CN109432030A - A kind of saxagliptin melbine double-layer tablets and preparation method thereof - Google Patents
A kind of saxagliptin melbine double-layer tablets and preparation method thereof Download PDFInfo
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- CN109432030A CN109432030A CN201811468528.6A CN201811468528A CN109432030A CN 109432030 A CN109432030 A CN 109432030A CN 201811468528 A CN201811468528 A CN 201811468528A CN 109432030 A CN109432030 A CN 109432030A
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- melbine
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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
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
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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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Abstract
The present invention provides a kind of saxagliptin melbine double-layer tablets and preparation method thereof, are mainly made of melbine particle and saxagliptin particle；Melbine particle mainly includes following component: in terms of mass fraction, 500-1000 parts of Metformin hydrochloride, 25-50 parts of carboxymethyl cellulose, 3.5-7 parts of silica, 190-390 parts of hypromellose, 5-10 parts of magnesium stearate；Saxagliptin particle mainly includes following component: in terms of mass fraction, 2.5-5.4 parts of saxagliptin monohydrate, 138-142 parts of microcrystalline cellulose, 30-60 parts of lactose, 3-6 parts of hypromellose, 0.5-2 parts of magnesium stearate.After saxagliptin melbine double-layer tablets of the invention are by carrying out effective interworking for supplementary material, so that double-layer tablets efficacy stability obtained after cooperation, highly-safe, it is at low cost.
Description
Technical field
The present invention relates to saxagliptin melbine compound medicine preparation fields, in particular to a kind of saxagliptin
Melbine double-layer tablets and preparation method thereof.
Background technique
Saxagliptin is secretin's class antidiabetic drug, and different from other simple promotion drugs of insulin secretion, intestines promote pancreas
Plain class antidiabetic drug is since its effect is in glucose dependency, i.e., only " commander " produces pancreas islet when blood glucose rise
Element, therefore it has protective effect to islet beta cell function.Multinomial international research shows that secretin's class can not only promote pancreas
Island β cells secrete insulin reduces blood glucose, moreover it is possible to reduce the apoptosis of β cell, to delay disease process, be expected to fundamentally
Contain the process of diabetes B.
Melbine belongs to biguanides hypoglycemic drug, has the glucose tolerance for improving type 2 diabetic patient, reduces
The effect on basis and postprandial blood sugar.The blood sugar reducing function mechanism of melbine are as follows: reduce the generation of glycogen, reduce small intestine to glucose
Absorption, and the uptake and utilization of glucose can be improved with the sensibility of insulin by increasing peripheral tissues.Currently, two
First biguanides is the widely used antidiabetic drug of developed country in the world, be particularly suitable for treatment concomitant fertilizer is fat, plasma insulin is higher, after
The hair property sulfonylureas failure patient bad with type 1 diabetes insulin therapy and control.
Since melbine and saxagliptin have complementarity in treating diabetes mechanism, both drugs are joined
When sharing medicine, the therapeutic effect of drug can be enhanced, therefore melbine and saxagliptin can be made into compound system in the prior art
Agent, but saxagliptin is to belong to alkaline drug, Metformin hydrochloride belong to acidic drug, and the Mechanism of Drug Release of the two is completely not yet
Together, if degradation may be played the role of to drug itself by directly carrying out mixing, the normal performance of drug effect is influenced, is also influenced multiple
The medicine stability of square preparation.
In view of this, the present invention is specifically proposed.
Summary of the invention
The first object of the present invention is to provide a kind of formula of saxagliptin melbine double-layer tablets, pass through in the formula
After supplementary material is carried out effective interworking, so that double-layer tablets efficacy stability obtained after cooperation, highly-safe, it is at low cost, it is worth
It is widely popularized and is applied.
The second object of the present invention is to provide the specific preparation method of above-mentioned saxagliptin melbine double-layer tablets, itself
Preparation method is simple, easy to operate, and operating condition is also relatively milder, and the linking of forward/backward operation step is close, provides for subsequent operation
The foundation that can be referred to, using melbine as matrix sustained release tablet in preparation process, it is slow that saxagliptin is wrapped in melbine
On piece is released, and one layer of separation layer will be increased between two kinds of main ingredients in preparation process, the drug effect of two drugs can be made equal
Can stable performance, do not have it is any interact, be also more favorable for the marketing of the compound preparation.
