CN106727554A - Pharmaceutical composition containing Repaglinide and Metformin hydrochloride and preparation method thereof - Google Patents
Pharmaceutical composition containing Repaglinide and Metformin hydrochloride and preparation method thereof Download PDFInfo
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- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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Abstract
The invention discloses a kind of Pharmaceutical composition containing Repaglinide and Metformin hydrochloride and preparation method thereof, it is made up of Repaglinide, Metformin hydrochloride, meglumine, PVP K30, microcrystalline cellulose, sorbierite, sodium carboxymethyl starch and/or Ac-Di-Sol, magnesium stearate；Wherein microcrystalline cellulose preferably is selected from microcrystalline cellulose PH101.Component is few in the pharmaceutical composition, wide material sources, preparation is simple, and can produce fixed dosage, meet marketing drugs standard, the Pharmaceutical composition with good bioavilability, especially Repaglinide melbine Compound Tablet, while avoiding the defect of prior art.
Description
Technical field
The present invention relates to a kind of Pharmaceutical composition containing Repaglinide and Metformin hydrochloride and preparation method thereof, specifically
Say and be related to two kinds for diet control, lose weight and motion exercise can not effectively control the diabetes B of its hyperglycaemia（Non- pancreas
Island element dependent form）The active constituents of medicine of patient：Medicine group after Repaglinide and Metformin hydrochloride, with certain auxiliary material combination
The prescription and preparation method of compound, particularly tablet.
Background technology
2 patients with type Ⅰ DM are one group
The metabolic disease of principal character, the great public health problem as serious threat human health in recent decades.With warp
Ji fast development, the raising of the average life span and living-pattern preservation, the illness rate of diabetes are worldwide significantly carried
It is high.(http is counted according to IDF (International DiabetesFederation, IDF)://
Www.diabetesatlas.org/resources/2015-atlas.html), the whole world in 2015 there are about diabetic
4.15 hundred million, it is contemplated that be up to 6.42 hundred million within 2040.
Metformin hydrochloride has been listed for many years in the whole world, from China's diabetes B guideline of prevention and treatment and the types of AACE/ACE 2
As can be seen that it is using melbine as line first-selection medication in the recommendation of the big guide of diabetes integrated management scheme two.And
Repaglinide is developed by Novo Nordisk Co., Ltd, and non-sulfonylureas oral insulin promotees to secrete agent.As single therapy, for non-pancreas
Island element dependent diabetes（Diabetes B）Patient aids in diet and motion to improve glycemic control.In Japan, the product is also used
In with the OHA drug combination in addition to sulfonylureas and insulin preparation.
Current diabetes B patient using only a kind of OHA, it is difficult to by glycemic control to perfect condition.It is clinical
On, Patients' rights blood sugar is helped using the OHA drug combination of different mechanism of action more.And Repaglinide and hydrochloric acid
The drug combination of melbine has become classical scheme.But being used in combination for OHA of two kinds and the above may
Cause patient's compliance bad and medicine miss, the problem of wrong clothes.For diabetes B patient, problem above will all cause
Blood glucose fluctuation in patient's body, and then body is made a very bad impression.
Therefore consider to combine Repaglinide with Metformin hydrochloride the composition to form fixed dosage（Compound preparation）, come
Evade above risk.But, in Clinical practice, the single taking dose of Metformin hydrochloride is larger, about Repaglinide
250 ~ 500 times of single taking dose.Therefore to face Repaglinide dosage small for the preparation of said composition, poorly water-soluble and big agent
The Metformin hydrochloride combination of amount is difficult to ensure that its content uniformity；Metformin hydrochloride specification is big, poor fluidity, in crystallization
Type, is unfavorable for the final form of preparation；Repaglinide itself dissolution rate is poor, and after Metformin hydrochloride combination, how to realize closing
The dissolution rate of lattice, curve, and then good vivo biodistribution availability is formed, all it is the content for needing high spot reviews.
Repaglinide melbine Compound Tablet, Yuan Yan companies are Novo Nordisk Co., Ltd, and original has used pool Lip river husky in grinding prescription
Nurse 188 makees cosolvent and polacrilin potassium cooks disintegrant.Wherein, PLURONICS F87, fusing point is 52 DEG C ~ 57 DEG C, easily forms low common
Fusant, may change dosage form in heated drying process, tableting processes, coating process, between in turn resulting in product batch, batch
Difference is big, and quality is unstable.And polacrilin potassium, the country is without legitimate origin, it is difficult to be applied in industrialization.Meanwhile, original grinds place
Coating material includes talcum powder and polyethylene glycol in side, by auxiliary material compatibility experiments, it was demonstrated that containing talcum powder or polyethylene glycol
Coating material is bad with Repaglinide compatibility.
