CN107432869A - Include net double-layer tablets of Metformin hydrochloride and En Gelie and preparation method thereof - Google Patents
Include net double-layer tablets of Metformin hydrochloride and En Gelie and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
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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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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Abstract
The present invention provides a kind of double-layer tablets net comprising Metformin hydrochloride and En Gelie, wherein, the metformin hydrochloride tablet layer is slow release layer, and the net lamellas of En Gelie are release layer；Also, the diabecron sustained-release layer is the slow release layer of 12 hours to 24 hours.Present invention also offers the purposes of the preparation method of double-layer tablets and the double-layer tablets in preparing treatment and/or improving the medicine of diabetes B.The double-layer tablets net comprising Metformin hydrochloride and En Gelie of the present invention are that ensure that the slow release characteristic of Metformin hydrochloride, also solve the net rapid dissolutions of En Gelie, and daily medication is secondary, significant to the clinical treatment of increase diabetic.Method of the preparation of the present invention comprising Metformin hydrochloride and the net double-layer tablets of En Gelie, its preparation technology is simple, and production cost is low, and ensure that two active components mix homogeneous sex chromosome mosaicism in production, improve the stability of product.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, is related to a kind of medicaments compound system for being used to treating and/or improving diabetes B
A kind of agent and preparation method thereof, and in particular to double-layer tablets net comprising Metformin hydrochloride and En Gelie and preparation method thereof.
Background technology
At present, China has turned into the most country of global diabetic's number.Shown according to latest data, by 2014
Year, diabetes mellitus in China patient numbers up to 1.14 hundred million, account for 1/3rd of global diabetes patient's sum.Diabetes are divided into 1 type
With 2 types, diabetes B has accounted for more than the 90% of diabetic patient population.China diabetes B patient accounts for 93%~95%.2
Patients with type Ⅰ DM is a kind of life-long disease, and it is usually started by middle age or later stage of life, but also may begin at any age.Patient's body is produced
The ability of raw insulin not completely loses, and some patient's body insulin even produces excessively, but the action effect of insulin
It is poor, thus the insulin of patient's body be it is a kind of relative lack, some mechanism prevent insulin from by suction pressure to carefully
In born of the same parents.Because insulin can not be suitably used in body, therefore the glucose in blood is increased to unsafe level and claimed
For the state of hyperglycemia.Over time, lasting hyperglycemia causes glucose toxicity, and it makes insulin resistance tighter
Weigh and facilitate Pancreatic beta cells function obstacle.The degree of lasting hyperglycemia it is directly related with Diabetic microvascular complication and
Macrovascular complications can also be facilitated.Therefore, hyperglycemia makes illeffects constantly circulate, and this has aggravated the control of diabetes B
And complication.
The target for the treatment of diabetes is realization and maintained as close possible to normal blood glucose at present, with prevention and blood glucose rise
Related long-term capilary and macrovascular complications.Oral medication for treating diabetes B can be selected from known chemical combination
Thing：Sulfonylurea, biguanides (melbine (metformin)), thiazolidinediones and alpha-glucosidase restrainer, it is all kinds of
Active medicine is generally administered alone in patient.However, when single therapy becomes inappropriate, it is necessary to drug combination.
Metformin hydrochloride chemical name is 1,1- dimethylbiguanide hydrochloride (molecular formula：C4H11N5HCl, molecule
Amount：165.63), the mechanism of action is different from other types of oral anti-blood glucose medicine, and it can reduce the generation of glycogen, reduces intestines to sugar
Absorption, and the sensitiveness of insulin can be improved by increasing the uptake and utilization of periphery sugar.With sulfonylureas not
With Metformin hydrochloride will not produce hypoglycemia to diabetes B patient or the patient of euglycemia.Pancreas islet after treatment
The secretion of element keeps constant, and reduces Fasting insulin level and daily plasma insulin level.Metformin hydrochloride promotes pancreas
Island element combines with acceptor and improves sensitiveness of the diabetic to insulin, increases surrounding tissue and sugared anerobic glycolysis is promoted
The utilization of sugar entering, suppress lipolysis, reduce plasma free fatty acid level, weaken insulin resistance and improve the profit of glucose
With and play hypoglycemic, reducing blood lipid, suppress artery sclerosis effect.Metformin hydrochloride has turned into light moderate diabetes B and suffered from
The choice drug of the particularly fat diabetes B patient of person.
En Gelie net (empagliflozin) as sodium glucose co-transporters carrier 2 (SGLT2) inhibitor in kidney,
Its chemical formula is (1S) -1,5- dehydrations -1-C- [chloro- 3- of 4- [[4- [[(3S)-tetrahydrochysene -3- furyls] epoxide] phenyl] methyl]
Phenyl]-D-Glucose alcohol, it can increase the excretion of glucose in urine, therefore can reduce blood independent of the function of beta cell
Sugar level.One is related to the national random, double blinding in 15, the whole world, parallel packet, placebo, III phase clinical study results
Prompting, in diabetes B patient, in the case where other hypoglycemic drugs are ineffective, add and treats 52 only with En Gelie
Glycosylated hemoglobin (HbA1c) level, its tolerance good (Lancet Diabetes can be significantly improved week
Endocrinol.2014 May；2(5):369-84.).
