CN109528706A - A kind of pharmaceutical composition and its preparation method and application for treating diabetes - Google Patents
A kind of pharmaceutical composition and its preparation method and application for treating diabetes Download PDFInfo
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- CN109528706A CN109528706A CN201710856818.7A CN201710856818A CN109528706A CN 109528706 A CN109528706 A CN 109528706A CN 201710856818 A CN201710856818 A CN 201710856818A CN 109528706 A CN109528706 A CN 109528706A
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- metformin hydrochloride
- pharmaceutical composition
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
Abstract
The present invention relates to a kind of for treating the pharmaceutical composition of diabetes, and it includes Tags to arrange net and Metformin hydrochloride, wherein Tag column are only 1:50~1:200 with the mass ratio of Metformin hydrochloride.The present invention also provides Tag column only with the preparation method of metformin hydrochloride medicinal composition and purposes.Pharmaceutical composition of the invention is composed only with Metformin hydrochloride with the SGLT2 inhibitor Tag column of special ratios, can more effectively be controlled life rate of blood glucose etc. and be haved the function that synergistic treatment diabetes, so that patient is taken medicine convenient, increase compliance.The method of preparation described pharmaceutical composition of the invention arranges net partial size by control Metformin hydrochloride particle and Tag, to guarantee the mixing homogeneity of two kinds of active components and the mobility and compressibility of particle, and is suitble to industrialized production.Pharmaceutical composition of the invention can be used for treating type-2 diabetes mellitus.
Description
Technical field
The present invention relates to the relevant drug fields of antihypelipidemic preparation, in particular to a kind of for treating the medicine of diabetes
Compositions and its preparation method and application.
Background technique
The disease incidence of diabetes persistently rises, it has also become one of highest 5 kinds of diseases of whole world morbidity and mortality, especially
Increased with China, the print developing countries such as branch subcontinent and Africa more significant.Diabetes can be divided into I type, i.e. insulin relies on
Property diabetes (IDDM) and II type, i.e. adult-onset diabetes (NIDDM) amphitypy.Diabetes are normal with disease progression
Vascular complication, including macroangiopathy and microangiopathies occurs, the chronic progressive of the organs such as the heart, brain, kidney, eye is caused to damage
Evil.The harm of diabetes is mainly from these complication.According to diabetes branch, Chinese Medical Association, China's diabetic vascular
The illness rate of complication are as follows: hypertension 31.9%, cerebrovascular disease 12.2%, cardiovascular disease 15.9%, lower limb vascular disease 5.0%,
Kidney trouble (glomerular microangiopathy change) 33.6%, retinopathy 24.3%, total prevalence rate 73.2%.Quantitatively sharply increase
In diabetic, NIDDM at least accounts for 90% or more of patient populations.NIDDM therapeutic agent include sulfonylurea, biguanides,
Alpha-glucosaccharase enzyme inhibitor, Insulin sensitizing drugs and mealtime blood sugar adjust medicine etc..
The choice drug for the type-2 diabetes mellitus drug therapy that China's updated Guidelines are recommended is melbine.If do not avoided
Disease, melbine should be maintained in the therapeutic scheme of diabetes.Being not suitable for Or Metformin In Treating person may be selected phlorose
Glycosides enzyme inhibitor or Insulin secretagogues.Or Metformin In Treating such as is used alone and blood glucose is still below standard, then can add with α-Portugal
Polyglycoside enzyme inhibitor, Insulin secretagogues, DPP-4 inhibitor or thiazolidinedione (second line treatment).It is double to be not suitable for diformazan
The combination therapy between other oral medicines can be used in guanidine person.Two kinds of oral medicine combination therapies and blood glucose person still not up to standard, can add and use pancreas
Combination therapy between the 3 kinds of oral medicines of island extract for treating (basal insulin or daily 1~2 Mixed insulin one time a day) or use.
GLP-1 receptor stimulating agent can be used for the treatment of three lines.As basal insulin or Mixed insulin and oral medicine combination therapy control blood
Sugar is not still up to standard, then therapeutic scheme should be adjusted to multiple insulin therapy (insulin or 3 times a day when basal insulin snack
Mixed insulin analog).Insulin secretagogues should be deactivated when using Mixed insulin treatment and multiple insulin therapy.
Above-mentioned therapeutic regimen is the clinical evidence and China according to drug health economics, efficacy and saferry etc.
The type-2 diabetes mellitus In Treatment of Hyperglycemia path that guide is recommended after the tradeoff of the factors such as national conditions considers.
2 (SGLT2) inhibitor of sodium glucose co-transport albumen includes Dapagliflozin (dapagliflozin), Rui Gelie
Only (remogliflozin), Sergliflozin (sergliflozin), canagliflozin (canagliflozin), A Gelie are net
(atigliflozin) etc., wherein Dapagliflozin is the 1st SGLT2 inhibitor that is granted and listing in Europe, glycosuria
Sick therapeutic effect has obtained the tentative confirmation of clinical research.
It loses weight it is reported that SGLT2 inhibitor has, hypoglycemia, therapeutic effect is seldom caused not to depend on insulin
There are the advantages that.But there is also some " congenital " deficiencies for SGLT2 inhibitor: compared with traditional hypoglycemic medicine, SGLT2 suppression
Preparation not no evidence of evidence-based medicine EBM in terms of prevention or delaying complications of diabetes, whether it causes long-term glycosuria state to kidney
It is dirty to have an adverse effect (such as urinary system infection contamination, kidney function damage or nephrosis aggravate), still need to be investigated.
SGLT2 inhibitor, can be many-sided next from blood glucose, weight, blood pressure etc. as a non-insulin-depending type drug
The progress of control type-2 diabetes mellitus provides another choosing for the medication of the existing single therapy of patient for clinical treatment
It selects.
2012 so far, shares 6 SGLT2 inhibitors and successively exists at present in European Union, the U.S. and Japan's listing, these drugs
It is domestic to be still in approval stage.
It is new SGLT2 inhibitor that Tag, which arranges net (Tianagliflozin), has 5 chiral centre stereochemical structures.Change
Scientific name: (1S) -1,5- dehydration -6- deoxidation -1-C- [the chloro- 3- of 4- [(4- ethoxyl phenenyl) methyl] phenyl]-D-Glucose alcohol, point
Minor: C21H25ClO5, molecular weight: 392.87, structural formula:
Current commercialized product has the use in conjunction of PIOGITAZONE HYDROCHLORIDE and Metformin hydrochloride, and the compound preparation is by day
This force field pharmacy exploitation listing, specification have 15/500mg and 15/850mg, trade name ACTOPLUS MET.Glimepiride and salt
The compound preparation original of sour melbine is ground by U.S.'s Shi Guibao pharmacy exploitation, and specification is 2.5/500mg and 5/500mg.
