CN106924237B - It is a kind of containing En Gelie is net and the pharmaceutical composition of Metformin hydrochloride - Google Patents
It is a kind of containing En Gelie is net and the pharmaceutical composition of Metformin hydrochloride Download PDFInfo
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- CN106924237B CN106924237B CN201710123019.9A CN201710123019A CN106924237B CN 106924237 B CN106924237 B CN 106924237B CN 201710123019 A CN201710123019 A CN 201710123019A CN 106924237 B CN106924237 B CN 106924237B
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- gelie
- net
- metformin hydrochloride
- pharmaceutical composition
- adhesive
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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)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
Abstract
The invention discloses a kind of containing En Gelie only and the pharmaceutical composition of Metformin hydrochloride, and containing filler, adhesive, glidant, lubricant, wherein adhesive is 9-11%；Prepare that En Gelie is net and the method for metformin hydrochloride medicinal composition the invention also discloses a kind of.En Gelie disclosed in this invention is net and metformin hydrochloride medicinal composition hardness is big, and rapidly, dissolution rate RSD is small between piece for dissolution.
Description
Technical field
The invention belongs to pharmaceutical technology fields, more specifically to arrive containing En Gelie is net and the medicine of Metformin hydrochloride
Compositions.
Background technique
The disease incidence of type-2 diabetes mellitus is higher and higher, and complication (such as diabetes, blindness, kidney failure) not only influences
To the quality of life of patient, and it is possible to lead to the shortening in service life.
En Gelie net (empagliflozin) is a kind of oral sodium glucose co-transporter 2 white -2 (SGLT-2)
Inhibitor.SGLT-2 is to be mainly responsible for reabsorb the transporter that glucose enters body circulation from glomerular filtrate, passes through inhibition
SGLT-2, En Gelie only reduces kidney reduce the kidney threshold value of glucose to the re-absorption of filtration glucose, to increase
The excretion of glucose in urine.Metformin hydrochloride is classical hypoglycemic medicine, can reduce type 2 diabetes patient's empty stomach and postprandial height
Blood glucose.
En Gelie is net/and metformin hydrochloride tablet is that En Gelie is net and the compound preparation of Metformin hydrochloride.Through Oral Administration in Rats
Sugar tolerance experimental study shows that En Gelie is net and Metformin hydrochloride individually takes orally and is administered simultaneously and can reduce blood glucose water
It is flat, and at the same time the blood sugar reducing function (reducing by 63%) of administration, which is significantly higher than, individually gives En Gelie net (reducing by 37%) or hydrochloric acid two
First biguanides (reduce by 39%) group, show En Gelie it is net/metformin hydrochloride tablet has better hypoglycemic effect.
En Gelie is net/and metformin hydrochloride tablet is the compound system developed by Boehringer Ingelheim company for treating diabetes
Agent.In May, 2015, European Union ratify En Gelie it is net/application for quotation of Metformin hydrochloride.In August, 2015, FDA ratify En Gelie
Net Metformin hydrochloride compound listing.China not yet ratifies the import of the medicine at present, and the country there is no launch.
The net raw material of En Gelie is white to yellowish powder；The atomic water that is dissolved in is (in pH1.0, pH4.0, pH7.4 aqueous medium
All it is soluble,very slightly), it is slightly soluble in acetonitrile, 50% methanol, ethyl alcohol, 50% acetonitrile is dissolved in, is slightly soluble in methanol, be practically insoluble in first
Benzene.Metformin hydrochloride raw material is white crystalline powder；It is odorless.It is soluble easily in water, it dissolves in methyl alcohol, in ethanol slightly soluble,
It is insoluble in chloroform or ether.
In patent application " phenyl derivatives, the drug containing the compound, its purposes and its system that glucopyranosyl replaces
Make method " in (application number 200580006944.9), proposing can be with melbine group comprising the net general formula compound of En Gelie
It closes and uses, or be included in same preparation；But this patent application does not disclose prescription of two drugs as same preparation when；
" using the combined therapy and its pharmaceutical composition of SGLT-2 inhibitor " (application number 200780041878.8) discloses En Gelie
Only with the combination of melbine and its for type-1 diabetes mellitus, type-2 diabetes mellitus purposes etc..Point out composition dosage form include can medicine
With carrier and auxiliary agent, dosage form may include tablet, capsule, Caplet etc..Also disclosing selected pharmaceutical carrier can be corn
Starch, lactose, glucose, microcrystalline cellulose, polyvinylpyrrolidone, citric acid etc..But undisclosed specific prescription.