In order to realize above-mentioned purpose of the invention, the following technical scheme is adopted:
The embodiment of the invention provides a kind of saxagliptin melbine double-layer tablets, mainly by melbine particle and husky lattice
Arrange spit of fland particle composition；
The melbine particle mainly includes following component: in terms of mass fraction, 500-1000 parts of Metformin hydrochloride,
25-50 parts of carboxymethyl cellulose, 3.5-7 parts of silica, 190-390 parts of hypromellose, 5-10 parts of magnesium stearate；
The saxagliptin particle mainly includes following component: in terms of mass fraction, saxagliptin monohydrate 2.5-5.4
Part, 138-142 parts of microcrystalline cellulose, 30-60 parts of lactose, 3-6 parts of hypromellose, 0.5-2 parts of magnesium stearate.
In above-mentioned formula, carboxymethyl cellulose has excellent water imbibition and water swellability, can achieve improvement tablet
Mouldability effect, lactose be excellent diluent, property stablize, microcrystalline cellulose excipients are also excellent diluent, firmly
Fatty acid magnesium, silica belong to common filler, after the present invention is by carrying out reasonable compatibility for these auxiliary materials and bulk pharmaceutical chemicals,
Melbine particle and saxagliptin particle are first prepared respectively, double-layer tablets then are made in the two tabletting again, although above-mentioned
Auxiliary material belongs to the common auxiliary material in pharmacy procedure, but in order to prepare double-layer tablets of the invention, applicant is for above-mentioned dosage
The optimization for being suitable for, so that the effective ingredient dissolution rate for the double-layer tablets being prepared is high, efficacy stability, greatly
The marketing dynamics of the compound preparation is improved, provides a kind of new dosage form for saxagliptin melbine compound preparation,
The dosage form is more suitable the drug release process of saxagliptin melbine, therefore the benefit that more should be widely promoted compared to other dosage forms
With.
It should be noted that formula of the invention belong to it is open, in addition to the above-mentioned ingredient for including, however not excluded that also contain
Have in other ingredients, such as the ingredient of saxagliptin particle, also may include sodium hydroxide, hydrochloric acid, purified water, and be coated
Used some components etc. in journey, these components can directly QS be added according to national standards certainly.
Preferably, in order to optimize the proportion between each component, the melbine particle mainly includes following component: with
Mass fraction meter, 600-800 parts of Metformin hydrochloride, 30-40 parts of carboxymethyl cellulose, 4-6 parts of silica, hydroxypropyl is fine
200-350 parts of element of dimension, 6-8 parts of magnesium stearate.
Preferably, in order to optimize the proportion between each component, the saxagliptin particle mainly includes following component: with
Mass fraction meter, 3-4 parts of saxagliptin monohydrate, 139-140 parts of microcrystalline cellulose, 40-50 parts of lactose, hydroxypropyl methylcellulose
It is 4-5 parts plain, 1-1.5 parts of magnesium stearate.
In addition to this, on the mass fraction of each component, Metformin hydrochloride can also be 610 parts, 620 parts, 630 parts
Can also be 31 parts, 32 parts, 33 parts and 34 parts etc. Deng, carboxymethyl cellulose, hypromellose can also for 210 parts,
220 parts, 240 parts, 250 parts, 300 parts, 310 parts, 330 parts etc..
Saxagliptin monohydrate can also be 3.2 parts, 3.3 parts, 3.4 parts, 3.5 parts etc., and microcrystalline cellulose can also be
139.5 parts, 139.6 parts, 139.7 parts, 139.8 parts etc., the dosage of lactose can also be 41 parts, 43 parts, 44 parts, 46 parts, 47 parts
Deng.
The present invention additionally provides the system of the double-layer tablets in addition to providing a kind of formula of saxagliptin melbine double-layer tablets
Preparation Method includes the following steps:
(A) by Metformin hydrochloride, carboxymethyl cellulose, silica adds one after hypromellose mixing
Point magnesium stearate, after dry granulation, add the magnesium stearate mixing of surplus, obtain melbine particle；
(B) saxagliptin monohydrate is dissolved to form solution, after adding hypromellose powder, adjusts solution
Microcrystalline cellulose and lactose are mixed to binder is made between 1.0-5.0 and add the binder, wet process system for a period of time by pH
Grain, stiffened fatty acid magnesium total mix obtain saxagliptin particle；
(C) after saxagliptin particle described in melbine particle described in inner layer piece and outer-skin sheet being total to tabletting, coating.