U.S. Food and Drug Administration (FDA) has approved SGLT2 inhibitor canagliflozin (canagliflozin) and two
The immobilised compound preparation of first biguanides is for treating Adult type II diabetes.The entitled Invokamet of the medicine, including 50 or 150mg bank
Lattice column are net or the tablet of 500 or 1000mg melbine, recommended dose be the first Kan Gelie on American market twice daily
Only with the immobilised compound preparation of melbine.
FDA ratify recently diabetes compound drug Xigduo XR under AstraZeneca (AstraZeneca) (Dapagliflozin/
Slow-release Metformin hydrochloride) it is listed in the U.S., for treating type-2 diabetes mellitus.
Xigduo XR is for the first time by SGLT2 inhibitor Dapagliflozin (dapagliflozin, trade name Forxiga) and sustained release
Type Metformin hydrochloride combines；It, should for needing the type-2 diabetes mellitus adult patient of Dapagliflozin joint Or Metformin In Treating
Medicine can be used as ancillary drug, and cooperation diet and movement are to control blood glucose.Before this, (Dapagliflozin/quick-release hydrochloride is double by Xigduo
Guanidine) European Union's approval has been obtained in January, 2014, it is the first SGLT2 inhibitor and melbine compound product of European Union's listing.
The usage of Xigduo XR is one time a day, to take when having meal in the morning.Slow release type preparation can reduce two by amount release drug ingedient
First biguanides bring gastrointestinal side effect.Daily maximum recommended dosage is Dapagliflozin 10mg/ slow-release Metformin hydrochloride
2000mg。
EMEA is on vildagliptin/Metformin hydrochloride Compound Tablet of approval on November 14th, 2007 Novartis (Novartis)
City, treat type-2 diabetes mellitus, for treat not can be effectively controlled still using melbine maximum tolerated dose blood glucose patient or
The patient of vildagliptin (Galvus) and melbine has been used in combination at present.The dosage strengths of the composite tablet are Wei Gelie
Spit of fland/Metformin hydrochloride 50mg/850mg or 50mg/1000mg.The compound preparation product table of commercialized product and Metformin hydrochloride
Bright curative effect is superior to single preparations of ephedrine.
In the prior art there is still a need for it is a kind of it is stable, can be effectively controlled blood glucose and treatment diabetes with synergy
Pharmaceutical composition.
Summary of the invention
Therefore, it is an object of the present invention to provide it is a kind of it is stable, can be effectively controlled blood glucose and have preferably collaboration make
The pharmaceutical composition for treating diabetes.
It is a further object to provide a kind of methods for preparing pharmaceutical composition of the invention.
A further object of the present invention is to provide a kind of purposes of pharmaceutical composition of the invention.
The purpose of the present invention is achieved through the following technical solutions.
On the one hand, the present invention provides a kind of for treating the pharmaceutical composition of diabetes, and it includes Tags to arrange net and hydrochloric acid
Melbine, wherein Tag column are only 1:50~200, preferably 1:50~170 with the mass ratio of Metformin hydrochloride.
Preferably, in per unit preparation, the Tag arrange net content be 2.5mg~20mg, preferably 2.5mg~
10mg, most preferably 5mg~10mg；The Metformin hydrochloride content be 250mg~1000mg, preferably 500mg~
1000mg, most preferably 500mg~850mg.
Preferably, described pharmaceutical composition is oral preparation, such as tablet, capsule, preferably tablet；Preferably, institute
Stating oral preparation is by including obtaining salt after first Metformin hydrochloride is individually pelletized together with pharmaceutically acceptable auxiliary material
Sour melbine particle, then the Metformin hydrochloride particle pharmaceutically acceptable auxiliary material net and other with Tag column is mixed
The method of the step of conjunction is made.
Preferably, the pharmaceutically acceptable auxiliary material is selected from one of filler, disintegrating agent, adhesive and lubricant
Or it is a variety of.
It is highly preferred that the filler be selected from microcrystalline cellulose, optimization one of microcrystalline cellulose and calcium monohydrogen phosphate or
It is a variety of；The disintegrating agent is selected from crospovidone, croscarmellose sodium, calcium carboxymethylcellulose and low substituted hydroxy-propyl
One of cellulose is a variety of；Described adhesive be selected from one of hydroxypropylcellulose, povidone and hydroxypropyl methylcellulose or
It is a variety of；And/or the lubricant be selected from magnesium stearate, calcium stearate, Compritol 888 ATO, sodium stearyl fumarate, silica,
One of superfine silica gel powder and talcum powder are a variety of.
On the other hand, the present invention provides a kind of method for being used to prepare pharmaceutical composition of the present invention, including following
Step:
(1) Metformin hydrochloride is mixed with pharmaceutically acceptable auxiliary material, and is prepared by wet granulation technology
Grain to get arrive Metformin hydrochloride particle；
(2) Metformin hydrochloride particle obtained in step (1) and Tag are arranged into net and in addition pharmaceutically acceptable
Auxiliary material is uniformly mixed, and described pharmaceutical composition is made.
Preferably, the wet granulation technology is bulk drug of pretreatment adds with interior granulating process and/or fluidized-bed process, preferably high shear
Wet granulation technology.
Preferably, the partial size of the Metformin hydrochloride particle is D90≤180 μm and/or the Tag arranges before mixing
Net partial size be D10≤5 μm, D50≤25 μm, D90≤70 μm, preferably D10≤3 μm, D50≤20 μm, D90≤55 μm, thus
It can guarantee the mixing homogeneity of two kinds of active components and the mobility and compressibility of particle.
Another aspect, the present invention provide pharmaceutical composition of the invention in preparing the drug for treating type-2 diabetes mellitus
Purposes.
The invention has the following advantages:
Pharmaceutical composition of the invention is combined only with Metformin hydrochloride with the SGLT2 inhibitor Tag column of special ratios
It forms, can more effectively control life rate of blood glucose etc. and have the function that synergistic treatment diabetes.Pharmaceutical composition of the invention can
So that patient is taken medicine convenient, increase compliance, there is preferably synergistic effect.
