valley phenomenon, therefore meaningful with the expected therapeutic effect of this T；In addition, preparation of different nature may The height of this T value straight line is different, it is possible to the problem of comparability can be caused, but in the case of dosage identical or In the case of projected dose identical, this comparable sex chromosome mosaicism can overcome.T value is schematically drawn and is seen Fig. 1.

In time effect in figure, each group of Determination of Metformin Plasma Concentration is calculated below its curve during 0-40 hour Long-pending (AUC).

With standard available preparation IR group as reference, the relative value calculating the above-mentioned each parameter of other each reagent groups (is that certain organizes certain Parameter value is divided by the ratio of this parameter value gained of IR group), result is shown in table 1 below.

Table 1：

Result shows, is with reference to the blood sugar lowering ability that can more directly characterize preparation with GLP-1 and PYY relative value, and And show the commercial preparation of the blood sugar decreasing effect considerably higher than various performances of Tablets；And its medicine blood drug level and DR Group is essentially identical and is all maintained at low-level, shows that invention formulation will have low adverse reaction rate like that with DR preparation And lower to metformin contraindication sensitivity, this is the feature that IR preparation and XR preparation do not have；In addition, for T value, this Invention preparation will have than in the broader therapeutic window (can reach the longer time in therapeutic window) of DR preparation and more flat Slow medicine peak bottom, on the premise of reaching identical treatment effect, this feature of T value will be helpful to reduce on the whole medicine The taking dose of thing.

Claims

1. a kind of pharmaceutical composition in tablet form, it include label, the first coatings wrapping up this label, be wrapped in this The second coatings outside one coatings, the active component in described label is metformin hydrochloride.

2. pharmaceutical composition according to claim 1 it is characterised in that：

Described label includes active ingredient hydrochloric acid metformin, binding agent and lubricant；

In described label, binding agent used is selected from：Hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, Polyvidone, Polyethylene Glycol (molecular weight 2000～8000)；

Binding agent is selected from：Polyvidone, Macrogol 4000, polyethylene glycol 6000；

In described label, binding agent used accounts for 2～10% (w/w) of metformin hydrochloride weight, for example, account for metformin hydrochloride 3～6% (w/w) of weight；

In described label, lubricant used is selected from：Stearic acid, magnesium stearate, calcium stearate, micropowder silica gel, Pulvis Talci, hydrogenation Vegetable oil, sodium lauryl sulphate；

Preferably lubricant is selected from：Magnesium stearate, calcium stearate；

In described label, lubricant used accounts for 0.2～2% (w/w) of metformin hydrochloride weight, for example, account for hydrochloride double 0.5～1.5% (w/w) of guanidine weight；

Inorganic salt is also included in described label；

Described inorganic salt be selected from sodium chloride, potassium chloride, sodium bicarbonate, potassium bicarbonate, calcium chloride, sodium sulfate etc., and combinations thereof；

Inorganic salt be selected from sodium chloride, potassium chloride, and combinations thereof；

In described label, inorganic salt used accounts for 0～20% (w/w) of metformin hydrochloride weight, for example, account for metformin hydrochloride 2～8% (w/w) of weight；

Also optional in described label comprise diluent；

Described diluent is selected from：Corn starch, Pregelatinized Starch, dextrin, Lactose, Mannitol, Microcrystalline Cellulose；

Described diluent is selected from：Lactose, Mannitol；And/or

In described label, diluent used accounts for 0～25% (w/w) of metformin hydrochloride weight, for example, account for metformin hydrochloride 0～10% (w/w) of weight.

3. pharmaceutical composition according to claim 1 it is characterised in that：

The coating material of described first coatings includes filmogen；

Described filmogen is ethyl cellulose；

Inorganic salt is also included in the coating material of described first coatings；

Described inorganic salt is identical with the inorganic salt in described label；

In the coating material of described first coatings, in terms of the ethyl cellulose of every 100 weight portions, amount 20～50 weight of inorganic salt Amount part, the amount of such as inorganic salt is 20～40 weight portions；

The Polyethylene Glycol that molecular weight is 200～600 is also included in the coating material of described first coatings；

In the coating material of described first coatings, in terms of the ethyl cellulose of every 100 weight portions, the amount 5～30 of Polyethylene Glycol The amount of weight portion, such as Polyethylene Glycol is 10～20 weight portions；

The coating material of described first coatings be configured to the coating solution of solid concentration 2～10% (w/v) for Described label is coated；

The coating material of described first coatings is the coating solution being configured to solid concentration 3～8% (w/v) for right Described label is coated；

The solvent preparing described coating solution is 30～90% ethanol solution, e.g. 50～85% ethanol solution；And/or

The coating material weight of described first coatings is 1～10% (w/w) of label weight, such as 2～6% (w/w).

