CN105663131A - Repaglinide and metformin hydrochloride tablet pharmaceutical composition and preparation method thereof - Google Patents

Repaglinide and metformin hydrochloride tablet pharmaceutical composition and preparation method thereof Download PDF

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Publication number
CN105663131A
CN105663131A CN201610009632.3A CN201610009632A CN105663131A CN 105663131 A CN105663131 A CN 105663131A CN 201610009632 A CN201610009632 A CN 201610009632A CN 105663131 A CN105663131 A CN 105663131A
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repaglinide
granule
metformin
preparation
microcrystalline cellulose
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CN105663131B (en
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王颖
伍熹
黄磊
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Chengdu Easton Biopharmaceuticals Co Ltd
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Chengdu Easton Biopharmaceuticals Co Ltd
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • 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)
    • 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
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • 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
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Abstract

The invention provides a repaglinide and metformin hydrochloride tablet pharmaceutical composition; in a prescription, the amount of a disintegrating agent is greatly reduced compared with the prior art; in a process, microcrystalline cellulose particles are prepared in advance, repaglinide is made into a solution, repaglinide particles are prepared on the microcrystalline cellulose particles through fluidized bed atomizing, and the repaglinide particles are mixed and tabletted with metformin hydrochloride particles. The prepared repaglinide and metformin hydrochloride tablet product is stable, the insoluble drug repaglinide and the water-soluble drug metformin hydrochloride are both released synchronously according to requirements, and the bioavailability is better compared with that of the prior art; and at the same time, the problem of uneven mixing of the low-dosage drug repaglinide is solved, and the drug efficacy playing is greatly promoted.

Description

A kind of repaglinide metformin tablet medicament composition and preparation method thereof
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of repaglinide metformin tablet medicament composition and preparation method thereof.
Background technology
Repaglinide diformin tablet, principal agent composition is repaglinide and metformin hydrochloride. Repaglinide, chemistry S by name (+)-2-ethyoxyl-4-{2-[(3-methyl isophthalic acid-(2-(piperidino) phenyl) butyl) amino]-2-oxoethyl benzoic acid, chemical structural formula is:
Metformin, clinically its hydrochlorate conventional, i.e. metformin hydrochloride, chemistry 1,1-Dimethylbiguanide hydrochloride by name, chemical structural formula is:
The compound of repaglinide and metformin hydrochloride can control blood sugar content from two different approaches. Metformin hydrochloride is biguanide antidiabetic medicament, and it reduces glycogen output by suppressing gluconeogenesis function of liver, suppresses intestinal wall cellular uptake glucose simultaneously, can be obviously improved resistance to sugar amount and the hyperinsulinemia of patient, improve the human body natural reaction to insulin; Different from insulin action, it, without the effect promoting lipogenesis, to normal person without obvious hypoglycemic activity, therefore, does not generally cause hypoglycemia. Repaglinide is non-sulfonylurea Insulin-secreting agent, its 36KDA protein-specific on the potassium-channel of the outer dependency ATP of d cell film is combined, potassium channel is made to close, D cell depolarization, calcium channel is open, flow of calcium ions, promotes Postprandial insulin secretion, thus comparatively fast reducing by 2 hours blood glucoses (PPG) after the meal. Papillary has good cooperative effect, more can efficiently control blood glucose than independent medication, and therefore, exploitation compound Repaglinide metformin hydrochloride tablet can bring good economic benefit and social benefit.
Those skilled in the art are devoted to the compound preparation of exploitation repaglinide and metformin hydrochloride. But owing to repaglinide dissolubility is little, the dissolubility in water is 0.005mg/mL, and metformin hydrochloride is water soluble drug, repaglinide will can not discharge out if metformin hydrochloride rate of releasing drug is suitable to adopt conventional technique preparation to cause. And repaglinide rate of releasing drug is properly, the release of metformin hydrochloride will be lost control of, and cause that the prominent of metformin hydrochloride is released. Conventional technique is adopted to be difficult to meet its synchronous release requirement in vivo and in vitro. It addition, according to commercialized product it can be seen that in compound preparation the dose difference of repaglinide and metformin hydrochloride huge, the repaglinide at preparation process small faces the difficult problem that mixing is uneven.