The method of preparation described pharmaceutical composition of the invention is arranged only by control Metformin hydrochloride particle and Tag
Partial size, to guarantee that the mixing homogeneity of two kinds of active components and the mobility and compressibility of particle, Tag arrange net partial size
Such as D90 > 70 μm, later period dissolution rate is slower, cannot be dissolved out completely at 60 minutes, influence intracorporal absorption.Preparation side of the invention
Method is suitble to industrialized production.
Detailed description of the invention
Hereinafter, carrying out the embodiment that the present invention will be described in detail in conjunction with attached drawing, in which:
Fig. 1 shows the Tag column uv absorption spectra in 0.1mol/L hydrochloric acid solution only；
Fig. 2 shows uv absorption spectra of the Metformin hydrochloride in 0.1mol/L hydrochloric acid solution；
Fig. 3 shows the Tag column purple with the mixture of Metformin hydrochloride (1:1) in 0.1mol/L hydrochloric acid solution only
Outer abosrption spectrogram；
The Tag that Fig. 4 shows in the embodiment of the present invention 1,2,3,4,5,6,10 arranges the Thailand of net melbine pharmaceutical composition
Lattice arrange net dissolution determination curve；
The Tag that Fig. 5 shows in the embodiment of the present invention 1,2,3,4,5,6,10 arranges the salt of net melbine pharmaceutical composition
Sour melbine dissolution determination curve；
The Tag that Fig. 6 shows 7,8,9 different-grain diameter of the embodiment of the present invention arranges the Tag of net melbine pharmaceutical composition
Net dissolution determination curve is arranged to compare；
The Tag that Fig. 7 shows 7,8,9 different-grain diameter of the embodiment of the present invention arranges the hydrochloric acid of net melbine pharmaceutical composition
Melbine dissolution determination curve compares；
The Tag that Fig. 8 shows in the embodiment of the present invention 1 arranges the Tag column of net melbine pharmaceutical composition only in relation to object
Matter measures map；
The Metformin hydrochloride that the Tag that Fig. 9 shows in the embodiment of the present invention 1 arranges net melbine pharmaceutical composition has
Close substance-measuring map；
The Tag that Figure 10 shows in the embodiment of the present invention 2 arranges the Tag column of net melbine pharmaceutical composition only in relation to object
Matter measures map；
The Metformin hydrochloride that the Tag that Figure 11 shows in the embodiment of the present invention 2 arranges net melbine pharmaceutical composition has
Close substance-measuring map；
The Tag that Figure 12 shows in the embodiment of the present invention 3 arranges the Tag column of net melbine pharmaceutical composition only in relation to object
Matter measures map；
The Metformin hydrochloride that the Tag that Figure 13 shows in the embodiment of the present invention 3 arranges net melbine pharmaceutical composition has
Close substance-measuring map；
The Tag that Figure 14 shows in the embodiment of the present invention 4 arranges the Tag column of net melbine pharmaceutical composition only in relation to object
Matter measures map；
The Metformin hydrochloride that the Tag that Figure 15 shows in the embodiment of the present invention 4 arranges net melbine pharmaceutical composition has
Close substance-measuring map；
The Tag that Figure 16 shows in the embodiment of the present invention 5 arranges the Tag column of net melbine pharmaceutical composition only in relation to object
Matter measures map；
The Metformin hydrochloride for arranging net melbine pharmaceutical composition Figure 17 shows the Tag in the embodiment of the present invention 5 has
Close substance-measuring map；
The Tag that Figure 18 shows in the embodiment of the present invention 6 arranges the Tag column of net melbine pharmaceutical composition only in relation to object
Matter measures map；
The Metformin hydrochloride that the Tag that Figure 19 shows in the embodiment of the present invention 6 arranges net melbine pharmaceutical composition has
Close substance-measuring map；
The Tag that Figure 20 shows in the embodiment of the present invention 7 arranges the Tag column of net melbine pharmaceutical composition only in relation to object
Matter measures map；
The Metformin hydrochloride that the Tag that Figure 21 shows in the embodiment of the present invention 7 arranges net melbine pharmaceutical composition has
Close substance-measuring map；
The Tag that Figure 22 shows in the embodiment of the present invention 8 arranges the Tag column of net melbine pharmaceutical composition only in relation to object
Matter measures map；
The Metformin hydrochloride that the Tag that Figure 23 shows in the embodiment of the present invention 8 arranges net melbine pharmaceutical composition has
Close substance-measuring map；
The Tag that Figure 24 shows in the embodiment of the present invention 9 arranges the Tag column of net melbine pharmaceutical composition only in relation to object
Matter measures map；
The Metformin hydrochloride that the Tag that Figure 25 shows in the embodiment of the present invention 9 arranges net melbine pharmaceutical composition has
Close substance-measuring map；
The Tag column that the Tag that Figure 26 shows in the embodiment of the present invention 10 arranges net melbine pharmaceutical composition are net related
Substance-measuring map；
The Tag that Figure 27 shows in the embodiment of the present invention 10 arranges the Metformin hydrochloride of net melbine pharmaceutical composition
Related substance-measuring map；
Figure 28 shows Tag column related substance-measuring map only；
Figure 29 shows the related substance-measuring map of Metformin hydrochloride；
Figure 30 shows dicyandiamide reference substance measurement HPLC map.
Specific embodiment
Present invention will be further explained by specific examples below, it should be understood, however, that, these embodiments are only
It is used, is but should not be understood as present invention is limited in any form for specifically describing in more detail.
This part carries out general description to the material and test method that arrive used in present invention test.Although being
It realizes many materials used in the object of the invention and operating method is it is known in the art that still the present invention still uses up herein
It may detailed description.It will be apparent to those skilled in the art that within a context, if not specified, material therefor of the present invention and behaviour
It is well known in the art as method.
Unless specifically stated otherwise, reagent used in following embodiment and raw material are commercially available.
Test apparatus and equipment:
In following embodiment, unless otherwise instructed, the Metformin hydrochloride particle through the following steps that preparation: will
The Metformin hydrochloride of recipe quantity is mixed with adhesive, and suitable ethanol water is added, with speed (stirring 450rpm, shearing
470rpm) wet granular processed 3~5 minutes.Wet granular oscillating granulator is pelletized through 20 mesh screens.Wet granular pours into after whole grain
The fluidizing fluid-bed machine of Glatt, in 50~60 DEG C of inlet air temperature, 50 DEG C of temperature of charge or so, drying time about 8~14 minutes.Control
Moisture≤3.5% processed is dry terminal.Metformin hydrochloride particle is made with 20 mesh screen whole grains in material.