In above-mentioned preparation process, melbine particle is relatively difficult due to itself meeting wet grain of controlling, using dry method
The mode of granulation, and saxagliptin particle makes two by first pelletizing respectively using a mode is controlled than convenient wet process
After drug is divided mutually, then the method for carrying out tabletting, influence of two kinds of drugs to dissolution rate each other can be effectively avoided in this way, especially
In its saxagliptin preparation process, the pH in binder preparation process is the key that need to control, because saxagliptin particle is
Outer-skin sheet is main ingredient to be coated to production, therefore only control the ginseng of the operation in preparation process during the preparation process
Number, could make the double-layer tablets being prepared not only and can solve the stability of two main ingredients, but also cannot influence the release of two main ingredients
Behavior.
PH in above-mentioned technique can also be 2.0,3.0,4.0,2.5,3.5,4.5 etc..
In addition, in order to improve giving full play to for drug effect, the thickness of outer-skin sheet itself and the thickness of inner layer piece are preferably also controlled
Than convenient range, thickness control is at (1-3): between 2.
Preferably, in the step (A), Metformin hydrochloride, carboxymethyl cellulose mesh granularity control more than 40 mesh；
Preferably, magnesium stearate, silica mesh granularity control more than 60 mesh, by by the mesh granularity of each ingredient
It carries out being suitable for control, so that the melbine granular texture being prepared is than more uniform.
Preferably, in the step (A), Metformin hydrochloride, carboxymethyl cellulose, silica, hydroxypropyl methylcellulose
The time of element mixing controls between 40-60min, mixes 4-6min after adding the magnesium stearate of a part；
Preferably, in dry granulation process, in 200-400rpm, mesh size is controlled in 0.7- for the revolving speed control of whole grain
0.9mm；
Preferably, after the magnesium stearate for adding surplus, 4-6min is mixed.
Preferably, in the step (B), it is molten that hydrochloric acid and water are first mixed to form the hydrochloric acid between 0.05-0.15mol/L
The saxagliptin monohydrate is dissolved in the hydrochloric acid solution by liquid, stirs 4-6min, best in order to increase dissolubility
It is that saxagliptin monohydrate is dissolved in hydrochloric acid solution, and is smoothly carried out for the ease of subsequent step, mole of hydrochloric acid
Concentration is preferably controlled in certain range, cannot it is excessively high can not be too low, behind adjust pH value and also facilitate operation, and adjust below
The pH value of section is adapted.
Preferably, it is adjusted when adjusting pH value using the sodium hydroxide solution of 3-7mol/L, in addition to using sodium hydroxide
Other inorganic bases also can be used.
Preferably, in the step (B), microcrystalline cellulose and lactose mixing 8-12min are added；
Preferably, in wet-granulation process, drying is to moisture in 2.0wt% or less.
Preferably, in the step (B), after wet granulation, the revolving speed of whole grain is controlled in 400-600rpm, mesh size control
System is between 0.7-0.9mm.
Preferably, in the step (B), after adding the magnesium stearate, 4-6min is mixed.
Compared with prior art, the invention has the benefit that
(1) formula of saxagliptin melbine double-layer tablets provided by the invention, by carrying out supplementary material in the formula
After effective interworking, so that double-layer tablets efficacy stability obtained after cooperation, highly-safe, at low cost, should be widely promoted progress
Using；
(2) the specific preparation method of saxagliptin melbine double-layer tablets provided by the invention, preparation method itself is simple,
Easy to operate, operating condition is also relatively mild, and the linking of forward/backward operation step is close, provided for subsequent operation can refer to according to
According to using melbine as matrix sustained release tablet in preparation process, saxagliptin is wrapped on Metformin Extended-release Tablets, and is passed through
One layer of separation layer will be increased between two kinds of main ingredients in preparation process, can make the drug effect stable hair of energy of two drugs
Wave, do not have it is any interact, be also more favorable for the marketing of the compound preparation.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and is not construed as limiting the scope of the invention.It is not specified in embodiment specific
Condition person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer is
The conventional products that can be obtained by commercially available purchase.