For solving the problems referred to above, Yuan Yan house journal CN101516347A discloses a kind of pharmaceutical preparation comprising metformin and repaglinide, by before mixing repaglinide being made preformulation and this preformulation, there is the dissolution characteristic unrelated with pH value and specific relative humidity, it is dispersed in high dose highly-water-soluble metformin hydrochloride obtaining low dosage low solubility repaglinide, and both active substances can both with the effect of desired rate release. But, the technical scheme of this patent disclosure needs the strict relative humidity controlling repaglinide pre-formulation, and the adopted desiccant of this patent dry step of being responsible for a task until it is completed is dfficult to apply to produce in amplification. It addition, the releasing effect of two kinds of active ingredient in its description and in unexposed obtained compositions, and the information such as its bioavailability in vivo. Those skilled in the art cannot be known, adopts whether the technical scheme of this patent disclosure can reach its technique effect improving release declared.
Chinese patent CN103251593A discloses a kind of pharmaceutical composition comprising repaglinide and metformin hydrochloride. This patent adopts the previously prepared granule I containing repaglinide, repaglinide and alkaline agent, solubilizing agent, suitable amount of adhesive are dissolved in suitable quantity of water and make solution, by in this spray solution to appropriate filler such as silica sol, it is sufficiently mixed uniformly, it is dried to the moisture granule lower than 2%, again this dry particulate abrasive is become the granularity fine powder less than 80 orders, obtain granule I. The repaglinide diformin tablet uniformity of dosage units A+1.8S=8.3 that this patent system obtains. Owing to the method needs strictly to control pellet moisture, and needing grinding to control particle diameter, production operation requires higher, and in process of lapping, loss is bigger.
Chinese patent CN103070864A provides one and prepares repaglinide metformin drug formulation process. Repaglinide, meglumine, poloxamer and polyvidone are dissolved in 50% ethanol, metformin hydrochloride and certain adjuvant are placed in fluid bed and carry out hot melt granulation; Then repaglinide solution is sprayed in fluid bed, carry out one-step palletizing. Hot melt is granulated and is combined with one-step palletizing technology by this operation, operate easier, then research finds that repaglinide exists interaction with metformin, adopt this operational approach, repaglinide solution Direct spraying is on metformin granule, increase both contact surfaces, accelerate it and react to each other, be unfavorable for that product is stable.
Chinese patent CN101843617A discloses the compound slow release preparation of a kind of repaglinide metformin hydrochloride. By adding a certain amount of framework material respectively in repaglinide and metformin hydrochloride, it is prepared into slow releasing preparation, thus solving insoluble drug repaglinide and the problem of water soluble drug metformin hydrochloride synchronous slow. But the slow-release material price needed for preparing compound slow release preparation is costly, the requirement of preparation equipment is also higher, thus adding production cost.
Summary of the invention
It is an object of the invention to provide a kind of repaglinide metformin tablet medicament composition, under guaranteeing the premise that product is stable, it is achieved insoluble drug repaglinide and water soluble drug metformin hydrochloride synchronous release all on request; Solve the problem that the mixing of low-dose drugs repaglinide is uneven simultaneously.
For achieving the above object, the present invention provides a kind of repaglinide metformin tablet medicament composition, and in the pharmaceutical composition of per unit preparation, the quality of each component is:
Further, in the pharmaceutical composition of per unit preparation, the quality of each component is:
Or, in the pharmaceutical composition of per unit preparation, the quality of each component is:
Or, in the pharmaceutical composition of per unit preparation, the quality of each component is:
Or, in the pharmaceutical composition of per unit preparation, the quality of each component is:
Or, in the pharmaceutical composition of per unit preparation, the quality of each component is:
Or, in the pharmaceutical composition of per unit preparation, the quality of each component is:
Or, in the pharmaceutical composition of per unit preparation, the quality of each component is:
The preparation method that present invention also offers a kind of above-mentioned repaglinide metformin tablet medicament composition, comprises the following steps:
(1) preparing repaglinide solution: the poloxamer of recipe quantity, meglumine and PVP K30 are added in suitable quantity of water, stirring makes material be completely dissolved, and is slow added into the repaglinide of recipe quantity, continuously stirred makes dissolving, prepares repaglinide solution;
(2) preparing repaglinide granule: the microcrystalline cellulose crude granule taking recipe quantity is placed in fluid bed top spray pot, set inlet temperature as 40～60 DEG C, air intake flow is 60～150m3/ h, atomizing pressure is 1.0～2.0Pa, starts solution feed pump, is sprayed in fluid bed by the repaglinide solution that step (1) prepares and granulates, after hydrojet completes, dry, obtains repaglinide granule;
(3) metformin granule is prepared: take the metformin hydrochloride of recipe quantity, add the PVP K30 of recipe quantity, sorbitol, polyethylene glycol 6000, it is placed in granulation pot, mixing 10min, stirring is slowly added into suitable quantity of water simultaneously and granulates, it is 1.0mm screen cloth granulate with hole diameter of sieve (perforated) plate, dry, obtain metformin granule;
(4) the metformin granule that the repaglinide granule that blend step (2) prepares prepares with step (3), hybrid particles adds the polacrilin potassium of recipe quantity, microcrystalline Cellulose, mixing 20min, add the magnesium stearate of recipe quantity, be mixed to get total mixed granule;
(5) tabletting.