The Tag arrange net combination with metformin object through the following steps that preparation: the Tag of certain partial size will be controlled
Column are added to the mixer with Metformin hydrochloride particle and suitable filler, disintegrating agent, lubricant only, are covered and are locked
Lid opens Mixers with Multi-direction Movement, and incorporation time is 3~5 minutes, pours out material after mixing and weighs and measures midbody particle
Content.Survey the moisture (≤3.5%) of total mix material.
By 100% equivalent tabletting slice weight range, using single-punch tablet press tabletting, special-shaped punch die tabletting.Quality measurement, or make
With No. 1 or No. 0 capsule filling of stomach dissolution type.
In following embodiment, unless otherwise instructed, the ratio, number are weight ratio, parts by weight.For the side of description
Just, raw material uses grams, can also be replaced using parts by weight.
FIG. 1 to FIG. 3 respectively illustrate Tag column are net, Metformin hydrochloride, Tag column only with Metformin hydrochloride (1:1)
Uv absorption spectra of the mixture in 0.1mol/L hydrochloric acid solution.
Embodiment 1
The present embodiment be used to illustrate Tag column of the invention only with metformin hydrochloride medicinal composition and preparation method thereof,
It is specific that details are as follows: specification 2.5mg/250mg
Preparation process:
The Metformin hydrochloride of recipe quantity and polyvinylpyrrolidone are crossed into 80 meshes respectively, then put into wet granulator material
It is 5~10 minutes dry-mixed with speed (stirring 450rpm, shearing 470rpm) in storehouse.Suitable 50% ethanol water is added, with speed
(stirring 450rpm, shearing 470rpm) wet granular processed 3~5 minutes.Wet granular oscillating granulator is pelletized through 20 mesh screens.It is whole
Wet granular pours into the fluidizing fluid-bed machine of Glatt after grain, in 50~60 DEG C of inlet air temperature, 50 DEG C of temperature of charge or so, drying time
About 8~14 minutes.Controlling moisture≤3.5% is dry terminal.Metformin hydrochloride is made with 20 mesh screen whole grains in material
Grain.
Preparation process:
It is (D by partial size103.076 D5020.35 D9065.13) Tag column are net, microcrystalline cellulose 102, are crosslinked poly- dimension
Ketone, Metformin hydrochloride particle, talcum powder, magnesium stearate are added to the mixer, and cover and locking lid, unlatching Multidirectional motion mix
Machine, incorporation time are 3~5 minutes, pour out material after mixing and weigh and measure midbody particle content.Survey the water of total mix material
Divide (≤3.5%).
By 100% equivalent tabletting slice weight range, using single-punch tablet press tabletting, special-shaped punch die tabletting.Quality measurement, packaging
To obtain the final product.
Embodiment 2
The present embodiment be used to illustrate Tag column of the invention only with metformin hydrochloride medicinal composition and preparation method thereof,
It is specific that details are as follows: specification 5mg/250mg
Preparation process:
The Metformin hydrochloride of recipe quantity and hydroxypropyl methylcellulose are crossed into 80 meshes respectively, then put into wet granulator feed bin
In, it is 5~10 minutes dry-mixed with speed (stirring 450rpm, shearing 470rpm).Suitable 30% ethanol water is added, (is stirred with speed
Mix 450rpm, shearing 470rpm) wet granular processed 3~5 minutes.Wet granular oscillating granulator is pelletized through 20 mesh screens.Whole grain
Wet granular pours into the fluidizing fluid-bed machine of Glatt afterwards, in 50~60 DEG C of inlet air temperature, 50 DEG C of temperature of charge or so, drying time about 8
~14 minutes.Controlling moisture≤3.5% is dry terminal.Metformin hydrochloride particle is made with 20 mesh screen whole grains in material.
Preparation process:
It is (D by partial size103.637 D5021.24 D9060.83) Tag column are net, microcrystalline cellulose 101, are crosslinked carboxylic first fibre
It ties up plain sodium, Metformin hydrochloride particle, talcum powder, superfine silica gel powder to be added to the mixer, covers simultaneously locking lid, open Multidirectional motion
Mixing machine, incorporation time are 3~5 minutes, pour out material after mixing and weigh and measure midbody particle content.Survey total mix material
Moisture (≤3.5%).
By 100% equivalent tabletting slice weight range, using single-punch tablet press tabletting, special-shaped punch die tabletting.Quality measurement, packaging
To obtain the final product.
Embodiment 3
The present embodiment be used to illustrate Tag column of the invention only with metformin hydrochloride medicinal composition and preparation method thereof,
It is specific that details are as follows: specification 5mg/500mg
Preparation process:
The Metformin hydrochloride of recipe quantity and polyvinylpyrrolidone are crossed into 80 meshes respectively, then put into wet granulator material
It is 5~10 minutes dry-mixed with speed (stirring 480rpm, shearing 500rpm) in storehouse.Suitable 50% ethanol water is added, with speed
(stirring 480rpm, shearing 500rpm) wet granular processed 3~5 minutes.Wet granular oscillating granulator is pelletized through 20 mesh screens.It is whole
Wet granular pours into the fluidizing fluid-bed machine of Glatt after grain, in 50~60 DEG C of inlet air temperature, 50 DEG C of temperature of charge or so, drying time
About 8~14 minutes.Controlling moisture≤3.5% is dry terminal.Metformin hydrochloride is made with 20 mesh screen whole grains in material
Grain.
Preparation process:
It is (D by partial size102.405 D5016.38 D9055.96) Tag column are net, calcium monohydrogen phosphate, microcrystalline cellulose 102,
Crospovidone, Metformin hydrochloride particle, talcum powder, magnesium stearate are added to the mixer, and cover and locking lid, unlatching are multidirectional
Movement mixer, incorporation time are 3~5 minutes, pour out material after mixing and weigh and measure midbody particle content.Survey total mix
The moisture (≤3.5%) of material.
By 100% equivalent tabletting slice weight range, using single-punch tablet press tabletting, special-shaped punch die tabletting.Quality measurement, packaging
To obtain the final product.