The domestic patent of invention about Repaglinide and Metformin hydrochloride composition also includes patent application
CN200780036006.2、CN201110190175.X、CN201110100196.8、CN201310219926.5、
CN201310312240.0 etc..Wherein, in CN201110190175.X and CN201110100196.8, by Repaglinide and salt
Sour melbine is pelletized together, because the consumption and physicochemical property of two kinds of active components have a long way to go, and Repaglinide and salt
Sour melbine is pelletized together, the relevant material rapid development of Repaglinide.Therefore it is difficult to control to product quality using the technique.
In CN201310219926.5 and CN201310312240.0, from poloxamer as solubilizer, auxiliary material compatibility experiments card
Bright poloxamer is bad with Repaglinide compatibility, easily causes the unstable of product quality.Wherein, CN201310219926.5
In, adhesive is contained in Repaglinide particle and is needed further that Repaglinide particulate abrasive is thin less than 80 purposes into granularity
Powder, improves equipment requirement, increased technology difficulty and control point, easily causes loss of material.
The content of the invention
In order to solve drawbacks described above of the prior art, Repaglinide and Metformin hydrochloride are contained the invention provides one kind
Pharmaceutical composition and preparation method thereof, component is few in the pharmaceutical composition, wide material sources, and preparation is simple, and
Fixed dosage can be produced, meet marketing drugs standard, the Pharmaceutical composition with good bioavilability, it is especially auspicious
Ge Lienai melbine Compound Tablets.Compared with existing composition and preparation method, the progress with highly significant.
The invention aims to provide a kind of Pharmaceutical composition containing Repaglinide and Metformin hydrochloride, wherein,
Pharmaceutical composition containing Repaglinide and Metformin hydrochloride, by Repaglinide, Metformin hydrochloride, meglumine, PVP
K30, microcrystalline cellulose, sorbierite, sodium carboxymethyl starch and/or Ac-Di-Sol, magnesium stearate composition；It is wherein micro-
Crystalline cellulose preferably is selected from microcrystalline cellulose PH101.
Preferably, in the above-mentioned Pharmaceutical composition containing Repaglinide and Metformin hydrochloride, containing 1 ~ 4 part of Repaglinide, salt
500 parts of sour melbine, 0.5 ~ 12 part of meglumine, 1 ~ 30 part of PVP K30,10 ~ 100 parts of microcrystalline cellulose, sorbierite 1 ~ 60
Part, sodium carboxymethyl starch and/or 5 ~ 40 parts of Ac-Di-Sol, 3 ~ 12 parts of magnesium stearate.
The present invention has the advantages that prescription element is few, big in Metformin hydrochloride dosage（500mg/ pieces）Premise
Under, supplementary product kind and usage amount are reduced, solve that Repaglinide melbine Compound Tablet piece weight is too high, asking of being difficult to take
Topic.
Preferably, Repaglinide and Metformin hydrochloride are respectively prepared Repaglinide particle and Metformin hydrochloride particle,
By Repaglinide particle and Metformin hydrochloride particle and sodium carboxymethyl starch and/or Ac-Di-Sol, stearic acid
Tablet is made after magnesium mixing；Wherein Repaglinide particle is made up of Repaglinide, meglumine, microcrystalline cellulose, sorbierite；Hydrochloric acid
Melbine particle is made up of Metformin hydrochloride, PVP K30, microcrystalline cellulose.
Above-mentioned composition avoids the consumption and physicochemical property of Repaglinide and Metformin hydrochloride two kinds of active components, molten
Out-degree etc. has a long way to go, and is pelletized together usually using Repaglinide and Metformin hydrochloride, and the relevant material of Repaglinide increases
Rapid defect.
It is well known that Repaglinide is water-soluble poor, and the key factor for increasing internal dissolution rate be dissolution rate and
Dissolution total amount, generally needed to be added the methods such as solubilizer, cosolvent, improve Repaglinide dissolution rate.Repaglinide in the present invention
Particle, the solubilizer such as poloxamer are not used, and cosolvent meglumine also use only conventional amount used, and be bonded without using
Agent, only containing Repaglinide, meglumine, sorbierite and microcrystalline cellulose, supplementary product kind grinds less than original, but investigates the molten of Repaglinide
Out-degree and stripping curve grind consistent with original, and then assess it and have good vivo biodistribution availability, realize identical even better
Therapeutic effect.