Wherein, the present invention prepares microcrystalline cellulose crude granule by the following method: be sequentially added in granulation pot by microcrystalline Cellulose and PVP K30, mixes 10min; Slowly add water in stirring simultaneously, soft material processed; Being extruded by the soft material extruder of preparation, hole diameter of sieve (perforated) plate is 0.8mm, the material of extrusion is proceeded to spheronizator and carries out round as a ball, rotating speed 160～300rpm; Round as a ball material is proceeded to drying machine, and inlet temperature is set to 50～70 DEG C, when moisture is 2%～8%, stops dry; The dried granule screen cloth of 40～60 orders is sieved, obtains microcrystalline cellulose crude granule.
Repaglinide metformin tablet medicament composition prepared by the present invention has the advantage that
(1) in prescription of the present invention, the consumption relatively prior art of polacrilin potassium greatly reduces, in obtained repaglinide diformin tablet, the repaglinide of slightly solubility and water miscible metformin hydrochloride all can according to each requiring synchronous release, dissolved corrosion is good, is conducive to medicine to absorb in vivo;
(2) previously prepared microcrystalline cellulose crude granule, again repaglinide is configured to solution, bed spray is adopted to prepare repaglinide granule on microcrystalline cellulose crude granule, improve the problem that the mixing of low dosage repaglinide is uneven, be conducive to repaglinide Fast Stripping simultaneously, the performance of drug effect is greatly facilitated;
(3), in repaglinide particulate production of the present invention, do not need its moisture and grain graininess are controlled especially, easy and simple to handle, be conducive to the big production of socialization;
(4) prepare repaglinide granule and metformin granule respectively, remix, decrease the contact of two active component to greatest extent, it is to avoid it interacts, improve product stability.
Detailed description of the invention
Below in conjunction with test example and embodiment, the present invention is described in further detail, but not limitation of the present invention, the equivalent replacement of all any this areas made according to the disclosure of invention, belong to protection scope of the present invention.
Microcrystalline cellulose crude granule prepares example:
51g microcrystalline Cellulose and 9g PVP K30 are sequentially added in granulation pot and mix 10min; Slowly add water in stirring simultaneously, soft material processed; Being extruded by the soft material extruder of preparation, hole diameter of sieve (perforated) plate is 0.8mm, the material of extrusion is proceeded to spheronizator and carries out round as a ball, rotating speed 160～300rpm; Round as a ball material is proceeded to drying machine, and inlet temperature is set to 50～70 DEG C, when moisture is 2%～8%, stops dry;Being sieved by the dried granule screen cloth of 40～60 orders, obtain microcrystalline cellulose crude granule, yield is 90%, for following example.