Embodiment 4
The present embodiment be used to illustrate Tag column of the invention only with metformin hydrochloride medicinal composition and preparation method thereof,
It is specific that details are as follows: specification 10mg/500mg
Preparation process:
The Metformin hydrochloride of recipe quantity and hydroxypropylcellulose are crossed into 80 meshes respectively, then put into wet granulator feed bin
In, it is 5~10 minutes dry-mixed with speed (stirring 480rpm, shearing 500rpm).Suitable 50% ethanol water is added, (is stirred with speed
Mix 480rpm, shearing 500rpm) wet granular processed 3~5 minutes.Wet granular oscillating granulator is pelletized through 20 mesh screens.Whole grain
Wet granular pours into the fluidizing fluid-bed machine of Glatt afterwards, in 50~60 DEG C of inlet air temperature, 50 DEG C of temperature of charge or so, drying time about 8
~14 minutes.Controlling moisture≤3.5% is dry terminal.Metformin hydrochloride particle is made with 20 mesh screen whole grains in material.
Preparation process:
It is (D by partial size102.468 D5021.51 D9057.23) Tag column are net, optimization microcrystalline cellulose, are crosslinked carboxylic first
Sodium cellulosate, Metformin hydrochloride particle, talcum powder, calcium stearate are added to the mixer, and are covered simultaneously locking lid, are opened multidirectional fortune
Dynamic mixing machine, incorporation time are 3~5 minutes, pour out material after mixing and weigh and measure midbody particle content.Survey total mixture
The moisture (≤3.5%) of material.
By 100% equivalent tabletting slice weight range, using single-punch tablet press tabletting, special-shaped punch die tabletting.Quality measurement, packaging
To obtain the final product.
Embodiment 5
The present embodiment be used to illustrate Tag column of the invention only with metformin hydrochloride medicinal composition and preparation method thereof,
It is specific that details are as follows: specification 5mg/850mg
Preparation process:
The Metformin hydrochloride of recipe quantity and polyvinylpyrrolidone, hydroxypropylcellulose are crossed into 80 meshes respectively, then put into
It is 5~10 minutes dry-mixed with speed (stirring 550rpm, shearing 600rpm) in wet granulator feed bin.Suitable 50% second is added
Alcohol water, with speed (stirring 550rpm, shearing 600rpm) wet granular processed 3~5 minutes.Wet granular oscillating granulator is through 20 mesh
Sieve granulation.Wet granular pours into the fluidizing fluid-bed machine of Glatt after whole grain, in 50~60 DEG C of inlet air temperature, 50 DEG C of left sides of temperature of charge
The right side, drying time about 8~14 minutes.Controlling moisture≤3.5% is dry terminal.Salt is made with 20 mesh screen whole grains in material
Sour melbine particle.
Preparation process:
It is (D by partial size102.876 D5016.67 D9053.75) Tag column are net, microcrystalline cellulose 102, are crosslinked poly- dimension
Ketone, Metformin hydrochloride particle, talcum powder, silica, magnesium stearate are added to the mixer, and cover and locking lid, unlatching are more
To movement mixer, incorporation time is 3~5 minutes, pours out material after mixing and weighs and measures midbody particle content.It surveys total
The moisture (≤3.5%) of mixed material.
By 100% equivalent tabletting slice weight range, using single-punch tablet press tabletting, special-shaped punch die tabletting.Quality measurement, packaging
To obtain the final product.
Embodiment 6
The present embodiment be used to illustrate Tag column of the invention only with metformin hydrochloride medicinal composition and preparation method thereof,
It is specific that details are as follows: specification 5mg/1000mg
Preparation process:
The Metformin hydrochloride of recipe quantity and polyvinylpyrrolidone, hydroxypropyl methylcellulose are crossed into 80 meshes respectively, then thrown
Enter in wet granulator feed bin, it is 5~10 minutes dry-mixed with speed (stirring 550rpm, shearing 600rpm).It is added suitable 50%
Ethanol water, with speed (stirring 550rpm, shearing 600rpm) wet granular processed 3~5 minutes.Wet granular oscillating granulator is through 20
Mesh screen granulation.Wet granular pours into the fluidizing fluid-bed machine of Glatt after whole grain, in 50~60 DEG C of inlet air temperature, 50 DEG C of temperature of charge
Left and right, drying time about 8~14 minutes.Controlling moisture≤3.5% is dry terminal.Material is made with 20 mesh screen whole grains
Metformin hydrochloride particle.
Preparation process:
It is (D by partial size102.468 D5021.51 D9057.23) Tag column are net, microcrystalline cellulose 101, are crosslinked poly- dimension
Ketone, Metformin hydrochloride particle, talcum powder, superfine silica gel powder, magnesium stearate are added to the mixer, and cover and locking lid, unlatching are more
To movement mixer, incorporation time is 3~5 minutes, pours out material after mixing and weighs and measures midbody particle content.It surveys total
The moisture (≤3.5%) of mixed material.
By 100% equivalent tabletting slice weight range, using single-punch tablet press tabletting, special-shaped punch die tabletting.Quality measurement, packaging
To obtain the final product.
Embodiment 7
The present embodiment be used to illustrate Tag column of the invention only with metformin hydrochloride medicinal composition and preparation method thereof,
It is specific that details are as follows: specification 5mg/250mg
Preparation process:
The Metformin hydrochloride of recipe quantity and hydroxypropyl cellulose are crossed into 80 meshes respectively, then put into wet granulator feed bin
In, it is 5~10 minutes dry-mixed with speed (stirring 480rpm, shearing 500rpm).Suitable 30% ethanol water is added, (is stirred with speed
Mix 480rpm, shearing 500rpm) wet granular processed 3~5 minutes.Wet granular oscillating granulator is pelletized through 20 mesh screens.Whole grain
Wet granular pours into the fluidizing fluid-bed machine of Glatt afterwards, in 50~60 DEG C of inlet air temperature, 50 DEG C of temperature of charge or so, drying time about 8
~14 minutes.Controlling moisture≤3.5% is dry terminal.Metformin hydrochloride particle is made with 20 mesh screen whole grains in material.
Preparation process:
It is (D by partial size102.876 D5016.67 D9053.75) Tag arranges net, lactose, cross-linked carboxymethyl cellulose sodium, hydrochloric acid
Melbine particle, talcum powder, magnesium stearate are added to the mixer, and cover and locking lid, unlatching Mixers with Multi-direction Movement mix
Time is 3~5 minutes, pours out material after mixing and weighs and measures midbody particle content.Survey total mix material moisture (≤
3.5%).