Preferably, 1 ~ 4 part of Repaglinide is contained in Repaglinide particle；0.5 ~ 12 part of meglumine, 5 ~ 50 parts of microcrystalline cellulose,
1 ~ 60 part of sorbierite, wherein sorbitol particle size are less than 250 μm.
Preferably, 500 parts of hydrochloric melbine, 1 ~ 30 part of PVP K30, crystallite are fine in Metformin hydrochloride particle
5 ~ 50 parts of dimension element；Wherein Metformin hydrochloride granularity is less than 250 μm.
Preferably, Repaglinide particle and Metformin hydrochloride particle are fine with sodium carboxymethyl starch and/or cross-linked carboxymethyl
Compressing tablet, coating after plain 5 ~ 40 parts of the sodium of dimension, 3 ~ 12 parts of mixing of magnesium stearate.
Metformin hydrochloride particle in the present invention, few using supplementary product kind, pioneering ground consumption is much smaller than main ingredient, reduces
The weight of final composition.The granularity of Metformin hydrochloride is controlled simultaneously, it is possible to reduce Metformin hydrochloride is in itself（Crystal type powder
End）Influence to tableting processes and the final form of preparation, is conducive to the content uniformity of product.
The invention provides a kind of preparation method of the Pharmaceutical composition containing Repaglinide and Metformin hydrochloride, the preparation
Method is comprised the following steps：
（1）Weigh：Weigh each former, auxiliary material respectively by recipe quantity；
（2）Repaglinide and meglumine are configured into solution to be added in the material being well mixed；
（3）Mixing, granulation；（4）Wet whole grain；（5）Dry；（6）Dry whole grain；
（7）It is mixed eventually：The material that sodium carboxymethyl starch and/or Ac-Di-Sol, magnesium stearate are added to preparation is mixed
Close uniform；
（8）Compressing tablet；
（9）It is coated：Coating weight gain 2 ~ 4%.
Present invention also offers the preparation method of Pharmaceutical composition of the another kind containing Repaglinide and Metformin hydrochloride, should
Preparation method is comprised the following steps：
（1）Material pre-treatment：Metformin hydrochloride, sorbierite are crushed respectively, 60 ~ 80 mesh sieves are crossed；
（2）Weigh：Each former, auxiliary material of ormal weight is weighed respectively；
（3）Repaglinide particle preparation
1. drug solns are carried to prepare
Meglumine is added to the water, is stirred to dissolve, Repaglinide is added in ethanol, stirring makes uniformly, by meglumine
The aqueous solution is added in Repaglinide ethanol solution, and stirring makes uniform；
2. mix, pelletize
Microcrystalline cellulose, sorbierite are added in wet mixing pelletizer respectively, are stirred；Add and carry drug solns；Granulation；
3. wet whole grain；4. the particle after wet whole grain is dried；5. dry whole grain is carried out to dried particle；
（4）Metformin hydrochloride particle preparation
1. prepared by adhesive
Add water in ethanol, stirring makes uniformly, to be configured to 50 ~ 70% w/w ethanol solutions, standby；By PVP under stirring
K30 is added in 50 ~ 70% w/w ethanol solutions, and stirring makes uniform;
2. mix, pelletize
Metformin hydrochloride, microcrystalline cellulose are added in wet mixing pelletizer respectively, are stirred；Plus adhesive；Granulation；
3. wet whole grain；4. the particle after wet whole grain is dried；5. dry whole grain is carried out to dried particle；
（5）It is total mixed
1. mixed in：By Repaglinide particle, Metformin hydrochloride particle, sodium carboxymethyl starch and/or cross-linked carboxymethyl cellulose
Sodium is well mixed；
2. it is mixed eventually：Magnesium stearate is added to be well mixed；
（6）Compressing tablet；
（7）It is coated.