Embodiment 1: repaglinide metformin tablet recipe (in 1000, unit: g):
Preparation technology:
0.2g poloxamer, 0.5g meglumine and 0.6g PVP K30 being added in suitable quantity of water, stirring makes material be completely dissolved, and is slow added into 1g repaglinide, continuously stirred makes dissolving, prepares repaglinide solution; Taking 15g microcrystalline cellulose crude granule to be placed in fluid bed top spray pot, set inlet temperature as 40～60 DEG C, air intake flow is 60～150m3/ h, atomizing pressure is 1.0Pa, starts solution feed pump, is sprayed in fluid bed by repaglinide solution and granulate, and hydrojet is dry after completing, and obtains repaglinide granule; Take 500g metformin hydrochloride, add 16g PVP K30,8g sorbitol, 4g polyethylene glycol 6000, be placed in granulation pot, mixing 10min, stirring is slowly added into suitable quantity of water simultaneously and granulates, and is 1.0mm screen cloth granulate with hole diameter of sieve (perforated) plate, dry, obtain metformin granule; Repaglinide granule and metformin granule are added in mixed-hopper, mixes 20min, hybrid particles adds 4.5g polacrilin potassium, 10g microcrystalline Cellulose, mixes 20min, add 1g magnesium stearate, be mixed to get total mixed granule; Tabletting, to obtain final product.
Embodiment 2: repaglinide metformin tablet recipe (in 1000, unit: g):
Preparation technology:
0.9g poloxamer, 1.0g meglumine and 1.2g PVP K30 being added in suitable quantity of water, stirring makes material be completely dissolved, and is slow added into 2g repaglinide, continuously stirred makes dissolving, prepares repaglinide solution; Taking 36g microcrystalline cellulose crude granule to be placed in fluid bed top spray pot, set inlet temperature as 40～60 DEG C, air intake flow is 60～150m3/ h, atomizing pressure is 1.5Pa, starts solution feed pump, is sprayed in fluid bed by repaglinide solution and granulate, and hydrojet is dry after completing, and obtains repaglinide granule; Take 500g metformin hydrochloride, add 22g PVP K30,12g sorbitol, 6g polyethylene glycol 6000, be placed in granulation pot, mixing 10min, stirring is slowly added into suitable quantity of water simultaneously and granulates, and is 1.0mm screen cloth granulate with hole diameter of sieve (perforated) plate, dry, obtain metformin granule; Repaglinide granule and metformin granule are added in mixed-hopper, mixes 20min, hybrid particles adds 9.0g polacrilin potassium, 20g microcrystalline Cellulose, mixes 20min, add 3g magnesium stearate, be mixed to get total mixed granule; Tabletting, to obtain final product.
Embodiment 3: repaglinide metformin tablet recipe (in 1000, unit: g):
Preparation technology:
0.9g poloxamer, 1.0g meglumine and 1.2g PVP K30 being added in suitable quantity of water, stirring makes material be completely dissolved, and is slow added into 1g repaglinide, continuously stirred makes dissolving, prepares repaglinide solution; Taking 36g microcrystalline cellulose crude granule to be placed in fluid bed top spray pot, set inlet temperature as 40～60 DEG C, air intake flow is 60～150m3/ h, atomizing pressure is 2.0Pa, starts solution feed pump, is sprayed in fluid bed by repaglinide solution and granulate, and hydrojet is dry after completing, and obtains repaglinide granule; Take 500g metformin hydrochloride, add 20g PVP K30,10g sorbitol, 5g polyethylene glycol 6000, be placed in granulation pot, mixing 10min, stirring is slowly added into suitable quantity of water simultaneously and granulates, and is 1.0mm screen cloth granulate with hole diameter of sieve (perforated) plate, dry, obtain metformin granule;Repaglinide granule and metformin granule are added in mixed-hopper, mixes 20min, hybrid particles adds 9.0g polacrilin potassium, 20g microcrystalline Cellulose, mixes 20min, add 3g magnesium stearate, be mixed to get total mixed granule; Tabletting, to obtain final product.
Embodiment 4: repaglinide metformin tablet recipe (in 1000, unit: g):
Preparation technology:
0.9g poloxamer, 1.0g meglumine and 1.2g PVP K30 being added in suitable quantity of water, stirring makes material be completely dissolved, and is slow added into 2g repaglinide, continuously stirred makes dissolving, prepares repaglinide solution; Taking 36g microcrystalline cellulose crude granule to be placed in fluid bed top spray pot, set inlet temperature as 40～60 DEG C, air intake flow is 60～150m3/ h, atomizing pressure is 1.6Pa, starts solution feed pump, is sprayed in fluid bed by repaglinide solution and granulate, and hydrojet is dry after completing, and obtains repaglinide granule; Take 500g metformin hydrochloride, add 20g PVP K30,10g sorbitol, 5g polyethylene glycol 6000, be placed in granulation pot, mixing 10min, stirring is slowly added into suitable quantity of water simultaneously and granulates, and is 1.0mm screen cloth granulate with hole diameter of sieve (perforated) plate, dry, obtain metformin granule; Repaglinide granule and metformin granule are added in mixed-hopper, mixes 20min, hybrid particles adds 9.0g polacrilin potassium, 20g microcrystalline Cellulose, mixes 20min, add 3g magnesium stearate, be mixed to get total mixed granule; Tabletting, to obtain final product.