By 100% equivalent capsule quality, filled, packed using No. 1 stomach dissolution type capsule to obtain the final product.
Embodiment 8
Tag in 7 prescription of embodiment is arranged into the raw material that net partial size selects D90 > 70 μm, i.e. D106.076 D5026.45,
D9085.23, remaining formulation and technology is the same as embodiment 7.
Embodiment 9
The present embodiment uses preparation method of the invention to prepare the Tag that specification is 10mg/250mg and arranges only and hydrochloride
Biguanide drug composition, specific details are as follows:
Preparation process:
The Metformin hydrochloride of recipe quantity and hydroxypropyl cellulose are crossed into 80 meshes respectively, then put into wet granulator feed bin
In, it is 5~10 minutes dry-mixed with speed (stirring 480rpm, shearing 500rpm).Suitable 30% ethanol water is added, (is stirred with speed
Mix 480rpm, shearing 500rpm) wet granular processed 3~5 minutes.Wet granular oscillating granulator is pelletized through 20 mesh screens.Whole grain
Wet granular pours into the fluidizing fluid-bed machine of Glatt afterwards, in 50~60 DEG C of inlet air temperature, 50 DEG C of temperature of charge or so, drying time about 8
~14 minutes.Controlling moisture≤3.5% is dry terminal.Metformin hydrochloride particle is made with 20 mesh screen whole grains in material.
Preparation process:
It is (D by partial size103.637 D5021.24 D9060.83) Tag arranges net, lactose, cross-linked carboxymethyl cellulose sodium, salt
Sour melbine particle, talcum powder, magnesium stearate are added to the mixer, and cover and locking lid, unlatching Mixers with Multi-direction Movement mix
Closing the time is 3~5 minutes, pours out material after mixing and weighs and measures midbody particle content.Survey total mix material moisture (≤
3.5%).
By 100% equivalent capsule quality, filled, packed using No. 1 stomach dissolution type capsule to obtain the final product.
Embodiment 10
Tag in embodiment 3 is arranged into net raw material particle size and is changed to larger D106.076 D5026.45 D9085.23 other places
Side and technique are the same as embodiment 3.
Embodiment 11
Dissolubility measurement result of the Tag column only in different solutions and different pH buffer shows: this product is in first
It is dissolved in alcohol, acetonitrile, ethyl alcohol or ethyl acetate, it is almost insoluble in water or 0.1mol/L sodium hydroxide solution, and this product dissolves
Property there is no pH rely on.It is specific as follows:
1 Tag of table arranges the dissolubility in different solutions (25 DEG C) only
| Solvent | Solubility (mg/ml) | Dissolubility |
| Methanol | 83.17 | Dissolution |
| Ethyl alcohol | 83.50 | Dissolution |
| Acetonitrile | 100.2 | Dissolution |
| Ethyl acetate | 99.90 | Dissolution |
| Water | 0.06 | It is almost insoluble |
| 0.1mol/L sodium hydroxide | 0.05 | It is almost insoluble |
2 Tag of table arranges the dissolubility in different pH buffer (25 DEG C) only
Embodiment 12
The determination of physical appearance of particle and tablet of the present invention
The particle and tablet of above-described embodiment 1-10 are taken, mobility of particle, tablet hardness, friability test are carried out
Mobility of particle moisture, (angle of repose), heap density, tap density, the measurement result of tablet hardness, friability are seen below
Table:
Embodiment 1-10 granular powder is almost the same, and it is encapsulated to be appropriate for tabletting according to Ka Ershi law.
Embodiment 13
Net combination with metformin object is arranged to the Tag of embodiment 1-10 preparation, related substance-measuring has been carried out, with independent Thailand
Lattice column are net or Metformin hydrochloride is compared, as a result as follows:
The testing conditions of HPLC method:
Tag arranges net HPLC condition: using octadecylsilane key and silica gel (such as Waters Symmetry C18,150mm
× 4.6mm, 5 μm) it is filler；Mobile phase A is acetonitrile-water (42:58), and Mobile phase B is acetonitrile, and flow velocity is 1.0mL per minute,
According to the form below carries out linear gradient elution；Column temperature is 35 DEG C；Detection wavelength is 210nm.20 μ L of contrast solution is taken to inject liquid chromatogram
Instrument, precision measure test solution, contrast solution and each 20 μ l of system suitability solution, inject liquid chromatograph, record chromatography
Figure wavelength: 210nm；Column temperature: 30~35 DEG C；Chromatographic column: chiral separation column 150mm × 4.6mm, 5 μm
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 100 | 0 |
| 11 | 100 | 0 |
| 40 | 8.6 | 91.4 |
| 50 | 8.6 | 91.4 |
| 51 | 100 | 0 |
| 60 | 100 | 0 |
The HPLC condition of Metformin hydrochloride: mobile phase: 1.7% ammonium dihydrogen phosphate is (extremely with phosphorus acid for adjusting pH value
3.0)；Flow velocity: 1mL/min；Wavelength: 218nm；Column temperature: 30~35 DEG C；Chromatographic column: bonded silica gel is exchanged with sulfonic group cation
For filler, UltimateXB-SCX C184.6mm × 250mm, 5 μm, 10 μ l of sample introduction.It is compareed by impurity of dicyandiamide, external standard
Method calculates.With specific reference to Chinese Pharmacopoeia 2015 editions two, measured under Metformin hydrochloride item.
Testing result is shown in Table 3~4.
The different embodiment Tag column of table 3 are only related substance-measuring result (normalization method)
The related substance-measuring result of the different embodiment Metformin hydrochlorides of table 4
The Tag that Fig. 8~Figure 27 respectively illustrates in the embodiment of the present invention 1~10 arranges net melbine pharmaceutical composition
Tag arranges net, the related substance-measuring map of Metformin hydrochloride；Figure 28~Figure 30 respectively illustrates the net related substance of Tag column and surveys
Determine the related substance-measuring map of map, Metformin hydrochloride and dicyandiamide reference substance measurement HPLC map.
The results showed that Tag column are net in each embodiment after being prepared into compound preparation and Metformin hydrochloride and folk prescription
Compare related substance known impurities and total miscellaneous have no obviously increases.