" pharmaceutical composition, pharmaceutical dosage form, preparation method, treatment method and application thereof " (application number
201080044077.9) solid pharmaceutical preparation of SGLT-2 and melbine is disclosed, prescription is also disclosed, specially adhesive is
3.9-8.3%, filler 1 is 2.3-8.0%, filler 2 is 0-4.4%, filler 3 is 0-33%, and lubricant is
0.7-1.5%, glidant 0.05-0.5%, disintegrating agent 0.00-3.0%.In this prescription, because of the amount of adhesive
On the low side, when prepared as tablets, obtained tablet, it is small to have hardness, unqualified so as to cause friability, is unfavorable for subsequent packet
The progress of clothing process；Dissolution RSD between piece final simultaneously is bigger than normal, and it is more than 10% that 15min, which dissolves out RSD, this would potentially result in day
Between blood concentration have compared with Big mutation rate, cause blood glucose fluctuation.
Therefore from the angle for improving drug quality, a kind of preparation prescription and suitable production technology is needed, makes to make
While standby obtained compound preparation has good dissolubility, there is greater hardness, dissolve out RSD between smaller.
Summary of the invention
The object of the present invention is to provide it is a kind of containing En Gelie only with the pharmaceutical composition of melbine.
The present invention also aims to obtained composition have higher drug quality, reach more preferable hardness with it is smaller
Piece between dissolve out RSD.In order to reach industrialization and high-quality, the present invention is provided containing the En Gelie compound system with melbine only
Agent, can achieve the net 15min dissolution rate of En Gelie therein must not be lower than 85%, and preparation hardness controls target and is not less than 12kg,
Particle habit is greater than 70% (weight ratio) of granulation total amount of feeding.
The melbine that refers in the present invention, Metformin hydrochloride indistinction between the two, refer both at present in the drug used
Metformin hydrochloride.The va64 occurred in the present invention is writing a Chinese character in simplified form for copolyvidone VA64.
The present invention provides a kind of containing En Gelie is net and the composition of Metformin hydrochloride, containing filler, adhesive,
Glidant, lubricant, by weight, wherein the adhesive is 9-11%；Wherein the filler is microcrystalline cellulose,
Adhesive is copolyvidone VA64, and glidant is silica, and lubricant is magnesium stearate.
Type, model, the dosage of adhesive significantly affect tablet hardness and dissolution rate.The selected adhesive of the present invention and
Its dosage ensure that the realization of the technology of the present invention purpose.
Wherein solid pharmaceutical preparation, such as tablet, capsule, preferably tablet can be made in the composition.
The invention also discloses preparations containing En Gelie is net and the method for the composition of Metformin hydrochloride:
A. by En Gelie it is net/melbine and microcrystalline cellulose mix, obtain En Gelie it is net/melbine and microcrystalline cellulose
Plain mixture；
B. the mixture is placed in fluidised bed granulator, sprays into copolyvidone VA64 to the mixture, particle is made；
C, glidant, lubricant is added, solid pharmaceutical preparation is made in conventional manner.
Drug necessarily is in dissolved state and can just be absorbed by the body, and the net dissolubility of En Gelie is poor, needs to pass through particular technology
Increase its solubility.Particle made from fluidized bed granulation technology disclosed in this invention is loose porous, and particle is more uniform, and
After pressing, compared with traditional wet granulation, there is stronger, faster stripping property, reproducibility is good, and yield is adjustable.
Present invention En Gelie obtained is net/and melbine pharmaceutical composition solution rate is significantly faster than that without the formula
With the pharmaceutical composition after process, there is preferable solution rate and dissolution uniformity and compressibility is good.
The concentration for wherein spraying into the copolyvidone VA64 of En Gelie net, melbine and microcrystalline cellulose mixt is 22-
24.8%.