Embodiment 5: repaglinide metformin tablet recipe (in 1000, unit: g):
Preparation technology:
0.4g poloxamer, 0.8g meglumine and 0.6g PVP K30 being added in suitable quantity of water, stirring makes material be completely dissolved, and is slow added into 2g repaglinide, continuously stirred makes dissolving, prepares repaglinide solution; Taking 30g microcrystalline cellulose crude granule to be placed in fluid bed top spray pot, set inlet temperature as 40～60 DEG C, air intake flow is 60～150m3/ h, atomizing pressure is 1.0Pa, starts solution feed pump, is sprayed in fluid bed by repaglinide solution and granulate, and hydrojet is dry after completing, and obtains repaglinide granule; Take 500g metformin hydrochloride, add 20g PVP K30,9g sorbitol, 4g polyethylene glycol 6000, be placed in granulation pot, mixing 10min, stirring is slowly added into suitable quantity of water simultaneously and granulates, and is 1.0mm screen cloth granulate with hole diameter of sieve (perforated) plate, dry, obtain metformin granule; Repaglinide granule and metformin granule are added in mixed-hopper, mixes 20min, hybrid particles adds 7.5g polacrilin potassium, 18g microcrystalline Cellulose, mixes 20min, add 2g magnesium stearate, be mixed to get total mixed granule; Tabletting, to obtain final product.
Embodiment 6: repaglinide metformin tablet recipe (in 1000, unit: g):
Preparation technology:
0.6g poloxamer, 0.5g meglumine and 1.0g PVP K30 being added in suitable quantity of water, stirring makes material be completely dissolved, and is slow added into 1g repaglinide, continuously stirred makes dissolving, prepares repaglinide solution; Taking 25g microcrystalline cellulose crude granule to be placed in fluid bed top spray pot, set inlet temperature as 40～60 DEG C, air intake flow is 60～150m3/ h, atomizing pressure is 2.0Pa, starts solution feed pump, is sprayed in fluid bed by repaglinide solution and granulate, and hydrojet is dry after completing, and obtains repaglinide granule; Take 500g metformin hydrochloride, add 18g PVP K30,11g sorbitol, 6g polyethylene glycol 6000, be placed in granulation pot, mixing 10min, stirring is slowly added into suitable quantity of water simultaneously and granulates, and is 1.0mm screen cloth granulate with hole diameter of sieve (perforated) plate, dry, obtain metformin granule;Repaglinide granule and metformin granule are added in mixed-hopper, mixes 20min, hybrid particles adds 5.5g polacrilin potassium, 15g microcrystalline Cellulose, mixes 20min, add 2g magnesium stearate, be mixed to get total mixed granule; Tabletting, to obtain final product.
Embodiment 7: repaglinide metformin tablet recipe (in 1000, unit: g):
Preparation technology:
0.5g poloxamer, 0.7g meglumine and 1.0g PVP K30 being added in suitable quantity of water, stirring makes material be completely dissolved, and is slow added into 2g repaglinide, continuously stirred makes dissolving, prepares repaglinide solution; Taking 20g microcrystalline cellulose crude granule to be placed in fluid bed top spray pot, set inlet temperature as 40～60 DEG C, air intake flow is 60～150m3/ h, atomizing pressure is 1.2Pa, starts solution feed pump, is sprayed in fluid bed by repaglinide solution and granulate, and hydrojet is dry after completing, and obtains repaglinide granule; Take 500g metformin hydrochloride, add 18g PVP K30,9g sorbitol, 6g polyethylene glycol 6000, be placed in granulation pot, mixing 10min, stirring is slowly added into suitable quantity of water simultaneously and granulates, and is 1.0mm screen cloth granulate with hole diameter of sieve (perforated) plate, dry, obtain metformin granule; Repaglinide granule and metformin granule are added in mixed-hopper, mixes 20min, hybrid particles adds 8.5g polacrilin potassium, 16g microcrystalline Cellulose, mixes 20min, add 2g magnesium stearate, be mixed to get total mixed granule; Tabletting, to obtain final product.