Sustained release preparation has lot of superiority compared with ordinary preparation.For example, sustained release preparation energy long period maintaining treatment institute
The blood concentration needed, while the peak valley change of blood concentration is reduced, reduce the incidence and the order of severity of toxic side effect.Sustained release system
Agent can also take number by reducing, and improve the compliance of patient.Metformin hydrochloride is because half-life period is shorter, ordinary preparation
Need to take daily 2 or 3 times, and En Gelie net half-life period is 12.4 hours, is not required to be prepared into sustained release preparation.The grace of foreign countries' listing
Lattice arrange the problem of net common compound preparation Synjardy of melbine is due to melbine half-life period, it is necessary to take medicine for multiple daily,
And the net single preparationss of ephedrine of En Gelie of external listing only need medication once daily.The inconsistency of medicining times causes very to patient
Big puzzlement.Therefore a kind of compound preparation is prepared, Metformin hydrochloride and the effect that commonly releases the drug simultaneously containing slow releasing medicinal effect
En Gelie only to increase diabetic clinical treatment it is significant.
The dosage of Metformin hydrochloride is 500~2000mg/ days, and dosage net En Gelie is 1~30mg/
My god, both dose difference is very big, compound preparation is prepared into production homogeneity is mixed to two-component it is also proposed that huge challenge.
Further, because En Gelie is only insoluble drug (solubility 0.3mg/mL, pH4.0 buffer solution in 0.1mol/L hydrochloric acid
Middle solubility 0.21mg/mL, solubility 0.14mg/mL in pH7.4 buffer solutions), and Metformin hydrochloride is soluble in water.
Based on this, exploitation is a kind of can to control Metformin hydrochloride soluble in water slowly to discharge, and and can ensures slightly solubility
The net quick releases of En Gelie double-layer tablets, make it have desired dissolution rate and stability, it is no doubt very challenging,
And current needs.
The content of the invention
Therefore, it is an object of the present invention to provide a kind of double-layer tablets net comprising Metformin hydrochloride and En Gelie, this pair
Synusia is while ensureing that Metformin hydrochloride soluble in water slowly discharges, net fast of and can control insoluble drug En Gelie
Quick-release is put.Present invention also offers the preparation method of the double-layer tablets.Method simple process provided by the invention, cost are low, and
The net mixing homogeneity of Metformin hydrochloride and En Gelie in production process is also solved, and is prepared according to the present processes
Double-layer tablets there is desired dissolution rate and stability.
It is a further object of the invention to provide a kind of method for preparing above-mentioned double-layer tablets.
A further object of the present invention is, there is provided the purposes of above-mentioned double-layer tablets.
Unless otherwise indicated, term " pharmaceutically acceptable auxiliary material " used herein refers to countries in the world drug control portion
Door approval, can be used in the auxiliary material of pharmaceutical production manufacture, such as filler, disintegrant, adhesive, lubricant, excipient,
Toner, pH adjusting agent, flavouring, sweetener, spices, glidant etc..
The purpose of the present invention is achieved through the following technical solutions：
On the one hand, the present invention provides a kind of double-layer tablets net comprising Metformin hydrochloride and En Gelie, the hydrochloride
Biguanides lamella is slow release layer, and the net lamellas of En Gelie are release layer；Also, the diabecron sustained-release layer is 12 hours
To the slow release layer of 24 hours.Preferably, the diabecron sustained-release layer is the slow release layer of 12 hours or 24 hours.
Preferably, the metformin hydrochloride tablet layer includes Metformin hydrochloride and sustained release agent；It is highly preferred that hydrochloride
Biguanides and sustained release agent account for the 40~80% and 10~50% of the metformin hydrochloride tablet layer weight percentage respectively；It is further excellent
Selection of land, the Metformin hydrochloride and sustained release agent account for 55~70% Hes of the metformin hydrochloride tablet layer weight percentage respectively
20~40%.
Preferably, 500~2000mg Metformin hydrochloride is included in the metformin hydrochloride tablet layer, is more preferably wrapped
Metformin hydrochloride containing 500,850 or 1000mg；
Preferably, the sustained release agent is selected from hydroxypropyl methyl cellulose；Its mechanism discharged is mainly hydroxypropyl methyl fibre
Dimension element is used as sustained-release matrix material.