The present invention carries the preparation method of drug solns in Repaglinide particulate production, solves Repaglinide water-soluble
Property it is poor, it is difficult to dissolve at normal temperatures and effectively mix with meglumine and be difficult to play the problem of meglumine hydrotropy effect.After preparation
Repaglinide particle and Metformin hydrochloride particle be mixed and made into tablet after, low dose of, dissolubility difference Repaglinide, in piece
Content is uniform in agent, and uniformity of dosage units meets medicinal requirements；The stability of tablet is high, and relevant material increasess slowly.Meanwhile, tablet
Dissolution rate and stripping curve ground with original and be consistent, degree of fitting is high, predicts that its vivo biodistribution availability grinds consistent with original.
Preferably, in step（3）In Repaglinide particle preparation, 3. step in wet whole grain, uses 10 ~ 20 mesh sieve whole grains；
4. during be dried for the particle after wet whole grain by step, 50 ~ 70 DEG C of EAT is dried to moisture below 5%；Step is 5. to dry
Particle after dry is carried out in dry whole grain, uses 30 ~ 60 mesh sieve whole grains；
In step（4）In Metformin hydrochloride particle preparation, 3. step in wet whole grain, uses 10 ~ 20 mesh sieve whole grains；4. step will
During particle after wet whole grain is dried, 20 ~ 45 DEG C of EAT is dried to moisture below 5%；Step is 5. to dried
Grain is carried out in dry whole grain, uses 30 ~ 60 mesh sieve whole grains.
In the present invention, by exploitative experiment, employed in Repaglinide particle and Metformin hydrochloride particle drying
Different EAT, it is ensured that the stabilization of granular active ingredients, relevant material are kept at low-level；In dry whole grain,
Mix after each crossing 30 ~ 60 mesh sieves, it is ensured that in follow-up total mixed and operating process of compressing tablet, Repaglinide, hydrochloride are double
Guanidine uniformly mixes, so as to reach the uniformity of dosage units requirement of Repaglinide.
Brief description of the drawings
Fig. 1 represents the relevant material HPLC of Repaglinide in the pharmaceutical composition 9 containing Repaglinide and Metformin hydrochloride
Collection of illustrative plates.
Fig. 2 represents the relevant material of Metformin hydrochloride in the pharmaceutical composition 9 containing Repaglinide and Metformin hydrochloride
HPLC collection of illustrative plates.
Fig. 3 represent in the pharmaceutical composition 9 containing Repaglinide and Metformin hydrochloride Repaglinide and melbine respectively with original
Grind the stripping curve comparison diagram of Repaglinide and melbine in PrandiMet.
Fig. 4 represents that pharmaceutical composition 9 accelerates the relevant material of the 0-6 months with Comparative composition stability（It is single miscellaneous and total miscellaneous）Data pair
Than figure
Specific embodiment
In order to the present invention is furture elucidated, a series of embodiments are given below.It is pointed out that these embodiments are complete
It is illustrative.The purpose for providing these embodiments is, in order to fully express meaning of the present invention and content, but therefore will not
Among scope of embodiments described in limiting the invention in.
Embodiment 1 ~ 4：Pharmaceutical composition 1 ~ 4 containing Repaglinide and Metformin hydrochloride
1st, the prescription of pharmaceutical composition 1 ~ 4（Table 1）
2nd, preparation method
（1）Weigh:Weigh each former, auxiliary material respectively by recipe quantity, actual weighing sees the above table.
（2）Repaglinide and meglumine are configured into solution to be added in the material being well mixed.
（3）Mixing, granulation；
（4）Wet whole grain；
（5）Dry；
（6）Dry whole grain；
（7）It is mixed eventually
The material that sodium carboxymethyl starch or Ac-Di-Sol, magnesium stearate are added to preparation is well mixed.
（8）Compressing tablet
Rushed using 16*8mm scrobiculas are special-shaped, more than hardness 8kg.
（9）It is coated
Use coating pan coating, coating weight gain 2 ~ 4%.
Comparative example：Comparative composition containing Repaglinide and Metformin hydrochloride
1st, the prescription of Comparative composition（Table 2）
2nd, preparation method
（1）Weigh:Weigh each former, auxiliary material respectively by recipe quantity, actual weighing sees the above table.
（2）Repaglinide and meglumine are configured into solution to be added in the material being well mixed.
（3）Mixing, granulation；
（4）Wet whole grain；
（5）Dry；
（6）Dry whole grain；
（7）It is mixed eventually；
The material that Ac-Di-Sol, magnesium stearate are added to preparation is well mixed.
（8）Compressing tablet
Rushed using 16*8mm scrobiculas are special-shaped, more than hardness 8kg.