Embodiment 1
The preparation process of saxagliptin melbine double-layer tablets is in accordance with the following steps:
1. melbine particle preparation:
1) Metformin hydrochloride 1000g, carboxymethyl cellulose 50g are weighed according to recipe quantity, crosses 40 meshes, stearic acid respectively
Magnesium 10g and superfine silica gel powder 7g (silica) crosses 60 mesh and sieves by hand；
2) melbine, carboxymethyl cellulose, hypromellose K100M grades of 260g, hypromellose will be taken
CR grades of 130g of K15M and superfine silica gel powder use hopper mixing machine mixing 40min, and magnesium stearate (interior to add) 5g mixing 6min is added；
3) material mixed is pelletized using dry granulating machine, whole grain revolving speed: 200rpm, whole grain mesh size:
0.9mm；
4) remaining magnesium stearate (additional) 5g mixing 4min total mix: is added.
2. saxagliptin particle preparation:
1) 138g microcrystalline cellulose 101 being weighed according to recipe quantity and 60g lactose crossing 40 meshes, 0.5g magnesium stearate crosses 60 mesh
Sieve by hand, 2.5g saxagliptin monohydrate and 6g hypromellose E5 are not sieved.
2) adhesive configures: the desired amount of purified water being added in liquid dispensing container and then hydrochloric acid is added, is configured to
0.05mol/L hydrochloric acid solution, stirring form it into whirlpool, saxagliptin monohydrate are even added in solvent, stir
4min makes it dissolve, and is then slowly even added to hypromellose E5 powder in solvent, continues to stir to completely molten
Solution adjusts coating solution pH between 1.0-5.0 with the sodium hydroxide solution of 3mol/L；
3) microcrystalline cellulose 101 and lactose are added in bulk drug of pretreatment adds with interior granulator, mix 8min, be added 2) adhesive into
Row granulation；
4) 3) gained wet granular is dried using fluidized bed, it is dry to moisture 2.0wt% or less；
5) it does whole grain: using 0.9mm circular hole sieve, whole grain revolving speed: 400rpm；
6) total mix: 5) particle and magnesium stearate are added in hopper mixing machine, mix 4min；
3. tabletting
1) hopper 1 is added in obtained melbine particle, hopper 2, melbine particle is added in saxagliptin particle
As inner layer piece, saxagliptin particle is as outer-skin sheet；
2) start tablet press machine, adjusting parameter to target weight and hardness carry out tabletting.
4. coating
Opadry is made into the coating solution of solid content 12.5%, is coated using seed-coating machine, coating weight gain range:
2.0%-4.0%.
Embodiment 2
The preparation process of saxagliptin melbine double-layer tablets is in accordance with the following steps:
1. melbine particle preparation:
1) Metformin hydrochloride 500g, sodium carboxymethylcellulose 25g are weighed according to recipe quantity, crosses 50 meshes respectively, it is stearic
Sour magnesium 5g and superfine silica gel powder 3.5g (silica) crosses 70 mesh and sieves by hand；
2) melbine, sodium carboxymethylcellulose, hypromellose K100M grades of 130g, hydroxypropyl methylcelluloses will be taken
Plain K15M CR grades of 60g and superfine silica gel powder use hopper mixing machine mixing 60min, and magnesium stearate (interior to add) 2.5g mixing is added
4min；
3) material mixed is pelletized using dry granulating machine, whole grain revolving speed: 400rpm, whole grain mesh size:
0.7mm；
4) remaining magnesium stearate (additional) 2.5g mixing 6min total mix: is added.
2. saxagliptin particle preparation:
1) 142g microcrystalline cellulose 101 being weighed according to recipe quantity and 30g lactose crossing 50 meshes, 0.5g magnesium stearate crosses 70 mesh
Sieve by hand, 5.4g saxagliptin monohydrate and 3g hypromellose E5 are not sieved.