4. pharmaceutical composition according to claim 1 it is characterised in that：

The coating material of described second coatings includes filmogen, and this filmogen is Hypromellose phthalic acid Ester (being commonly abbreviated as HPMCP, also known as Hypromellose phthalate), Hydroxypropyl Methyl Cellulose Phthalate (being commonly abbreviated as HPMCAS), EUDRAGIT RS PM (Eudragit of such as L or S type), and combinations thereof；

Described filmogen is the group of both Hydroxypropyl methyl cellulose phtalate and Hydroxypropyl Methyl Cellulose Phthalate Close；

Described filmogen is both Hydroxypropyl methyl cellulose phtalate and Hydroxypropyl Methyl Cellulose Phthalate with weight Amount compares 1：The combination of 0.5～1 ratio；

Described filmogen is both Hydroxypropyl methyl cellulose phtalate and Hydroxypropyl Methyl Cellulose Phthalate with weight Amount compares 1：The combination of 0.6～0.9 ratio；

Also plasticizer is included, described plasticizer is selected from the coating material of described second coatings：Glycerol, propylene glycol, PEG, essence Oleum Cocois processed, Oleum Ricini, Semen Maydis oil, liquid paraffin, monoacetin, triacetin (glyceryl triacetate), the dibutyl last of the ten Heavenly stems two Acid esters, dibutyl phthalate, diethyl phthalate, triethyl citrate etc. and combinations thereof；For example, plasticizer is Chinese holly Rafter triethylenetetraminehexaacetic acid ester；

The consumption of plasticizer is the 20～35% of filmogen consumption, such as 25～35%；

Also optional including selected from following antiplastering aid in the coating material of described second coatings：Pulvis Talci, magnesium stearate, two Silicon oxide etc. and combinations thereof；

Described antiplastering aid is Pulvis Talci；

The consumption of antiplastering aid is the 20～35% of filmogen consumption, such as 25～35%；

Also optional inclusion sodium lauryl sulphate in the coating material of described second coatings；

The consumption of sodium lauryl sulphate is the 2～3.5% of filmogen consumption, such as 2.5～3.5%；

The coating material of described second coatings be configured to the coating solution of solid concentration 3～15% (w/v) for Described label is coated；

The coating material of described second coatings be configured to the coating solution of solid concentration 5～10% (w/v) for Described label is coated；

The solvent preparing described coating solution is water；And/or

The coating material weight of described second coatings is 1～10% (w/w) of label weight, such as 2～6% (w/w).

5. pharmaceutical composition according to claim 1 it is characterised in that：

When it shines stripping quantity algoscopy and measures, it is (for example little less than the 5% of labelled amount in 2 little stripping quantities constantly in acid In the 4% of labelled amount, e.g., less than the 3% of labelled amount)；Little in 2 little stripping quantities constantly in the water for 5.0 ± 0.1 for the pH value In labelled amount 10% (e.g., less than labelled amount 8%, e.g., less than the 5% of labelled amount)；In buffer 1 little constantly Stripping quantity is less than 40% (for example in the range of the 25～40% of labelled amount) of labelled amount, is labelled amount in the stripping quantities of 2 hours 20～80% (such as 45～60%), 80% (be greater than labelled amount what the stripping quantities of 4 hours were more than labelled amount 85%)；Described stripping quantity algoscopy is as follows：

Specification according to the first method method 2 of Chinese Pharmacopoeia four general rules of version in 2015 " 0931 dissolution and drug release determination method " is surveyed Fixed；

With 0.1mol/L hydrochloric acid solution 900ml as dissolution medium, rotating speed be 100 turns per minute, operate in accordance with the law, through 2 little constantly, take Solution 20ml filters, and discards just filtrate 10ml, takes subsequent filtrate as need testing solution (1)；

In in addition parallel test, to adjust the water 900ml for 5.0 ± 0.1 for the pH value as dissolution with 0.1mol/L hydrochloric acid solution Medium, rotating speed is 100 turns per minute, operates in accordance with the law, through 2 little constantly, take solution 20ml to filter, discard just filtrate 10ml, take continuous Filtrate is as need testing solution (2)；