Preferably, one in E4M, E10M, K100LV, K4M, K15M, K100M of the hydroxypropyl methyl cellulose
Kind is a variety of, more preferably K4M, K15M, is still more preferably K4M；
Preferably, the sustained release agent in the present invention can also be that other have the auxiliary material of slow release effect, including carbomer, ethyl
One or more in cellulose, polyoxyethylene, PVP and sodium alginate.
Preferably, the metformin hydrochloride tablet layer also includes pharmaceutically acceptable auxiliary material, such as filler, bonding
Agent, lubricant and/or glidant；
Preferably, the filler accounts for the 0~15% of the metformin hydrochloride tablet layer weight percentage；
Preferably, described adhesive accounts for the 1~10% of the metformin hydrochloride tablet layer weight percentage；
Preferably, the lubricant accounts for the 0.1~2% of the metformin hydrochloride tablet layer weight percentage；
Preferably, the glidant accounts for the 0.1~2% of the metformin hydrochloride tablet layer weight percentage；
Preferably, the net lamellas of the En Gelie include that En Gelie is net and disintegrant；It is highly preferred that the En Gelie is net and collapses
Solution agent accounts for the 2~6% and 1~5% of the net lamella percentage by weights of the En Gelie respectively；
Preferably, En Gelie of the net lamellas of the En Gelie comprising 1~30mg is net, more preferably the grace comprising 2~25mg
Lattice row are net, and further preferably the En Gelie comprising 5mg, 10mg, 12.5mg or 25mg is net；
Preferably, the disintegrant in PVPP, Ac-Di-Sol, sodium carboxymethyl starch one
Kind is a variety of, and preferably described disintegrant is PVPP；
Preferably, the net lamellas of the En Gelie also include pharmaceutically acceptable auxiliary material, such as filler, adhesive, profit
Lubrication prescription and/or glidant；
Preferably, the filler accounts for the 83~94.8% of the net lamella percentage by weights of the En Gelie；
Preferably, described adhesive accounts for the 2~4% of the net lamella percentage by weights of the En Gelie；
Preferably, the lubricant accounts for the 0.1~1% of the net lamella percentage by weights of the En Gelie；
Preferably, the glidant accounts for the 0.1~1% of the net lamella percentage by weights of the En Gelie；
One or more of the filler in lactose, starch, mannitol, microcrystalline cellulose, it is therefore preferable to anhydrous
Lactose and/or microcrystalline cellulose；It is fine that described adhesive is selected from PVP, starch slurry, low molecule amount hydroxypropyl methylcellulose, carboxymethyl
Tie up the one or more in plain sodium, it is therefore preferable to sodium carboxymethylcellulose, PVP, low molecule amount hydroxypropyl cellulose；Lubrication
Agent and glidant in magnesium stearate, stearic acid, stearyl alcohol, rilanit special, silica and colloidal silica one
Kind is a variety of, it is preferable that glidant is that silica lubricant is magnesium stearate.
Preferably, the double-layer tablets also include optional film coating, and the film coating is used to cover the hydrochloric acid two
First biguanides slow release layer and the net release layers of En Gelie.
Preferably, the material of the film coating is selected from Opadry, cellulose acetate, acrylic resin, ethyl cellulose
In one or more, more preferably Opadry.
Preferably, the weightening of the film coating is the 0.5wt.%-5wt.% of the double-layer tablets, is more preferably
1.5wt.-2.5wt.%.
Preferably, in the metformin hydrochloride tablet layer Metformin hydrochloride particle diameter be 2~1000 μm, preferably 150
~1000 μm.
Preferably, particle diameter net En Gelie in the net lamellas of the En Gelie is 50~100 μm, preferably 60~80 μm.
The double-layer tablets of the present invention can stamp the label or letter for being easy to differentiate, it is possibility to have divisural line is used to separate.
The double-layer tablets of the present invention can be circular, oval, capsule shape；Preferably circular tablet.
The double-layer tablets Orally-administrable of the present invention parenteral safe delivers medicine to mammal (such as mouse, rat, rabbit
Son, cat, dog, ox, horse, monkey, gorilla and the mankind and other).
The present invention double-layer tablets in Metformin hydrochloride effective dose be typically grown up (60kg) per consumption per day 500~
2000mg。
Effective dose net En Gelie is typically grown up (60kg) per 1~30mg of consumption per day in the double-layer tablets of the present invention.
The double-layer tablets of the present invention are daily secondary, each one.Take before the meal or when eating.
The double-layer tablets of the present invention are preferably that Metformin hydrochloride/En Gelie is only：5mg/850mg, 5mg/1000mg,
12.5mg/850mg 12.5mg/1000mg.
On the other hand, the present invention provides a kind of preparation method of double-layer tablets, the described method comprises the following steps：
1) metformin hydrochloride tablet layer particle is prepared；
2) the net lamella particles of En Gelie are prepared；
3) double-layer tablets are suppressed on a bi-layer tablet press；
Preferably, the tablet press machine is ZPW23 rotary tablet machines.