Comparative formulation 1: prescription and technique with reference to Chinese patent CN101516347A embodiment 2 prepare Comparative formulation 1, specification: repaglinide/metformin hydrochloride (2mg/500mg);
Comparative formulation 2: prescription and technique with reference to Chinese patent CN103070864A embodiment 1 prepare Comparative formulation 2, and specification is: repaglinide/metformin hydrochloride (1mg/500mg). What adopt HPLC method mensuration Comparative formulation 2 has related substance, and wherein the total impurities of repaglinide is 0.59%, the total impurities of metformin is 0.47%.
Test example 1 mixing uniformity contrasts
Owing in compound preparation, the repaglinide of low dosage exists the problem being difficult to mix homogeneously, it is therefore desirable to the mixing uniformity of repaglinide in hybrid particles is investigated. Prepare the embodiment of the present invention 1,2,3,4 and Comparative formulation 1 sample respectively, and the mixing uniformity of repaglinide in total mixed granule before investigating tabletting, result of the test is as shown in table 1.
Mixing uniformity assay method: in the upper left corner of mixer upper surface, the lower right corner and intermediate point, the intermediate point in intermediate layer, the lower left corner of lower surface, the upper right corner and intermediate point sampling, measure the content of each sample point repaglinide, calculate the RSD% of 7 groups of assay results.
Table 1 embodiment of the present invention and repaglinide mixing uniformity contrast in Comparative formulation
Sequence number Embodiment 1 Embodiment 2 Embodiment 3 Embodiment 4 Comparative formulation 1
Sample point 1 100.6% 98.6% 99.2% 98.6% 103.4%
Sample point 2 98.9% 100.5% 98.5% 99.5% 94.5%
Sample point 3 99.1% 99.2% 99.3% 98.7% 102.6%
Sample point 4 98.5% 99.5% 100.8% 100.9% 95.4%
Sample point 5 100.8% 98.8% 99.6% 99.1% 93.4%
Sample point 6 99.5% 98.3% 100.7% 100.6% 92.8%
Sample point 7 98.7% 100.6% 98.6% 99.7% 102.7%
RSD% 0.92% 0.91% 0.92% 0.90% 4.93%
It is shown that the RSD% that in each sample point sample of the embodiment of the present invention 1,2,3,4 sample, repaglinide mixing uniformity measures is all less than 0.92%, hybrid particles is highly uniform;And repaglinide content difference is very big in each sample point of Comparative formulation 1 sample, the RSD% that mixing uniformity measures is 4.93%, it is far longer than the RSD% value of embodiment of the present invention sample, it is seen that the mixed effect of embodiment of the present invention sample particle is significantly better than Comparative formulation 1 sample.
Test example 2 influence factor tests
Take the embodiment of the present invention 3,4 sample and Comparative formulation 1 sample, at high temperature (60 DEG C), high humidity (25 DEG C, RH92.5%) place 10 days under, illumination (4500 ± 500Lx) condition, carry out content respectively at sampling in the 0th day, 10 days, have the uniformity of dosage units (according to the 4th general rule 0941 of " Chinese Pharmacopoeia " version in 2015) of related substance, dissolution (with pH5.0 citric acid phosphate buffer 900ml for dissolution medium) and repaglinide to measure, investigating sample mass change situation under these conditions, result of the test is referring to table 2.
Table 2 embodiment of the present invention compares with Comparative formulation influence factor's test mass
Note: what have related substance record is total impurities amount (%).
It is shown that when 0 day, in the embodiment of the present invention 3,4 sample and Comparative formulation 1 sample, the content of repaglinide and metformin hydrochloride two active component was without being clearly distinguished from, after placing 10 days in each condition, also have no significant change;
In having related substance, in the embodiment of the present invention 3,4 sample metformin hydrochloride have related substance to place 10 days under 0 day and high temperature, high humidity, illumination condition after, all convert, illustrate highly stable. Repaglinide in the embodiment of the present invention 3,4 sample had related substance when 0 day, and respectively 0.08%, 0.07%, all increase to some extent after placing 10 days when influence factor, rise between 0.12%～0.22%. And repaglinide and metformin hydrochloride were when 0 day in Comparative formulation 1 sample, there is related substance to be all significantly greater than embodiment of the present invention sample, after especially repaglinide places 10 days in each condition, have related substance significantly to increase, reach 0.49%. Visible, the embodiment of the present invention 3,4 sample relatively Comparative formulation 1 sample is stable.