2) adhesive configures: the desired amount of purified water being added in liquid dispensing container and then hydrochloric acid is added, is configured to
0.15mol/L hydrochloric acid solution, stirring form it into whirlpool, saxagliptin monohydrate are even added in solvent, stir
6min makes it dissolve, and is then slowly even added to hypromellose E5 powder in solvent, continues to stir to completely molten
Solution adjusts coating solution pH between 1.0-5.0 with the sodium hydroxide solution of 7mol/L；
3) microcrystalline cellulose 101 and lactose are added in bulk drug of pretreatment adds with interior granulator, mix 12min, 2) adhesive is added
It pelletizes；
4) 3) gained wet granular is dried using fluidized bed, it is dry to moisture 2.0wt% or less；
5) it does whole grain: using 0.7mm circular hole sieve, whole grain revolving speed: 600rpm；
6) total mix: 5) particle and magnesium stearate are added in hopper mixing machine, mix 6min；
3. tabletting
1) hopper 1 is added in obtained melbine particle, hopper 2, melbine particle is added in saxagliptin particle
As inner layer piece, saxagliptin particle is as outer-skin sheet；
2) start tablet press machine, adjusting parameter to target weight and hardness carry out tabletting.
4. coating
Opadry is made into the coating solution of solid content 12.5%, is coated using seed-coating machine, coating weight gain range:
2.0%-4.0%.
Embodiment 3
The preparation process of saxagliptin melbine double-layer tablets is in accordance with the following steps:
1. melbine particle preparation:
1) Metformin hydrochloride 600g, sodium carboxymethylcellulose 30g are weighed according to recipe quantity, crosses 40 meshes respectively, it is stearic
Sour magnesium 6g and superfine silica gel powder 4g (silica) crosses 60 mesh and sieves by hand；
2) melbine, sodium carboxymethylcellulose, hypromellose K100M grades of 150g, hydroxypropyl methylcelluloses will be taken
Plain K15M CR grades of 50g and superfine silica gel powder use hopper mixing machine mixing 50min, and magnesium stearate (interior to add) 3g mixing 5min is added；
3) material mixed is pelletized using dry granulating machine, whole grain revolving speed: 300rpm, whole grain mesh size:
0.8mm；
4) remaining magnesium stearate (additional) 3g mixing 5min total mix: is added.
2. saxagliptin particle preparation:
1) 140g microcrystalline cellulose 101 being weighed according to recipe quantity and 40g lactose crossing 50 meshes, 1.5g magnesium stearate crosses 70 mesh
Sieve by hand, 3g saxagliptin monohydrate and 5g hypromellose E5 are not sieved.
2) adhesive configures: the desired amount of purified water stirring being added in liquid dispensing container and forms it into whirlpool, by Sha Gelie
Spit of fland monohydrate is even added in liquid dispensing container, and stirring 5min makes it dissolve, and then delays hypromellose E5 powder
Slowly be even added in solvent, continue stirring to being completely dissolved, with the potassium hydroxide solution of 2mol/L adjust coating solution pH to
Between 1.0-5.0；
3) microcrystalline cellulose 101 and lactose are added in bulk drug of pretreatment adds with interior granulator, mix 10min, 2) adhesive is added
It pelletizes；
4) 3) gained wet granular is dried using fluidized bed, it is dry to moisture 2.0wt% or less；
5) it does whole grain: using 0.8mm circular hole sieve, whole grain revolving speed: 500rpm；
6) total mix: 5) particle and magnesium stearate are added in hopper mixing machine, mix 5min；
3. tabletting
1) hopper 1 is added in obtained melbine particle, hopper 2, melbine particle is added in saxagliptin particle
As inner layer piece, saxagliptin particle is as outer-skin sheet；
2) start tablet press machine, adjusting parameter to target weight and hardness carry out tabletting.
4. coating
Opadry is made into the coating solution of solid content 12.5%, is coated using seed-coating machine, coating weight gain range:
2.0%-4.0%.
Embodiment 4
The preparation process of saxagliptin melbine double-layer tablets is in accordance with the following steps:
1. melbine particle preparation:
1) Metformin hydrochloride 800g, sodium carboxymethylcellulose 40g are weighed according to recipe quantity, crosses 40 meshes respectively, it is stearic
Sour magnesium 8g and superfine silica gel powder 6g (silica) crosses 60 mesh and sieves by hand；
2) melbine, sodium carboxymethylcellulose, hypromellose K100M grades of 200g, hydroxypropyl methylcelluloses will be taken
Plain K15M CR grades of 150g and superfine silica gel powder use hopper mixing machine mixing 55min, and magnesium stearate (interior to add) 4g mixing is added
5min；
3) material mixed is pelletized using dry granulating machine, whole grain revolving speed: 300rpm, whole grain mesh size:
0.8mm；
4) remaining magnesium stearate (additional) 4g mixing 5min total mix: is added.