It is optionally possible to carry out film coating.
Preferably, the step 1) including the step of following methods by realizing：
A) adhesive is dissolved in water, compound concentration is 10% adhesive；
Preferably, described adhesive is sodium cellulose glycolate；
B) auxiliary material by Metformin hydrochloride and than adhesives crosses 100 mesh sieves respectively；
C) Metformin hydrochloride after sieving and sustained release agent, filler are added in granulator and mixed；
Preferably, the granulator is high-shearing granulation machine；
Preferably, the high-shearing granulation machine is the more pot wet-mixing fast granulating machines of SHK-10B；
It is highly preferred that the parameter of the high-shearing granulation machine is agitating paddle 800rpm, cutting knife 2000rpm, 120s；
D) adhesive made from step a) is added, using granulator wet granulation；
Preferably, the granulator is high-shearing granulation machine；
Preferably, the parameter of the high-shearing granulation machine is agitating paddle 800rpm, cutting knife 2000rpm, 180s；
E) particle obtained using fluidized bed drying step d), it is less than 2.0% to moisture；
Preferably, the fluid bed is UN1GLATT fluid beds；
Preferably, temperature of charge 35-45 degree is kept in the drying process；
F) the particle whole grain for obtaining step e)；
Preferably, the whole grain uses FZB150 crushing and pelletizing machines；
Preferably, the parameter of the pelletizing machine is rotating speed 2000rpm, mesh size 1.2um；
G) particle is transferred in hopper mixer, adds lubricant and glidant, be well mixed, it is double to obtain hydrochloride
Guanidine lamella particle；
Preferably, the hopper mixer is HLS-50 laboratories hopper mixer；
Preferably, the parameter of the hopper mixer is 24rrpm, 180s；
Preferably, the particle diameter of the Metformin hydrochloride is 2~1000 μm, preferably 150~1000 μm；
Preferably, obtained metformin hydrochloride tablet layer particle is subjected to intermediate detection, method is external standard method, using purple
Outer spectrophotometer determines its content, determines the piece weight of metformin hydrochloride tablet layer.
Preferably, the step 2) including the step of following methods by realizing：
A) it is net to handle En Gelie, it is 50 μm~100 μm to make its particle diameter；
Preferably, it is net using airslide disintegrating mill processing En Gelie；
B) other auxiliary materials in addition to adhesive are crossed into 100 mesh sieves respectively；
C) after disintegrant, the filler that the En Gelie for obtaining step a) is net and step b) is obtained weigh according to recipe quantity,
Mixed using granulator；
Preferably, the granulator is high-shearing granulation machine；
Preferably, the parameter of the high-shearing granulation machine is agitating paddle 800rpm, cutting knife 2000rpm, 120s；
D) adhesive is added in the particle that step c) is obtained, uses granulator wet granulation；
Preferably, the granulator is high-shearing granulation machine；
Preferably, the parameter of the high-shearing granulation machine is agitating paddle 800rpm, cutting knife 2000rpm, 180s；
E) particle obtained using fluidized bed drying step d), it is less than 2.0% to moisture；
Preferably, the fluid bed is UN1GLATT fluid beds；
Preferably, temperature of charge 35-45 degree is kept in the drying process；
F) the particle whole grain for obtaining step e)；
Preferably, the whole grain uses FZB150 crushing and pelletizing machines；
Preferably, the parameter of the pelletizing machine is rotating speed 2000rpm, mesh size 1.2um；
G) particle is transferred in hopper mixer, adds lubricant and glidant, be well mixed, obtain En Gelie net layers
Particle；
Preferably, the hopper mixer is HLS-50 laboratories hopper mixer；
Preferably, the parameter of the hopper mixer is 24rrpm, 180s；
Preferably, obtained particle is subjected to intermediate detection；Preferably methods described is external standard method, uses liquid chromatogram
Instrument determines the net piece synusia weights of En Gelie.
Optionally, film coating is carried out to the double-layer tablets, the described method comprises the following steps：
Operation is coated using the ordinary operation mode of film coating, double-deck sheet weight is reached with tablet coating weight gain
1.5%~2.5%, produce.
If it was found by the inventors of the present invention that using the net release layers of diabecron sustained-release tablet core outer wrapping En Gelie
Method prepares the net Metformin Extended-release Tablets of compound En Gelie, and theoretically analysis is feasible, but the results showed it does not have
Standby feasibility.Because the net day dosages of En Gelie are 1mg~30mg/ days, and En Gelie is insoluble in water in itself only, therefore
In preparation process, not only need En Gelie net suspensions being coated in coating solution, and be coated auxiliary material used to need to count
Net could realize of times En Gelie wraps up En Gelie in coatings only, and it is excessive so to not only result in coating weight gain, and
Clothing film is blocked up, and tablet dissolution will be caused to postpone, further have impact on the release of Metformin hydrochloride.