In dissolution, in the embodiment of the present invention 3,4 sample, repaglinide and metformin hydrochloride all can the complete dissolutions when 15min, the dissolution of repaglinide reaches more than 97.2%, the dissolution of metformin hydrochloride reaches more than 97.4%, and after placing 10 days under high temperature, high humidity and illumination condition, there is not significant change; And repaglinide was when 0 day in Comparative formulation 1 sample, dissolution is relatively slow, the dissolution only 89.3% when 15min, and after placing 10 days under conditions of high humidity, dissolution decreases. Visible, the embodiment of the present invention 3,4 sample is significantly improved compared with the dissolution of repaglinide in Comparative formulation 1 sample.
In repaglinide uniformity of dosage units, when 0 day, in the embodiment of the present invention 3,4 sample, the evaluating A+2.2S value of repaglinide Determination of Content Uniformity is only 3.01% and 2.99%, much smaller than in Comparative formulation 1 sample the 8.02% of repaglinide A+2.2S value; And after placing 10 days under high temperature, high humidity and illumination condition, the uniformity of dosage units A+2.2S value of the embodiment of the present invention 3,4 sample repaglinide slightly increases, but amplification is all less; And after Comparative formulation 1 sample places 10 days in each condition, A+2.2S value increases to 9.46%, it is seen then that in embodiment of the present invention sample, repaglinide composition mixing homogeneity is significantly better than Comparative formulation 1 sample.
Test example 3 beasle dog pharmacokinetic trial
1, test objective
Under the molar doses such as investigation, the concentration level of repaglinide and metformin and basic pharmacokinetic characteristics thereof in blood plasma after beasle dog single oral administration embodiment 1,3,4 sample and Comparative formulation 1 sample, and compare major parameter Cmax, Tmax, T1/2, AUClastDeng difference.
2, material and method
2.1, test medicine
Embodiment 1 sample: adopting the sample that the embodiment of the present invention 1 prepares, specification is repaglinide/metformin hydrochloride (1mg/500mg);
Embodiment 3 sample: adopting the sample that the embodiment of the present invention 3 prepares, specification is repaglinide/metformin hydrochloride (1mg/500mg);
Embodiment 4 sample: adopting the sample that the embodiment of the present invention 4 prepares, specification is repaglinide/metformin hydrochloride (2mg/500mg);
Comparative formulation 1: prescription and technique with reference to Chinese patent CN101516347A embodiment 2 prepare Comparative formulation 1, specification: repaglinide/metformin hydrochloride (2mg/500mg).
2.2, experimental animal:
Beagle dog 8, male and female half and half, body weight 10 ± 2kg, age 10-12 month;
2.3, EXPERIMENTAL DESIGN
Adopting 2 × 4 cross matchings, single test is totally 4 cycles, completes single test every kind preparation totally 8 samples, as shown in the table in detail:
Table 3 Repaglinide-metformin hydrochloride Beagle dog pharmacokinetic trial designs
The female Beagle dog of remarks: MD male Beagle dog FD
2.4, blood sampling point design
Before administration, after administration, 5min, 15min, 30min, 1h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 48h take blood 1mL in forelimb or hind leg vein, it is placed in EDTA-K2 pipe, 4 DEG C of low temperature 3000r/min, centrifugal 10min, separated plasma ,-70 DEG C of refrigerator freezings preserve. After each periodic test terminates, there are 3 days elimination phases, after the complete metabolism of medicine is complete, then carry out the test of next cycle.