2. saxagliptin particle preparation:
1) 139g microcrystalline cellulose 101 being weighed according to recipe quantity and 50g lactose crossing 40 meshes, 1g magnesium stearate crosses 60 mesh hands
Work sieve, 4g saxagliptin monohydrate and 4g hypromellose E5 are not sieved.
2) adhesive configures: the desired amount of purified water being added in liquid dispensing container and then hydrochloric acid is added, is configured to
0.10mol/L hydrochloric acid solution, stirring form it into whirlpool, saxagliptin monohydrate are even added in solvent, stir
5min makes it dissolve, and is then slowly even added to hypromellose E5 powder in solvent, continues to stir to completely molten
Solution adjusts coating solution pH between 1.0-5.0 with the sodium hydroxide solution of 4mol/L；
3) microcrystalline cellulose 101 and lactose are added in bulk drug of pretreatment adds with interior granulator, mix 10min, 2) adhesive is added
It pelletizes；
4) 3) gained wet granular is dried using fluidized bed, it is dry to moisture 2.0wt% or less；
5) it does whole grain: using 0.8mm circular hole sieve, whole grain revolving speed: 500rpm；
6) total mix: 5) particle and magnesium stearate are added in hopper mixing machine, mix 5min；
3. tabletting
1) hopper 1 is added in obtained melbine particle, hopper 2, melbine particle is added in saxagliptin particle
As inner layer piece, saxagliptin particle is as outer-skin sheet；
2) start tablet press machine, adjusting parameter to target weight and hardness carry out tabletting.
4. coating
Opadry is made into the coating solution of solid content 12.5%, is coated using seed-coating machine, coating weight gain range:
2.0%-4.0%.
Comparative example 1
Other operating procedures and above-described embodiment 5 are consistent, when only preparing melbine particle in step 1, auxiliary material carboxylic first
Base sodium cellulosate 80g, magnesium stearate 3g, superfine silica gel powder 10g (silica), hypromellose K100M grades of 200g, hydroxypropyls
CR grades of 150g of methylcellulose K15M.
Comparative example 2
Other operating procedures and above-described embodiment 5 are consistent, when only preparing saxagliptin particle in step 2, auxiliary material 150g
Microcrystalline cellulose 101 and 20g lactose, 0.2g magnesium stearate, 4g saxagliptin monohydrate and 1g hypromellose E5.
Comparative example 3
Other operating procedures and above-described embodiment 5 are consistent, only in step 2 during saxagliptin particle preparation, 2)
In adhesive configuration process, the pH of adjusting is between 6-7.
Experimental example 1
The result of extraction of saxagliptin melbine bilayer tablet preparation in above-mentioned each embodiment and comparative example is carried out
Detection, concrete outcome see the table below 1.
Table 1 dissolves out data result
It can be seen that the result of extraction of the main ingredient of the embodiment of the present invention is significantly better than comparative example from the data in above-mentioned table 1,
In addition to need to major-minor material formula carry out it is reasonably combined other than, it is also necessary to control each operating parameter in preparation method.
Although illustrate and describing the present invention with specific embodiment, it will be appreciated that without departing substantially from of the invention
Many other change and modification can be made in the case where spirit and scope.It is, therefore, intended that in the following claims
Including belonging to all such changes and modifications in the scope of the invention.
Claims (10)
1. a kind of saxagliptin melbine double-layer tablets, which is characterized in that mainly by melbine particle and saxagliptin particle
Composition；
The melbine particle mainly includes following component: in terms of mass fraction, 500-1000 parts of Metformin hydrochloride, and carboxylic first
25-50 parts of base cellulose, 3.5-7 parts of silica, 190-390 parts of hypromellose, 5-10 parts of magnesium stearate；
The saxagliptin particle mainly includes following component: in terms of mass fraction, 2.5-5.4 parts of saxagliptin monohydrate,
138-142 parts of microcrystalline cellulose, 30-60 parts of lactose, 3-6 parts of hypromellose, 0.5-2 parts of magnesium stearate.