And the present invention develops Metformin hydrochloride and the net double-layer tablets of En Gelie, wherein slow release layer is Metformin hydrochloride
Lamella, release layer are the net lamellas of En Gelie, are prepared into the slow release characteristic that double-layer tablets ensure that Metformin hydrochloride, also solve
Rapid dissolution net En Gelie, and ensure that two active components mix homogeneous sex chromosome mosaicism in production.
Another aspect, the present invention provide use of the above-mentioned double-layer tablets in preparing treatment and/or improving the medicine of diabetes B
On the way.
Metformin hydrochloride or the net single therapies of En Gelie or unsatisfactory curative effect when being combined with other hypoglycemic drugs, connect
By the patient of the net monolithic combination medication treatment of joint Metformin hydrochloride and En Gelie, and improve sustained release and be used for compliance, subtract
Few daily times for spraying, daily medication is once.
The double-layer tablets net comprising Metformin hydrochloride and En Gelie of the present invention are that ensure that the sustained release of Metformin hydrochloride
Characteristic, also solve the net rapid dissolutions of En Gelie, only need medication once daily, have to the clinical treatment for increasing diabetic
It is significant.Method of the preparation of the present invention comprising Metformin hydrochloride and the net double-layer tablets of En Gelie, its preparation technology is simple,
Production cost is low, and ensure that two active components mix homogeneous sex chromosome mosaicism in production, improve the stability of product.
Embodiment
By specific examples below, the present invention can be further appreciated that, but following examples are not the limits to the present invention
It is fixed.
High-shearing granulation machine used is the more pot wet-mixing fast granulating machines of SHK-10B in the embodiment of the present invention；
Bi-layer tablet press is ZPW23 rotary tablet machines；Fluid bed is UN1GLATT fluid beds.
Embodiment 1
According to the constituent shown in table 1, the double-layer tablets of the present invention are prepared, are concretely comprised the following steps：
1) metformin hydrochloride tablet layer particle is prepared；
A) sodium cellulose glycolate (50g) is dissolved in water, compound concentration is 10% adhesive；
B) by Metformin hydrochloride (850g), HPMC K4M (400g), magnesium stearate (15g), talcum powder
(15g) crosses 100 mesh sieves respectively；
C) Metformin hydrochloride after sieving and HPMC K4M are added into the more pot wet methods of SHK-10B to mix
Close and mixed in fast granulating machine, wherein agitating paddle 800rpm, cutting knife 2000rpm, 120s；
D) adhesive made from step a) is added, using high-shearing granulation mechanism grain, wherein agitating paddle 800rpm, cutting knife
2000rpm, 180s；
E) particle obtained using UN1GLATT fluidized bed drying steps d), it is less than 2.0% to moisture；In the drying process
Keep temperature of charge 35-45 degree；
F) particle for obtaining step e) uses FZB150 crushing and pelletizing machine whole grains, and the parameter of the pelletizing machine is rotating speed
2000rpm, mesh size 1.2um；
G) particle is transferred in the hopper mixer of HLS-50 laboratories, adds magnesium stearate and talcum powder, be well mixed,
Obtain metformin hydrochloride tablet layer particle；Wherein, the parameter of the hopper mixer is 24rrpm, 180s；
2) the net lamella particles of En Gelie are prepared；
A) net (5g) using airslide disintegrating mill processing processing En Gelie, it is 50 μm~100 μm to make its particle diameter；
B) by Ac-Di-Sol (5g), lactose (162.5), microcrystalline cellulose (62g), magnesium stearate
(1.25g), silica (1.25g) cross 100 mesh sieves respectively；
C) cross-linked carboxymethyl cellulose after the mesh sieve of mistake 100 that the En Gelie for obtaining step a) is net and step b) is obtained
Sodium, lactose, microcrystalline cellulose are mixed using high-shearing granulation machine；The parameter of the high-shearing granulation machine is agitating paddle
800rpm, cutting knife 2000rpm, 120s；
D) HPC7.5g is added in the particle that step c) is obtained, uses high-shearing granulation machine wet granulation；The high speed
The parameter of shear granulation machine is agitating paddle 800rpm, cutting knife 2000rpm, 180s；
E) particle obtained using UN1GLATT fluidized bed drying steps d), it is less than 2.0% to moisture；In the drying process
Keep temperature of charge 35-45 degree；
F) the particle whole grain for being obtained step e) using FZB150 crushing and pelletizing machines；The parameter of the pelletizing machine is rotating speed
2000rpm, mesh size 1.2um；
G) particle is transferred in the hopper mixer of HLS-50 laboratories, adds magnesium stearate and silica, mixing is equal
It is even, obtain En Gelie net layer particles；The parameter of the hopper mixer is 24rrpm, 180s；
3) double-layer tablets are suppressed on ZPW23 rotary double-layer tablet press machines.