（9）It is coated
Use coating pan coating, coating weight gain 4%.
Embodiment 5 ~ 8：Pharmaceutical composition 5 ~ 8 containing Repaglinide and Metformin hydrochloride
1st, the prescription of pharmaceutical composition 5 ~ 8（Table 3）
2nd, preparation method
（1）Material pre-treatment：60 and 80 mesh sieves are crossed after Metformin hydrochloride, sorbierite are crushed respectively；
（2）Weigh：Each former, auxiliary material of ormal weight is weighed respectively；
（3）Repaglinide particle preparation
1. drug solns are carried to prepare
Meglumine is added to the water, is stirred to dissolve, Repaglinide is added in ethanol, stirring makes uniformly, by meglumine
The aqueous solution is added in Repaglinide ethanol solution, and stirring makes uniform；
2. mix, pelletize
Microcrystalline cellulose, sorbierite are added in wet mixing pelletizer respectively, are stirred；Add and carry drug solns；Granulation；
3. wet whole grain：Pharmaceutical composition 5 and 7, uses 10 mesh sieve whole grains；Pharmaceutical composition 6 and 8, uses 20 mesh sieve whole grains；
4. the particle after wet whole grain is dried：50 ~ 70 DEG C of EAT, dries to moisture below 5%；
5. dry whole grain is carried out to dried particle：Pharmaceutical composition 5 and 7, uses 30 mesh sieve whole grains；Pharmaceutical composition 6 and 8,
Use 60 mesh sieve whole grains；
（4）Metformin hydrochloride particle preparation
1. prepared by adhesive
Add water in ethanol, stirring makes uniformly, to be configured to 50 ~ 70% w/w ethanol solutions, standby；By PVP under stirring
K30 is added in 50 ~ 70% w/w ethanol solutions, and stirring makes uniform.
2. mix, pelletize
Metformin hydrochloride, microcrystalline cellulose are added in wet mixing pelletizer respectively, are stirred；Plus adhesive；Granulation；
3. wet whole grain：Pharmaceutical composition 5 and 7, uses 10 mesh sieve whole grains；Pharmaceutical composition 6 and 8, uses 20 mesh sieve whole grains；
4. the particle after wet whole grain is dried：20 ~ 40 DEG C of EAT, dries to moisture below 5%；；
5. dry whole grain is carried out to dried particle：Pharmaceutical composition 5 and 7, uses 30 mesh sieve whole grains；Pharmaceutical composition 6 and 8,
Use 60 mesh sieve whole grains.
（5）It is total mixed
1. mixed in：By Repaglinide particle, Metformin hydrochloride particle, Ac-Di-Sol or sodium carboxymethyl starch
It is well mixed；
2. it is mixed eventually：Magnesium stearate is added to be well mixed；
（6）Compressing tablet；
（7）It is coated.
Testing result：By above-mentioned prescription and preparation process, the pharmaceutical composition 5-8 after preparation is satisfied by Repaglinide
The pharmaceutical requirements such as uniform content degree, Repaglinide material relevant with melbine, dissolution determination.
Embodiment 9：Pharmaceutical composition 9 containing Repaglinide and Metformin hydrochloride
1st, the prescription of pharmaceutical composition 9（Table 4）
2nd, the preparation method of pharmaceutical composition 9
（1）Material pre-treatment：Metformin hydrochloride, sorbierite are crushed respectively, 80 mesh sieves are crossed；
（2）Weigh：Each former, auxiliary material of ormal weight is weighed respectively；
（3）Repaglinide particle preparation
1. drug solns are carried to prepare
Meglumine is added to the water, is stirred to dissolve, Repaglinide is added in ethanol, stirring makes uniformly, by meglumine
The aqueous solution is added in Repaglinide ethanol solution, and stirring makes uniform；
2. mix, pelletize
Microcrystalline cellulose PH101, sorbierite are added in wet mixing pelletizer respectively, are stirred；Add and carry drug solns；Grain
Change；
3. wet whole grain：Use 20 mesh sieve whole grains；
4. the particle after wet whole grain is dried：50 ~ 70 DEG C of EAT, dries to moisture below 5%；
5. dry whole grain is carried out to dried particle：Use 40 mesh sieve whole grains.
（4）Metformin hydrochloride particle preparation
1. prepared by adhesive
Add water in ethanol, stirring makes uniformly, to be configured to 60% w/w ethanol solutions, standby；By PVP K30 under stirring
It is added in 60% w/w ethanol solutions, stirring makes uniform.