Embodiment 14
1,2,3,4,5,6,10 tablet of Example carries out dissolution determination
It measures chromatographic condition: shining high performance liquid chromatography, be packed column with octadecyl silane, methanol-water (80:
It 20) is mobile phase, Detection wavelength 222nm takes test solution and control solution to distinguish 20 μ l of sample introduction, and number of theoretical plate presses Tag
Column net calculation is not less than 3000.
Dissolution determination method:
This product is taken, according to dissolution method (2015 editions four general rules, 0,931 second methods of Chinese Pharmacopoeia), with 900ml's
0.1mol/L hydrochloric acid solution is dissolution medium, and paddle method revolving speed is 50rpm, is operated according to methods, when through 5,10,15,30,45,60 minutes,
It takes solution to filter, takes subsequent filtrate to arrange net test solution as Tag, while adding the isometric dissolution medium of equality of temperature；Separately take Tag
Net reference substance about 14mg is arranged, it is accurately weighed, it sets in 100ml volumetric flask, adds methanol to dissolve and be diluted to scale, shake up, precision is moved
It takes 2ml to set in 25ml volumetric flask, adds 0.1mol/L hydrochloric acid solution to be diluted to scale, shake up, as reference substance solution.According to efficient liquid
Phase chromatography (2015 editions four general rules 0512 of Chinese Pharmacopoeia) measurement takes each 20 μ l injection of test solution, reference substance solution high
Effect liquid phase chromatogram instrument records chromatogram, calculates according to external standard method.
Another precision pipettes test solution, and the dilution of 0.1mol/L hydrochloric acid solution is added to be configured in every 1ml make containing about 11.2 μ g
For the test solution of Metformin hydrochloride, it is appropriate that another precision weighs Metformin hydrochloride reference substance, molten with 0.1mol/L hydrochloric acid
Mother liquor is made in liquid dissolution, then is quantitatively diluted using 0.1mol/L hydrochloric acid and solution in every 1ml containing about 11.2 μ g is made as reference substance
Solution.It is measured according to ultraviolet spectrophotometry (2015 editions four general rules 0401 of Chinese Pharmacopoeia), takes test solution, reference substance solution
Absorption value is measured respectively, is calculated according to external standard method.
The different embodiment Tags of table 5 arrange the full dissolution curve measurement of net diformin tablet and compare (Tag column are net)
The different embodiment Tags of table 6 arrange the full dissolution curve measurement of net diformin tablet and compare (Metformin hydrochloride)
The Tag that Fig. 4 shows in the embodiment of the present invention 1,2,3,4,5,6,10 arranges the Thailand of net melbine pharmaceutical composition
Lattice arrange net dissolution determination curve；Fig. 5 shows the Tag in the embodiment of the present invention 1,2,3,4,5,6,10 and arranges net melbine
The Metformin hydrochloride dissolution determination curve of pharmaceutical composition.
The results showed that the net partial size difference dissolution rate of Tag column is variant in each embodiment after being prepared into compound preparation,
Metformin hydrochloride dissolution curve in 0.1mol/L hydrochloric acid solution is very fast, dissolves out no difference entirely substantially, shows that Tag column are net
It is reasonable with the pharmaceutical composition formulation and technology of Metformin hydrochloride.
Embodiment 15
7,8,9 capsule of Example compares Tag and arranges net different-grain diameter dissolution determination result.
It measures chromatographic condition: shining high performance liquid chromatography, be packed column with octadecyl silane, methanol-water (80:
It 20) is mobile phase, Detection wavelength 222nm takes test solution and control solution to distinguish 20 μ l of sample introduction, and number of theoretical plate presses Tag
Column net calculation is not less than 3000.
Dissolution determination method:
This product is taken, according to dissolution method (2015 editions four general rules, 0,931 first methods of Chinese Pharmacopoeia), with 900ml's
0.1mol/L hydrochloric acid solution is dissolution medium, and basket method revolving speed is 50rpm, is operated according to methods, when through 5,10,15,30,45,60 minutes,
It takes solution to filter, takes subsequent filtrate to arrange net test solution as Tag, while adding the isometric dissolution medium of equality of temperature；Separately take Tag
Net reference substance about 14mg is arranged, it is accurately weighed, it sets in 100ml volumetric flask, adds methanol to dissolve and be diluted to scale, shake up, precision is moved
It takes 2ml to set in 25ml volumetric flask, adds 0.1mol/L hydrochloric acid solution to be diluted to scale, shake up, as reference substance solution.According to efficient liquid
Phase chromatography (2015 editions four general rules 0512 of Chinese Pharmacopoeia) measurement takes each 20 μ l injection of test solution, reference substance solution high
Effect liquid phase chromatogram instrument records chromatogram, calculates according to external standard method.
7 different-grain diameter Tag of table arranges the full dissolution curve measurement of net melbine capsule and compares (Tag column are net)
8 different-grain diameter Tag of table arranges the full dissolution curve measurement of net melbine capsule and compares (Metformin hydrochloride)
The Tag that Fig. 6 shows 7,8,9 different-grain diameter of the embodiment of the present invention arranges the Tag of net melbine pharmaceutical composition
Net dissolution determination curve is arranged to compare；The Tag that Fig. 7 shows 7,8,9 different-grain diameter of the embodiment of the present invention arranges net melbine medicine
The Metformin hydrochloride dissolution determination curve of compositions compares.
The results showed that Tag arranges, net partial size is different, and dissolution results have certain difference, to melbine dissolution rate
Do not influence.8 Tag of embodiment arranges only in 60 minutes dissolution rates less than 90%, cannot dissolve out entirely, therefore the net control partial size of Tag column
For D10≤5 μm, D50≤25 μm, D90≤70 μm, preferably D10≤3 μm, D50≤20 μm, D90≤55 μm, so as to guarantee
The mixing homogeneity of two kinds of active components and the mobility of particle guarantee full Dissolution profiles at 30 minutes >=75%, 60 point
Clock >=90%, so as to ensure that body absorption is preferable.
Embodiment 16
Tag arranges net granularity and determination of particle size distribution (four general rules of Chinese Pharmacopoeia version in 2015,0982 third method) detection.
(1) instrument: BT-9300HT type laser fineness gage (Baite Instrument Co., Ltd., Dandong)
(2) sample source: self-control sample
(3) test method
Sample preparation: taking Tag to arrange, net bulk pharmaceutical chemicals are appropriate, are diluted with water to the suspension that concentration is 0.5g/100ml, stirring
It is allowed to be uniformly dispersed, it is to be measured.