The composition of the double-layer tablets of table 1
Sample is prepared according to embodiment 1, randomly selects six double-layer tablets, determines metformin hydrochloride tablet layer and grace lattice respectively
Arrange the dissolution velocity of net lamella：
Wherein, the assay method of metformin hydrochloride tablet layer is as follows：
Sample is taken, according to dissolution rate and drug release determination method (two methods of annex XD second of Chinese Pharmacopoeia version in 2010), with water
900ml is solvent, and rotating speed is 50 turns per minute, is operated in accordance with the law, in the 1st, 2 hour, 4 hours, 6 hours, 8 hours, 12 small time-divisions
Solution 10ml is not taken, is filtered, and supplements dissolution medium 10ml in process container immediately, takes subsequent filtrate to be measured as trying
Liquid is measured.
The assay method of the net lamellas of En Gelie is as follows：
Sample is taken, according to dissolution rate and drug release determination method (two methods of annex XD second of Chinese Pharmacopoeia version in 2010), with
PH6.8 phosphate buffer solution 900ml is solvent, and rotating speed is 50 turns per minute, is operated in accordance with the law, at 5,10,15,20,30 points
Clock takes solution 2ml respectively, filtration, takes subsequent filtrate to be measured and is measured as test liquid.
As a result respectively as shown in table 2 and table 3, it can learn that diabecron sustained-release layer is steady in 12 hours from table
Release；En Gelie net layers basically reach full dissolution in 30 minutes.
The metformin hydrochloride tablet layer drug release determination result of table 2
The net lamella dissolution determination results of the En Gelie of table 3
Embodiment 2
The composition of the double-layer tablets of table 4
Preparation method is with embodiment 1, while the solubility test method according to embodiment 1, randomly selects six pairs
Synusia, the dissolution velocity of metformin hydrochloride tablet layer and the net lamellas of En Gelie is determined respectively, as a result respectively as shown in table 5 and table 6.
It can learn that diabecron sustained-release layer steadily discharged in 12 hours from table；En Gelie net layers basically reach in 30 minutes
Full dissolution.
The metformin hydrochloride tablet layer drug release determination result of table 5
The net lamella dissolution determination results of the En Gelie of table 6
Embodiment 3
The composition of the double-layer tablets of table 7
Preparation method is with embodiment 1, while the solubility test method according to embodiment 1, randomly selects six pairs
Synusia, the dissolution velocity of metformin hydrochloride tablet layer and the net lamellas of En Gelie is determined respectively, as a result respectively as shown in table 8 and table 9.
It can learn that diabecron sustained-release layer steadily discharged in 12 hours from table；En Gelie net layers basically reach in 30 minutes
Full dissolution.
The metformin hydrochloride tablet layer drug release determination result of table 8
The net lamella dissolution determination results of the En Gelie of table 9
Embodiment 4
The composition of the double-layer tablets of table 10
Preparation method is with embodiment 1, while the solubility test method according to embodiment 1, randomly selects six pairs
Synusia, the dissolution velocity of metformin hydrochloride tablet layer and the net lamellas of En Gelie is determined respectively, as a result respectively such as table 11 and the institute of table 12
Show.It can learn that diabecron sustained-release layer steadily discharged in 12 hours from table；It is basic in En Gelie net layers 30 minutes
Reach full dissolution.
The metformin hydrochloride tablet layer drug release determination result of table 11
The net lamella dissolution determination results of the En Gelie of table 12
Embodiment 5
The composition of the double-layer tablets of table 13
Preparation method is with embodiment 1, while the solubility test method according to embodiment 1, randomly selects six pairs
Synusia, the dissolution velocity of metformin hydrochloride tablet layer and the net lamellas of En Gelie is determined respectively, as a result respectively such as table 14 and the institute of table 15
Show.It can learn that diabecron sustained-release layer steadily discharged in 12 hours from table；It is basic in En Gelie net layers 30 minutes
Reach full dissolution.
The metformin hydrochloride tablet layer drug release determination result of table 14
The net lamella dissolution determination results of the En Gelie of table 15
Embodiment 6
The composition of the double-layer tablets of table 16
Preparation method is with embodiment 1, while the solubility test method according to embodiment 1, randomly selects six pairs
Synusia, the dissolution velocity of metformin hydrochloride tablet layer and the net lamellas of En Gelie is determined respectively, as a result respectively such as table 17 and the institute of table 18
Show.It can learn that diabecron sustained-release layer steadily discharged in 12 hours from table；It is basic in En Gelie net layers 30 minutes
Reach full dissolution.