2. mix, pelletize
Metformin hydrochloride, microcrystalline cellulose are added in wet mixing pelletizer respectively, are stirred；Plus adhesive；Granulation；
3. wet whole grain：Use 20 mesh sieve whole grains；
4. the particle after wet whole grain is dried：25 ~ 45 DEG C of EAT, dries to moisture below 5%；；
5. dry whole grain is carried out to dried particle：Use 40 mesh sieve whole grains.
（5）It is total mixed
1. mixed in：Repaglinide particle, Metformin hydrochloride particle, Ac-Di-Sol, sodium carboxymethyl starch are mixed
Close uniform；
2. it is mixed eventually：Magnesium stearate is added to be well mixed；
（6）Compressing tablet；
（7）It is coated.
Embodiment 10：The detection data of the pharmaceutical composition 9 containing Repaglinide and Metformin hydrochloride
1st, the uniformity of dosage units evaluation of pharmaceutical composition 9
（1）The uniformity of dosage units data of Repaglinide（Table 5）
Remarks：Repaglinide content is extremely low in pharmaceutical composition 9, about the 0.4% of melbine content, so needs are examined
Examine the uniformity of dosage units of Repaglinide, and melbine content in pharmaceutical composition 9, more than 80%, therefore is not required to investigate its content
The uniformity.
（2）Evaluate
According to《Chinese Pharmacopoeia》（Version in 2015）4th general rule：The lower regulation of 0941 Content uniformity test：
Unless otherwise specified, test sample 10 is taken, according to the method for the lower regulation of each kind, each single dose is determined respectively to indicate
Measure the relative amount for 100, seek its averageWith standard deviation SAnd the difference of labelled amount and average
Absolute value A (A=| 100-| ) 。
If the S of A+2.2<L, then the uniformity of dosage units of test sample meet regulation；
If A+S>L, then it is against regulation；
If the S of A+2.2>L, and A+SL, then should separately take 20 retrials of test sample.
L is setting, unless otherwise specified, L=15.0 in above-mentioned formula.
Conclusion：It is extremely low in pharmaceutical composition 9 to contain from the uniformity of dosage units data of Repaglinide in pharmaceutical composition 9
The uniformity of dosage units of the active material Repaglinide of amount meets regulation.
2nd, the relevant substance data of the pharmaceutical composition 9 containing Repaglinide and Metformin hydrochloride
Table 6
Specific HPLC spectrograms are shown in accompanying drawing 1 and accompanying drawing 2.
As seen from the above table, the pharmaceutical composition 9 containing Repaglinide and Metformin hydrochloride（Embodiment 9）Examined by HPLC
Survey, relevant material meets limit regulation.
3rd, the pharmaceutical composition 9 containing Repaglinide and Metformin hydrochloride（Experiment lot number：R160107）Rui Ge is ground with original
Row how melbine Compound Tablet（PrandiMet）Vitro release correlation data
（1）Dissolution data（%）Comparative study（Table 7）
Dissolution medium is pH5.0 phosphate buffers, and composition and original grind Repaglinide and hydrochloride pair in PrandiMet
Guanidine, in the dissolution rate at each time point（%）Correction data, it is as shown in the table：
（2）Repaglinide grinds with original respectively with melbine in pharmaceutical composition 9 containing Repaglinide and Metformin hydrochloride
The stripping curve comparative study of Repaglinide and melbine in PrandiMet, as shown in Figure 3.
Conclusion：From table 7 and upper figure, the pharmaceutical composition 9 containing Repaglinide and Metformin hydrochloride（Experiment lot number：
R160107）By dissolution test, Repaglinide therein and Metformin hydrochloride dissolution data are ground with original respectively with stripping curve
Repaglinide melbine Compound Tablet（PrandiMet）Mutually it is fitted, it is seen that both release in vitro are evaluated basically identical.Predict that it has
There is good vivo biodistribution availability, realize identical even preferably therapeutic effect.
The present invention, by using different prescription and techniques are ground from original, by investigative test, developing drug content equal
Evenness, relevant material meet regulation, release in vitro evaluation and original grind it is consistent, meet medicine listing requirement, with good biology
The pharmaceutical composition of availability.