2. saxagliptin melbine double-layer tablets according to claim 1, which is characterized in that the melbine particle master
To include following component: in terms of mass fraction, 600-800 parts of Metformin hydrochloride, 30-40 parts of carboxymethyl cellulose, titanium dioxide
4-6 parts of silicon, 200-350 parts of hypromellose, 6-8 parts of magnesium stearate.
3. saxagliptin melbine double-layer tablets according to claim 1, which is characterized in that the saxagliptin particle master
To include following component: in terms of mass fraction, 3-4 parts of saxagliptin monohydrate, 139-140 parts of microcrystalline cellulose, lactose 40-
50 parts, 4-5 parts of hypromellose, 1-1.5 parts of magnesium stearate.
4. the preparation method of the described in any item saxagliptin melbine double-layer tablets of claim 1-3, which is characterized in that including
Following steps:
(A) by Metformin hydrochloride, carboxymethyl cellulose, silica adds a part after hypromellose mixing
Magnesium stearate after dry granulation, adds the magnesium stearate mixing of surplus, obtains melbine particle；
(B) saxagliptin monohydrate is dissolved to form solution, after adding hypromellose powder, adjust the pH of solution to
Binder is made between 1.0-5.0, microcrystalline cellulose and lactose are mixed and add the binder for a period of time, wet granulation,
Stiffened fatty acid magnesium total mix obtains saxagliptin particle；
(C) after saxagliptin particle described in melbine particle described in inner layer piece and outer-skin sheet being total to tabletting, coating.
5. the preparation method according to claim 4, which is characterized in that in the step (A), Metformin hydrochloride, carboxylic first
The mesh granularity of base cellulose controls more than 40 mesh；
Preferably, the mesh granularity control of magnesium stearate, silica is more than 60 mesh.
6. the preparation method according to claim 4, which is characterized in that in the step (A), Metformin hydrochloride, carboxylic first
The time of base cellulose, silica, hypromellose mixing controls between 40-60min, adds the tristearin of a part
4-6min is mixed after sour magnesium；
Preferably, in dry granulation process, in 200-400rpm, mesh size is controlled in 0.7-0.9mm for the revolving speed control of whole grain；
Preferably, after the magnesium stearate for adding surplus, 4-6min is mixed.
7. the preparation method according to claim 4, which is characterized in that in the step (B), hydrochloric acid is first mixed shape with water
At the hydrochloric acid solution between 0.05-0.15mol/L, the saxagliptin monohydrate is dissolved in the hydrochloric acid solution, is stirred
Mix 4-6min；
Preferably, it is adjusted when adjusting pH value using the sodium hydroxide solution of 3-7mol/L.
8. the preparation method according to claim 4, which is characterized in that in the step (B), add microcrystalline cellulose and cream
Sugar mixing 8-12min；
Preferably, in wet-granulation process, drying is to moisture in 2.0wt% or less.
9. the preparation method according to claim 4, which is characterized in that in the step (B), after wet granulation, whole grain
Revolving speed controls between 400-600rpm, and the mesh size of whole grain is controlled in 0.7-0.9mm.
10. the preparation method according to claim 4, which is characterized in that in the step (B), after adding the magnesium stearate,
Mix 4-6min.
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| CN112546013A (en) * | 2020-12-29 | 2021-03-26 | 平光制药股份有限公司 | Saxagliptin metformin double-layer tablet and preparation process thereof |
| CN114010612A (en) * | 2021-11-24 | 2022-02-08 | 上海普康药业有限公司 | Sitagliptin and metformin double-layer sustained release tablet and preparation method thereof |
| CN116211819A (en) * | 2023-04-12 | 2023-06-06 | 华润双鹤药业股份有限公司 | Liagliptin metformin hydrochloride multi-layer tablet and preparation method thereof |
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Inventor after: Du Jiaqiu Inventor after: Cai Qiuhua Inventor after: Dong Fuxia Inventor after: Ren Qian Inventor before: Cai Qiuhua Inventor before: Dong Fuxia Inventor before: Du Jiaqiu Inventor before: Ren Qian |
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Application publication date: 20190308 |