The metformin hydrochloride tablet layer drug release determination result of table 17
The net lamella dissolution determination results of the En Gelie of table 18
Claims (10)
- A kind of 1. double-layer tablets net comprising Metformin hydrochloride and En Gelie, it is characterised in that the metformin hydrochloride tablet layer For slow release layer, the net lamellas of En Gelie are release layer, also, the diabecron sustained-release layer is 12 hours to 24 hours Slow release layer；The slow release layer of preferably 12 hours or 24 hours.
- 2. double-layer tablets according to claim 1, wherein, the metformin hydrochloride tablet layer eases up including Metformin hydrochloride Release agent；Preferably, Metformin hydrochloride and sustained release agent account for the 40~80% of the metformin hydrochloride tablet layer weight percentage respectively With 10~50%；It is highly preferred that the Metformin hydrochloride and sustained release agent account for the 55 of the metformin hydrochloride tablet layer weight percentage respectively ~70% and 20~40%；Preferably, 500~2000mg Metformin hydrochloride is included in the metformin hydrochloride tablet layer；More preferably include 500th, 850 or 1000mg Metformin hydrochloride；Preferably, the sustained release agent be selected from hydroxypropyl methyl cellulose, carbomer, ethyl cellulose, polyoxyethylene, PVP and One or more in sodium alginate；It is highly preferred that the sustained release agent is selected from hydroxypropyl methyl cellulose；It is further preferred that the hydroxypropyl methyl cellulose in E4M, E10M, K100LV, K4M, K15M, K100M One or more, more preferably K4M, K15M, it is still more preferably K4M.
- 3. double-layer tablets according to claim 1 or 2, wherein, the metformin hydrochloride tablet layer also includes pharmaceutically connecing The auxiliary material received；The auxiliary material is preferably filler, adhesive, lubricant and/or glidant；Preferably, the filler accounts for the 0~15% of the metformin hydrochloride tablet layer weight percentage；Preferably, described adhesive accounts for the 1~10% of the metformin hydrochloride tablet layer weight percentage；Preferably, the lubricant accounts for the 0.1~2% of the metformin hydrochloride tablet layer weight percentage；Preferably, the glidant accounts for the 0.1~2% of the metformin hydrochloride tablet layer weight percentage.
- 4. according to the double-layer tablets any one of claim 1-3, wherein, the net lamellas of En Gelie include En Gelie only and Disintegrant；Preferably, the En Gelie is net and disintegrant accounts for the 2~6% and 1 of the net lamella percentage by weights of the En Gelie respectively ~5%；Preferably, En Gelie of the net lamellas of the En Gelie comprising 1~30mg is net, the more preferably En Gelie comprising 2~25mg Only, further preferably the En Gelie comprising 5mg, 10mg, 12.5mg or 25mg is net；Preferably, one kind in PVPP, Ac-Di-Sol, sodium carboxymethyl starch of the disintegrant or A variety of, preferably described disintegrant is PVPP.
- 5. according to the double-layer tablets any one of claim 1-4, wherein, the net lamellas of En Gelie also include pharmaceutically may be used The auxiliary material of receiving, the auxiliary material are preferably filler, adhesive, lubricant and/or glidant；Preferably, the filler accounts for the 83~94.8% of the net lamella percentage by weights of the En Gelie；Preferably, described adhesive accounts for the 2~4% of the net lamella percentage by weights of the En Gelie；Preferably, the lubricant accounts for the 0.1~1% of the net lamella percentage by weights of the En Gelie；Preferably, the glidant accounts for the 0.1~1% of the net lamella percentage by weights of the En Gelie.
- 6. according to the double-layer tablets any one of claim 1-5, wherein, the filler is selected from lactose, starch, sweet dew One or more in alcohol, microcrystalline cellulose, it is therefore preferable to Lactis Anhydrous and/or microcrystalline cellulose；One kind in PVP, starch slurry, low molecule amount hydroxypropyl methylcellulose, sodium carboxymethylcellulose of described adhesive or It is a variety of, it is therefore preferable to PVP, sodium carboxymethylcellulose, low molecule amount hydroxypropyl cellulose；Lubricant and the glidant choosing One or more from magnesium stearate, stearic acid, stearyl alcohol, rilanit special, silica and colloidal silica, preferably Ground glidant is that silica lubricant is magnesium stearate.
- 7. according to the double-layer tablets any one of claim 1-6, wherein, the double-layer tablets also include optional film bag Clothing, the film coating are used to cover the net release layer of the diabecron sustained-release layer and En Gelie；Preferably, the material of the film coating is in Opadry, cellulose acetate, acrylic resin, ethyl cellulose One or more, more preferably Opadry；Preferably, the weightening of the film coating is the 0.5wt.%-5wt.%, more preferably 1.5wt.- of the double-layer tablets 2.5wt.%.