Wherein the wriggling pump speed of the fluidized bed is 30rpm.
Tablet of the invention optionally carries out film coating.Coating membrane usually increases weight as 2-5%, coating membrane by: at
The composition such as film, plasticizer, pigment.
Formula disclosed in this invention and technique realize En Gelie it is net/melbine pharmaceutical composition hardness is big, dissolution
Rapidly, the small purpose of RSD is dissolved out between piece, is suitble to industrialized production.
Specific embodiment
Below with reference to embodiment, the present invention is described in further detail, but is not limited to following embodiments.
" particle habit " occurred in instances refers to the particle weight that can be crossed 24 meshes but cannot sieve with 100 mesh sieve, and accounts for system
The weight percent of grain total amount of feeding；Dissolution rate refers to that 15min accumulates dissolution rate；Va64 concentration is w/v (g/
Ml, %)
The selection of 1 recipe quantity of embodiment
The dosage of auxiliary material in prescription is determined by the method for experimental design (DOE), while investigating influence tablet Key Quality
The factor of attribute.Using 22The full factorial design of-three central points investigates binder dosage, binder concn to particle habit
The influence of (crossing the particle weight that 24 meshes cannot sieve with 100 mesh sieve), hardness, dissolution rate.Test combinations and result such as table 1.
1 supplementary product consumption of table and concentration 22- three central point full factorial design tables and result
Respectively combine specific supplementary material amount such as table 2
Table 2 respectively combines supplementary material scale
| Dosage (g) | std 1 | std 2 | std 3 | std 4 | std 5 | std 6 | std 7 |
| En Gelie is net | 25 | 25 | 25 | 25 | 25 | 25 | 25 |
| Melbine | 1000 | 1000 | 1000 | 1000 | 1000 | 1000 | 1000 |
| Microcrystalline cellulose | 34.0 | 33.6 | 9.9 | 10.1 | 21.4 | 21.8 | 20.9 |
| va64 | 106.2 | 106.3 | 129.8 | 129.7 | 118.3 | 118.0 | 119.0 |
| Silica | 5.9 | 5.9 | 5.9 | 5.9 | 5.9 | 5.9 | 5.9 |
| Magnesium stearate | 9.4 | 9.4 | 9.4 | 9.4 | 9.4 | 9.4 | 9.4 |
| Purified water | 482 | 332 | 590 | 405 | 438 | 438 | 438 |
Preparation method: the En Gelie for weighing recipe quantity is net, the sieving of melbine, microcrystalline cellulose after mixing, be placed in
In one-step-granulating method, 75 DEG C of inlet air temperature of setting, 50 DEG C of temperature of charge, blower frequency 25Hz, atomizing pressure 0.1mpa, with
The va64 that the wriggling pump speed of 30rpm sprays into certain density recipe quantity pelletizes, and Grain size controlling moisture is below 2%.It is whole
Particle weighing after grain, calculates particle habit, the magnesium stearate and silica of recipe quantity is added, be uniformly mixed, fixed tabletting
Under the conditions of parameter (label thickness), the sample hardness of square piece agent everywhere, dissolution rate are measured.
Data are carried out with Design-Expert software analysis shows that, va64 concentration be influence particle habit (cross 24 meshes
The particle that cannot be sieved with 100 mesh sieve account for again granulation total amount of feeding ratio) and hardness significant factor (P < 0.05) and va64 concentration
Significant (P < 0.01) with interaction influence of the dosage to hardness, va64 dosage dissolves out En Gelie only to be had an impact, variance analysis
The mathematical model that display is established reaches the level of signifiance (P < 0.05).
It is va64 concentration and its dosage that being had found by the above Factorial Design, which influences the key factor of product quality,.It is setting
The net 15min dissolution rate of En Gelie must not be lower than 85%, and hardness controls target and is not less than 12kg, and particle habit is greater than granulation and always feeds intake
Amount 70% (weight) when, va64 concentration range of choice between 22-24.8%, dosage range of choice 9.0-11% it
Between.In this design space, interior prediction can reach above-mentioned desired quality objective.