Then above-mentioned be dissolution medium with 0.1mol/L hydrochloric acid solution operation, basket emersion liquid level will be turned immediately, with basket will be turned Immersion phosphate buffer (pH6.8) (takes 0.1mol/L hydrochloric acid solution and 0.2mol/L sodium radio-phosphate,P-32 solution, by 3:1 mix homogeneously, 2mol/L hydrochloric acid solution or 2mol/L sodium hydroxide solution is used to adjust pH value to 6.8 ± 0.05 if necessary) dissolution medium of 900ml In, rotating speed is constant, continue operate in accordance with the law, through 1 hour, 2 hours, 4 little constantly take solution 10ml respectively, and immediately supplement identical Temperature, the dissolution medium of same volume, filtration, precision measures subsequent filtrate in right amount, and with water, quantitatively dilution is made in every 1ml if necessary Containing about the solution of metformin hydrochloride 5 μ g, respectively obtain the need testing solution of three sampling time points, as need testing solution (3)；

Separately take metformin hydrochloride reference substance, accurately weighed, be dissolved in water and quantitative dilution make molten containing about 25 μ g in every 1ml Liquid, as reference substance solution (2), it is used for calculating the concentration of the metformin hydrochloride in need testing solution (2)；

Separately take metformin hydrochloride reference substance, accurately weighed, plus 0.1mol/L hydrochloric acid solution dissolves and every 1ml is made in quantitative dilution In solution containing about 25 μ g, as reference substance solution (1), it is used for calculating the metformin hydrochloride in need testing solution (1) Concentration；

Separately take metformin hydrochloride reference substance, accurately weighed, be dissolved in water and quantitative dilution make molten containing about 5 μ g in every 1ml Liquid, as reference substance solution (3), it is used for calculating the concentration of the metformin hydrochloride in need testing solution (3)；

Take need testing solution (1), (2), (3) and reference substance solution (1), (2), (3), according to Chinese Pharmacopoeia four general rules of version in 2015 The specification of " 0401 ultraviolet visible spectrophotometry ", respectively mensuration absorbance at the wavelength of 233nm, calculate respectively every In acid 2 little stripping quantities constantly, in pH5.0 medium 2 little stripping quantities constantly and in buffer 1 hour, 2 little When, 4 little stripping quantities constantly.

6. pharmaceutical composition according to claim 1, it is prepared by a method comprising the following steps and obtains：

(1) prepare label：Binding agent is made into the solution that concentration is 3～6%, using binder solution to metformin hydrochloride or Itself and optional inorganic salt and diluent mixing gained mixture wet granular, are dried, and add mix lubricant uniformly, tabletting, Obtain final product label；

The coating of (2) first coatings：The coating material of the first coatings is configured to coating solution, by this coating solution to described Core is coated；

The coating of (3) second coatings：The coating material of the second coatings is configured to coating solution, by this coating solution to step (2) gained coated tablet is coated, and obtains final product；Wherein the solvent for preparing binder solution is water or concentration is 30～80% Ethanol solution.

7. the method preparing claim 1-6 any one described pharmaceutical composition, it comprises the steps：

The coating of (3) second coatings：The coating material of the second coatings is configured to coating solution, by this coating solution to step (2) gained coated tablet is coated, and obtains final product；For example, wherein the solvent for preparing binder solution is water or concentration is 30 ～80% ethanol solution.

8. metformin hydrochloride is used for treating diabetes in preparation or is used for treating hyperglycemia in preparation or uses in preparation Purposes in the pharmaceutical composition that induction loses weight, wherein said pharmaceutical composition is as described in any one of claim 1-6.

9. purposes according to claim 8, is wherein characterised by：Described diabetes are type 2 diabetes mellitus, for example obese type 2 type sugar Urine disease；Described pharmaceutical composition is used for sharing with insulin, to increase the hypoglycemic activity of insulin, and/or reduces insulin Consumption, and/or prevent hypoglycemia from occurring；Described hyperglycemia is chronic hyperglycemia；And/or described hyperglycemia is chronic height Blood glucose disease is caused by type ii diabetes.

10. purposes according to claim 8, is wherein characterised by：

Described pharmaceutical composition is used for treating diabetes and reducing the risk being used caused adverse events by metformin；

Described adverse events are lactic acidosis or are selected from following gastrointestinal complication：Nausea, diarrhoea, dyspepsia, Vomiting；

Described pharmaceutical composition is used for treating diabetes and avoiding the contraindication relevant with metformin；

The described contraindication relevant with metformin is selected from：Anoxia condition of illness, phosphagen system are impaired, metformin clearance rate is subject to Damage or a combination thereof；And/or

The impaired contraindication of described metformin clearance rate is selected from：Moderate renal impairment, severe renal impairment or end-stage renal disease or its group Close.