- 8. the preparation method of the double-layer tablets as described in claim 1~7, the described method comprises the following steps：1) metformin hydrochloride tablet layer particle is prepared；2) the net lamella particles of En Gelie are prepared；3) double-layer tablets are suppressed on a bi-layer tablet press；Preferably, the tablet press machine is ZPW23 rotary tablet machines；It is optionally possible to carry out film coating；Preferably, the step 1) including the step of following methods by realizing：A) adhesive is dissolved in water, compound concentration is 10% adhesive；Preferably, described adhesive is sodium cellulose glycolate；B) auxiliary material by Metformin hydrochloride and than adhesives crosses 100 mesh sieves respectively；C) Metformin hydrochloride after sieving and sustained release agent, filler are added in granulator and mixed；Preferably, the granulator is high-shearing granulation machine；Preferably, the high-shearing granulation machine is the more pot wet-mixing fast granulating machines of SHK-10B；It is highly preferred that the parameter of the high-shearing granulation machine is agitating paddle 800rpm, cutting knife 2000rpm, 120s；D) adhesive made from step a) is added, using granulator wet granulation；Preferably, the granulator is high-shearing granulation machine；Preferably, the parameter of the high-shearing granulation machine is agitating paddle 800rpm, cutting knife 2000rpm, 180s；E) particle obtained using fluidized bed drying step d), it is less than 2.0% to moisture；Preferably, the fluid bed is UN1GLATT fluid beds；Preferably, temperature of charge 35-45 degree is kept in the drying process；F) the particle whole grain for obtaining step e)；Preferably, the whole grain uses FZB150 crushing and pelletizing machines；Preferably, the parameter of the pelletizing machine is rotating speed 2000rpm, mesh size 1.2um；G) particle is transferred in hopper mixer, adds lubricant and glidant, be well mixed, obtain metformin hydrochloride tablet Layer particle；Preferably, the hopper mixer is HLS-50 laboratories hopper mixer；Preferably, the parameter of the hopper mixer is 24rrpm, 180s；Preferably, the particle diameter of the Metformin hydrochloride is 2~1000 μm, preferably 150~1000 μm；Preferably, obtained metformin hydrochloride tablet layer particle is subjected to intermediate detection, method is external standard method, using ultraviolet point Light photometer determines its content, determines the piece weight of metformin hydrochloride tablet layer；Preferably, the step 2) including the step of following methods by realizing：A) it is net to handle En Gelie, it is 50 μm~100 μm to make its particle diameter；Preferably, it is net using airslide disintegrating mill processing En Gelie；B) other auxiliary materials in addition to adhesive are crossed into 100 mesh sieves respectively；C) after the En Gelie for obtaining step a) is only and step b) obtained disintegrant, filler weigh according to recipe quantity, use Granulator mixes；Preferably, the granulator is high-shearing granulation machine；Preferably, the parameter of the high-shearing granulation machine is agitating paddle 800rpm, cutting knife 2000rpm, 120s；D) adhesive is added in the particle that step c) is obtained, uses granulator wet granulation；Preferably, the granulator is high-shearing granulation machine；Preferably, the parameter of the high-shearing granulation machine is agitating paddle 800rpm, cutting knife 2000rpm, 180s；E) particle obtained using fluidized bed drying step d), it is less than 2.0% to moisture；Preferably, the fluid bed is UN1GLATT fluid beds；Preferably, temperature of charge 35-45 degree is kept in the drying process；F) the particle whole grain for obtaining step e)；Preferably, the whole grain uses FZB150 crushing and pelletizing machines；Preferably, the parameter of the pelletizing machine is rotating speed 2000rpm, mesh size 1.2um；G) particle is transferred in hopper mixer, adds lubricant and glidant, be well mixed, obtain En Gelie net layers Grain；Preferably, the hopper mixer is HLS-50 laboratories hopper mixer；Preferably, the parameter of the hopper mixer is 24rrpm, 180s；Preferably, obtained particle is subjected to intermediate detection；Preferably methods described is external standard method, true using liquid chromatograph The net piece synusia weights of Ding Engelie.
- 9. method as claimed in claim 8, wherein, film coating is carried out to the double-layer tablets, methods described includes following step Suddenly：Operation is coated using the ordinary operation mode of film coating, double-deck sheet weight is reached with tablet coating weight gain 1.5%~2.5%, produce.
- 10. purposes of the double-layer tablets in preparing treatment and/or improving the medicine of diabetes B as described in claim 1-7.
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| CN114469896A (en) * | 2020-10-26 | 2022-05-13 | 江苏万邦生化医药集团有限责任公司 | Metformin hydrochloride sustained-release empagliflozin hydrochloride quick-release pellet and preparation method thereof |
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| CN115154456A (en) * | 2022-05-24 | 2022-10-11 | 通化东宝药业股份有限公司 | Pharmaceutical composition of metformin and engelizin and preparation method thereof |
| CN115154456B (en) * | 2022-05-24 | 2023-11-10 | 通化东宝药业股份有限公司 | Pharmaceutical composition of metformin and enggliflozin and preparation method thereof |
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