Embodiment 11：Pharmaceutical composition 9 is contrasted with the relevant substance data of Comparative composition
Pharmaceutical composition 9 and Comparative composition are put into stability test case, accelerated study on the stability, i.e.,：In temperature
40 ± 2 DEG C, place under conditions of relative humidity 75 ± 5%, be measured by sampling in 0,1,2,3,6 the end of month, investigate the relevant of Repaglinide
Material（Data are as shown in the table）, it is seen that：Comparative composition relevant material overrun when June is accelerated, increases obvious.
Table 8
Wherein, the material relevant with the Comparative composition stability acceleration 0-6 months of pharmaceutical composition 9（Single contaminant is miscellaneous with total）Data pair
Than as shown in Figure 4.
Therefore, the present invention successfully overcomes technology barriers of the prior art and defect, such as：It is right under certain condition of storage
Material rapid development more relevant than Repaglinide in composition, beyond medicinal limit, it is difficult to the problems such as clinical practice.
It should be noted that foregoing invention content and specific embodiment are intended to prove the reality of technical scheme provided by the present invention
Using should not be construed as limiting the scope of the present invention.Those skilled in the art in spirit and principles of the present invention, when
Can various modifications may be made, equivalent or improve.Protection scope of the present invention is defined by appended claims.
Claims (9)
1. a kind of Pharmaceutical composition containing Repaglinide and Metformin hydrochloride, it is characterised in that described containing Repaglinide and salt
The Pharmaceutical composition of sour melbine, by Repaglinide, Metformin hydrochloride, meglumine, PVP K30, microcrystalline cellulose, mountain
Pears alcohol, sodium carboxymethyl starch and/or Ac-Di-Sol, magnesium stearate composition；Wherein described microcrystalline cellulose is preferred
From microcrystalline cellulose PH101.
2. Pharmaceutical composition according to claim 1, it is characterised in that described containing Repaglinide and Metformin hydrochloride
In Pharmaceutical composition, containing 1 ~ 4 part of the Repaglinide, 500 parts of the Metformin hydrochloride, 0.5 ~ 12 part of the meglumine, institute
State 1 ~ 30 part of PVP K30,10 ~ 100 parts of the microcrystalline cellulose, 1 ~ 60 part of the sorbierite, the sodium carboxymethyl starch
And/or 5 ~ 40 parts of Ac-Di-Sol, 3 ~ 12 parts of the magnesium stearate.
3. Pharmaceutical composition according to claim 1, it is characterised in that the Repaglinide and the Metformin hydrochloride
Repaglinide particle and Metformin hydrochloride particle are respectively prepared, by the Repaglinide particle and the Metformin hydrochloride
Grain is made tablet after mixing with sodium carboxymethyl starch and/or Ac-Di-Sol, magnesium stearate；Qi Zhong Suo Shu Rui Gelie
How particle is made up of Repaglinide, meglumine, microcrystalline cellulose, sorbierite；The Metformin hydrochloride particle is by hydrochloride
Biguanides, PVP K30, microcrystalline cellulose composition.
4. Pharmaceutical composition according to claim 3, it is characterised in that in the Repaglinide particle, containing the auspicious lattice
Row how 1 ~ 4 part；0.5 ~ 12 part of the meglumine, 5 ~ 50 parts of the microcrystalline cellulose, 1 ~ 60 part of the sorbierite, wherein the mountain
Pears alcohol granularity is less than 250 μm.
5. Pharmaceutical composition according to claim 3, it is characterised in that in the Metformin hydrochloride particle, containing described
500 parts of Metformin hydrochloride, 1 ~ 30 part of the PVP K30,5 ~ 50 parts of the microcrystalline cellulose；Wherein described hydrochloride
Biguanides granularity is less than 250 μm.
6. Pharmaceutical composition according to claim 3, it is characterised in that the Repaglinide particle and the hydrochloride
Biguanides particle is mixed with the sodium carboxymethyl starch and/or 5 ~ 40 parts of Ac-Di-Sol, 3 ~ 12 parts of the magnesium stearate
Compressing tablet, coating after conjunction.
7. the preparation method of pharmaceutical composition according to claim 2, the preparation method is comprised the following steps：
（1）Weigh：Weigh each former, auxiliary material respectively by recipe quantity；
（2）The Repaglinide and the meglumine are configured into solution to be added in the material being well mixed；
（3）Mixing, granulation；（4）Wet whole grain；（5）Dry；（6）Dry whole grain；
（7）It is mixed eventually：The sodium carboxymethyl starch and/or Ac-Di-Sol, the magnesium stearate are added to preparation
Material be well mixed；
（8）Compressing tablet；
（9）It is coated：Coating weight gain 2 ~ 4%.