The selection of 2 adhesive type of embodiment
When using granulating process, adhesive type can dissolve out tablet and generate large effect, and the present invention is to adhesive
Type has carried out screening test, test combinations and the results are shown in Table 3-4
The different adhesive compositions of table 3
4 adhesive type of table influences tablet determinant attribute to investigate result
| Measurement item | Embodiment 2-1 | Embodiment 2-2 | Embodiment 2-3 |
| Particle habit (%) | 90 | 67 | 65 |
| Hardness (kg) | 12.1 | 7.0 | 8.9 |
| The net dissolution rate of En Gelie (%) | 94.8 | 98.6 | 76.6 |
| Melbine dissolution rate (%) | 101.1 | 100.5 | 89.2 |
| The net dissolution rate RSD (%) of En Gelie | 3.4 | 12 | 14 |
According to the above test result, va64 is suitable for completion of the invention compared with other types adhesive.
The specific prescription of embodiment 3
The group of net, Metformin hydrochloride 5mg/500mg and 12.5mg/500mg specification the individual layer tablet (label) of En Gelie
At being shown in Table in 5.
5 prescription of table
| Embodiment 3-1 (10,000) | Inventory (g) | Weight % |
| En Gelie is net | 50 | 0.85 |
| Melbine | 5000 | 84.75 |
| Microcrystalline cellulose | 153.1 | 2.6 |
| va64 | 620 | 10.5 |
| Silica | 41.4 | 0.7 |
| Magnesium stearate | 35.5 | 0.6 |
| Purified water | 2700L | (va64 concentration) 23 |
| Embodiment 3-2 (10,000) | Inventory (g) | Weight % |
| En Gelie is net | 125 | 2.12 |
| Metformin hydrochloride | 5000 | 84.75 |
| Microcrystalline cellulose PH101 | 167.1 | 2.83 |
| va64 | 531 | 9.00 |
| Colloidal silicon dioxide | 41.4 | 0.70 |
| Magnesium stearate | 35.5 | 0.60 |
| Purified water | 2140L | (va64 concentration) 24.8 |
Preparation manipulation:
Metformin hydrochloride and microcrystalline cellulose, En Gelie can be used as powder only and add and implement premixing and then pass through
It is spraying that fluidized bed granulation is implemented by " granulation liquid " that va64 and pure water form.After the completion of fluidized bed granulation, with suitable
Sieve screen particle.Particle and colloidal silica anhydrous through screening and the magnesium stearate as lubricant are admixed.Make
Final mixture is compressed into tablet with common rotary pelleting machine.
Embodiment 4 dissolves out comparative test
For deviateing the prescription (such as table 6) of va64 dosage of the invention, obtain following as a result, such as table 7.
The different polyvinylpyrrolidone dosages of table 6 and concentration prescription
| Dosage (g) | Embodiment 4-1 | Embodiment 4-2 | Embodiment 4-3 |
| En Gelie is net | 25 | 25 | 25 |
| Melbine | 1000 | 1000 | 1000 |
| Microcrystalline cellulose | 35.3 | 46.87 | 5.1 |
| va64 | 106.2 | 94.6 | 136.5 |
| Silica | 5.9 | 5.9 | 5.9 |
| Magnesium stearate | 7.6 | 7.6 | 7.6 |
| Purified water | 331 | 430 | 620 |
7 binder concn of table and dosage influence tablet determinant attribute to investigate result
The above test results show that the dosage of va64 is 8% (embodiment 4-2) and 11.6% (embodiment 4-3), Yi Jinong
Degree is that 32% (embodiment 4-1) can not achieve expectation target.That is the net 15min dissolution rate of particle habit > 70%, En Gelie must not
Lower than 85%, RSD < 10%, hardness is greater than 12kg.
4 granulating process parameter selection of embodiment
This preparation uses fluidized bed granulation technique, is adopted according to prescription such as table 8 with 10000 scales of 5mg/500mg specification
Grain made parameter is screened with Plackett-Burman experimental program, test combinations and the results are shown in Table 9.