Measuring method: distilled water is added into detection cell, ultrasonic circulation 1 minute, correcting background was added suitable into detection cell
Sample solution is measured, when shading rate being made to be about 20%, measures size distribution.
9 Tag of table arranges net each batch bulk pharmaceutical chemicals particle diameter distribution
Comprehensively consider raw material granularity inner quality standard are as follows: partial size D10≤5 μm, D50≤25 μm, D90≤70 μm can be protected
The quality of card preparation meets regulation.Preferable particle size D10≤3 μm, D50≤20 μm, D90≤55 μm.
Embodiment 17The measurement of sugar tolerance in rat body
One, experimental material:
1. sample: embodiment 2,3,4,5,6,9, portfolio ratio is respectively 5mg/250mg, 5mg/500mg, 10mg/
500mg、5mg/850mg、5mg/1000mg、10mg/250mg
2. animal: rat, male, weight 200-220g
3. reagent: glucose
4. instrument: blood glucose meter
Experimental method:
Rat Fast 16 hours, fasting blood-glucose is measured, is grouped at random according to fasting blood-glucose, every group 4 (first every group 3
Only), oral administration, Tag arrange net group, Metformin hydrochloride group, 2,3,4,5,6,9 groups of embodiment, dosage is respectively 5,
250,5+250,5+500,10+500,5+850,5+1000,10+250mg/kg oral give glucose in 0.5 hour after medicine
4.5g/kg, to 0.5 hour measurement each group rat blood sugar value after sugar, calculating each administration group rat reduces the inhibiting rate of blood glucose, calculates
Each prescription group and Tag arrange net and Metformin hydrochloride group blood glucose inhibiting rate ratio, judge blood sugar reducing function feelings after each prescription administration
Condition.
The measurement result of sugar tolerance in 10 rat body of table
The results showed that each embodiment is as follows to the sequence of normal rat glucose tolerance action intensity: 5 ﹥ of embodiment is real
Apply 6 ﹥ embodiment of example 3 ﹥ embodiment, 4 ﹥ embodiment, 2 ﹥ embodiment 9.Unexpectedly, embodiment 9 compared with Example 2, hydrochloric acid two
The dosage of first biguanides is identical, and Tag, which arranges net dosage, increases to 10mg by 5mg, but blood glucose inhibitory effect substantially reduces；And it is real
Apply example 4 compared with Example 9, Tag arranges that net dosage is identical, and the amount of Metformin hydrochloride increases to 500mg, blood glucose by 250mg
Inhibitory effect then greatly improves.It can be seen that Tag column compare blood with matching for Metformin hydrochloride only in the pharmaceutical composition
Glyco inhabiting influential effect is larger.Through further research, it has been found that when Tag column only with Metformin hydrochloride mass ratio be 1:50~
When 200, there is the apparent synergy for inhibiting blood glucose；It is preferred that Tag column only with the mass ratio of Metformin hydrochloride be 1:50~
170.It is 5mg~10mg that Tag, which arranges net preferable amount, and the preferable amount of Metformin hydrochloride is 500mg~850mg.
Claims (10)
1. a kind of for treating the pharmaceutical composition of diabetes, it includes Tags to arrange net and Metformin hydrochloride, wherein the Thailand
Lattice column are only 1:50~200 with the mass ratio of Metformin hydrochloride.
2. pharmaceutical composition according to claim 1, which is characterized in that Tag column only with the matter of Metformin hydrochloride
Amount is than being 1:50~170.
3. pharmaceutical composition according to claim 1 or 2, which is characterized in that in per unit preparation, the Tag arranges net
Content is 2.5mg~20mg, preferably 2.5mg~10mg, most preferably 5mg~10mg；The Metformin hydrochloride content is
250mg~1000mg, preferably 500mg~1000mg, most preferably 500mg~850mg.
4. pharmaceutical composition described in any one of claim 1 to 3, which is characterized in that described pharmaceutical composition is mouth
Formulation, such as tablet, capsule；Preferably, the oral preparation be by include first by Metformin hydrochloride with pharmaceutically
Acceptable auxiliary material obtains Metformin hydrochloride particle after pelletizing together, then the Metformin hydrochloride particle and Tag are arranged only
It is made with method the step of other pharmaceutically acceptable auxiliary material mixing.
5. pharmaceutical composition according to claim 4, which is characterized in that the pharmaceutically acceptable auxiliary material is selected from filling
One of agent, disintegrating agent, adhesive and lubricant are a variety of.
6. pharmaceutical composition according to claim 5, which is characterized in that the filler is selected from microcrystalline cellulose, optimization
One of microcrystalline cellulose and calcium monohydrogen phosphate are a variety of；The disintegrating agent is selected from crospovidone, cross-linked carboxymethyl cellulose
One of sodium, calcium carboxymethylcellulose and low-substituted hydroxypropyl cellulose are a variety of；Described adhesive be selected from hydroxypropylcellulose,
One of povidone and hydroxypropyl methylcellulose are a variety of；And/or the lubricant is selected from magnesium stearate, calcium stearate, behenyl
One of acid glyceride, sodium stearyl fumarate, silica, superfine silica gel powder and talcum powder are a variety of.
7. a kind of method for being used to prepare pharmaceutical composition according to any one of claim 1 to 6, including following step
It is rapid:
(1) Metformin hydrochloride is mixed with pharmaceutically acceptable auxiliary material, and particle is prepared by wet granulation technology, i.e.,
Obtain Metformin hydrochloride particle；
(2) the pharmaceutically acceptable auxiliary material that Metformin hydrochloride particle obtained in step (1) and Tag column is net and other
It is uniformly mixed, described pharmaceutical composition is made.
8. the method according to the description of claim 7 is characterized in that the wet granulation technology is bulk drug of pretreatment adds with interior granulating process
And/or fluidized-bed process.
9. pharmaceutical composition according to claim 7, which is characterized in that the partial size of the Metformin hydrochloride particle is
D90≤180μm；And/or before mixing the Tag arrange net partial size be D10≤5 μm, D50≤25 μm, D90≤70 μm, preferably
D10≤3 μm, D50≤20 μm, D90≤55 μm.
10. pharmaceutical composition according to any one of claims 1 to 6 is in preparing the drug for treating type-2 diabetes mellitus
Purposes.
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