8. the preparation method of the pharmaceutical composition according to any one of claim 3 ~ 6, the preparation method includes following
Step：
（1）Material pre-treatment：The Metformin hydrochloride, the sorbierite are crushed respectively, 60 ~ 80 mesh sieves are crossed；
（2）Weigh：Each former, auxiliary material of ormal weight is weighed respectively；
（3）The preparation of the Repaglinide particle
1. drug solns are carried to prepare
The meglumine is added to the water, is stirred to dissolve, the Repaglinide is added in ethanol, stirring makes uniformly,
The aqueous megiumine solution is added in the Repaglinide ethanol solution, stirring makes uniform；
2. mix, pelletize
The microcrystalline cellulose, the sorbierite are added in wet mixing pelletizer respectively, are stirred；Add and carry drug solns；
Granulation；
3. wet whole grain；4. the particle after wet whole grain is dried；5. dry whole grain is carried out to dried particle；
（4）The preparation of the Metformin hydrochloride particle
1. prepared by adhesive
Add water in ethanol, stirring makes uniformly, to be configured to 50 ~ 70% w/w ethanol solutions, standby；Stirring is lower will be described poly-
Dimension ketone K30 is added in 50 ~ 70% w/w ethanol solutions, and stirring makes uniform；
2. mix, pelletize
The Metformin hydrochloride, the microcrystalline cellulose are added in wet mixing pelletizer respectively, are stirred；Plus bonding
Agent；Granulation；
3. wet whole grain；4. the particle after wet whole grain is dried；5. dry whole grain is carried out to dried particle；
（5）It is total mixed
1. mixed in：By the Repaglinide particle, the Metformin hydrochloride particle, the sodium carboxymethyl starch and/or crosslinking
Sodium carboxymethylcellulose is well mixed；
2. it is mixed eventually：The magnesium stearate is added to be well mixed；
（6）Compressing tablet；
（7）It is coated.
9. the preparation method of pharmaceutical composition according to claim 8, it is characterised in that in the step（3）It is described auspicious
In Ge Lienai particle preparations, 3. the step in wet whole grain, uses 10 ~ 20 mesh sieve whole grains；The step is 4. by after wet whole grain
Particle be dried, 50 ~ 70 DEG C of EAT is dried to moisture below 5%；5. the step is entered to dried particle
In the dry whole grain of row, 30 ~ 60 mesh sieve whole grains are used；
In the step（4）In the Metformin hydrochloride particle preparation, 3. the step in wet whole grain, uses 10 ~ 20 mesh sieves
Whole grain；4. during be dried for the particle after wet whole grain by the step, 20 ~ 45 DEG C of EAT is dried to moisture below 5%；
5. the step is carried out in dry whole grain to dried particle, uses 30 ~ 60 mesh sieve whole grains.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101516347A (en) * | 2006-09-29 | 2009-08-26 | 诺沃-诺迪斯克有限公司 | Pharmaceutical formulation comprising metformin and repaglinide |
| CN102319245A (en) * | 2011-07-08 | 2012-01-18 | 杭州华东医药集团生物工程研究所有限公司 | Composition containing repaglinide and metformin hydrochloride and preparation thereof |
| CN103251593A (en) * | 2013-06-04 | 2013-08-21 | 杭州朱养心药业有限公司 | Repaglinide/metformin composition |
| CN106109428A (en) * | 2016-07-22 | 2016-11-16 | 江苏豪森药业集团有限公司 | The preparation process of repaglinide metformin |
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2016
- 2016-12-20 CN CN201611181497.7A patent/CN106727554A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101516347A (en) * | 2006-09-29 | 2009-08-26 | 诺沃-诺迪斯克有限公司 | Pharmaceutical formulation comprising metformin and repaglinide |
| CN102319245A (en) * | 2011-07-08 | 2012-01-18 | 杭州华东医药集团生物工程研究所有限公司 | Composition containing repaglinide and metformin hydrochloride and preparation thereof |
| CN103251593A (en) * | 2013-06-04 | 2013-08-21 | 杭州朱养心药业有限公司 | Repaglinide/metformin composition |
| CN106109428A (en) * | 2016-07-22 | 2016-11-16 | 江苏豪森药业集团有限公司 | The preparation process of repaglinide metformin |
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