8 En Gelie of table is net/melbine prescription
| Ingredient | Dosage (g) | Ratio (%) |
| En Gelie is net | 50 | 0.85 |
| Metformin hydrochloride | 5000 | 84.7 |
| Microcrystalline cellulose | 242.1 | 4.10 |
| va64 | 531 | 9 |
| Silica | 41.4 | 0.70 |
| Magnesium stearate | 35.5 | 0.60 |
| Purified water | 2413 | (va64 concentration) 22 |
9 Plackett-Burman experimental program of table and result
Data analysis shows that, wriggling pump speed be influence particle habit significant factor (P < 0.05).With wriggling pump speed
Increase, conforming particle quantity is reduced.
In this design space, the grain made parameter that conforming particle can be made most is wriggling pump speed 30rpm, inlet air temperature 75
DEG C, atomizing pressure 1bar, blower frequency 30Hz, 40 DEG C of temperature of charge.
Since wriggling pump speed is the significant factor of influence particle habit, therefore further individually to wriggling pump speed to particle
Tap density and tablet hardness are investigated.Wriggling pump speed and the linear negative correlation (R of particle tap density as the result is shown2
=0.976), (R is linearly positively correlated with hardness2=0.9925).Therefore, wriggling pump speed need to be set in a suitable range
It can be only achieved predetermined quality target, especially dissolution rate and control target.
Since wriggling pump speed is crucial granulating process parameter, different wriggling pump speeds (20,25,30rpm) is selected to be made
Tabletting when making hardness to about 12kg of particle adjustment tabletting parameter, respectively take 6, using selected dissolution method measurement 15,
30min accumulates dissolution rate, investigates influence of the dissolution method to the distinction and wriggling pump speed of critical process to dissolution, knot
Fruit is shown in Table 10.
Distinction of 10 dissolution method of table to critical process
* the vs of p < 0.05 25,30rpm, the vs of #p < 0.05 30rpm
Test result shows: selected dissolving-out method can distinguish process variations, and wriggling pump speed, which is set as 30rpm, can be only achieved
It is expected that 15min dissolution is greater than 85% target.
Claims (5)
1. it is a kind of containing En Gelie is net and the pharmaceutical composition of Metformin hydrochloride, contain filler, adhesive, glidant, profit
Lubrication prescription, it is characterized in that by weight, adhesive 9-11%；
Wherein the filler is microcrystalline cellulose, and adhesive is copolyvidone va64, and glidant is silica, lubricant
For magnesium stearate；
Wherein the copolyvidone va64 is added in the preparation with the concentration of 22-24.8% g/ml.
2. pharmaceutical composition as described in claim 1, it is characterised in that solid pharmaceutical preparation is made in the pharmaceutical composition.
3. pharmaceutical composition as claimed in claim 2, it is characterised in that the solid pharmaceutical preparation is tablet.
4. a kind of prepare as described in claim 1 containing En Gelie is net and the method for the pharmaceutical composition of Metformin hydrochloride:
A. by En Gelie, net, Metformin hydrochloride and microcrystalline cellulose are mixed, and obtain the net Metformin hydrochloride of En Gelie and crystallite
Cellulose mixtures；
B. the mixture is placed in fluidised bed granulator, sprays into copolyvidone va64 to the mixture, particle is made；
C, glidant, lubricant is added, solid pharmaceutical preparation is made in conventional manner.
5. the preparation method according to claim 4, it is characterised in that the wriggling pump speed of fluidized bed is 30rpm.
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| CN201710123019.9A CN106924237B (en) | 2017-03-03 | 2017-03-03 | It is a kind of containing En Gelie is net and the pharmaceutical composition of Metformin hydrochloride |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111588713B (en) * | 2020-06-22 | 2021-03-09 | 广州市力鑫药业有限公司 | A Chinese medicinal composition for treating diabetes, and its preparation method |
| CN114404436B (en) * | 2022-02-24 | 2023-07-28 | 北京百奥药业有限责任公司 | Metformin-enggliflozin composition and preparation method thereof |
| CN116850149A (en) * | 2022-03-28 | 2023-10-10 | 北京阳光诺和药物研究股份有限公司 | Metformin gliflozin tablet for reducing genotoxic impurity content |
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