3, result of the test and statistics
3.1, key data
After table 4 beasle dog single oral embodiment 1,3,4 and Comparative formulation 1 sample
The pharmacokinetic parameter of metformin in blood plasma
After table 5 beasle dog single oral embodiment 1,3,4 and Comparative formulation 1 sample
The pharmacokinetic parameter of repaglinide in blood plasma
Note: F relative bioavailability
4, conclusion (of pressure testing)
By table 4, table 5 test data it can be seen that compared with Comparative formulation 1, after beasle dog single oral embodiment 1 sample, the parameters of repaglinide and metformin all increases to some extent, and relative bioavailability relatively Comparative formulation 1 increases; After beasle dog single oral embodiment 3,4 sample, the C of repaglinide and metforminmax、AUClastDramatically increasing with relative bioavailability all relatively Comparative formulation 1, bioavailability is improved significantly. Visible embodiment of the present invention sample, especially embodiment 3,4 sample are compared Comparative formulation 1 sample quality and are significantly improved.
In sum, the present invention greatly reduces the prescription consumption of polacrilin potassium compared with prior art, adopt previously prepared microcrystalline cellulose crude granule, again repaglinide is configured to solution, on microcrystalline cellulose crude granule, repaglinide granule is prepared by bed spray, ensure that the repaglinide of slightly solubility and water miscible metformin hydrochloride are all according to each requiring synchronous release, dissolved corrosion is good, and bioavailability is more excellent compared with prior art; Improve the problem that the mixing of low dosage repaglinide is uneven simultaneously, the performance of drug effect is greatly facilitated; And the present invention eliminates subpackage repaglinide granule in prior art in preparation process, step with desiccant bag its moisture of drying control, do not need the moisture of repaglinide granule is controlled especially, also without controlling grain diameter, enormously simplify production operation, be more beneficial for the big production of socialization.Repaglinide and metformin granule remix after granulating respectively, it is to avoid two active component directly contact, and reduce the risk occurring to interact. Adopt repaglinide diformin tablet content prepared by technical scheme provided by the invention uniform, two kinds of active component energy synchronous release, and internal pharmacokinetics effect is substantially better than prior art.

Claims (10)

1. a repaglinide metformin tablet medicament composition, it is characterised in that in per unit preparation, the quality of each component is:
2. repaglinide metformin tablet medicament composition according to claim 1, it is characterised in that in per unit preparation, the quality of each component is:
3. repaglinide metformin tablet medicament composition according to claim 1, it is characterised in that in per unit preparation, the quality of each component is:
4. repaglinide metformin tablet medicament composition according to claim 1, it is characterised in that in per unit preparation, the quality of each component is:
5. repaglinide metformin tablet medicament composition according to claim 1, it is characterised in that in per unit preparation, the quality of each component is:
6. repaglinide metformin tablet medicament composition according to claim 1, it is characterised in that in per unit preparation, the quality of each component is:
7. repaglinide metformin tablet medicament composition according to claim 1, it is characterised in that in per unit preparation, the quality of each component is:
8. repaglinide metformin tablet medicament composition according to claim 1, it is characterised in that in per unit preparation, the quality of each component is:
9. the preparation method of the repaglinide metformin tablet medicament composition described in an any one of claim 1～8, it is characterised in that comprise the following steps:
(1) preparing repaglinide solution: the poloxamer of recipe quantity, meglumine and PVP K30 are added in suitable quantity of water, stirring makes material be completely dissolved, and is slow added into the repaglinide of recipe quantity, continuously stirred makes dissolving, prepares repaglinide solution;
(2) preparing repaglinide granule: the microcrystalline cellulose crude granule taking recipe quantity is placed in fluid bed top spray pot, set inlet temperature as 40～60 DEG C, air intake flow is 60～150m3/ h, atomizing pressure is 1.0～2.0Pa, starts solution feed pump, is sprayed in fluid bed by the repaglinide solution that step (1) prepares and granulates, after hydrojet completes, dry, obtains repaglinide granule;
(3) metformin granule is prepared: take the metformin hydrochloride of recipe quantity, add the PVP K30 of recipe quantity, sorbitol, polyethylene glycol 6000, it is placed in granulation pot, mixing 10min, stirring is slowly added into suitable quantity of water simultaneously and granulates, it is 1.0mm screen cloth granulate with hole diameter of sieve (perforated) plate, dry, obtain metformin granule;
(4) the metformin granule that the repaglinide granule that blend step (2) prepares prepares with step (3), hybrid particles adds the polacrilin potassium of recipe quantity, microcrystalline Cellulose, mixing 20min, add the magnesium stearate of recipe quantity, be mixed to get total mixed granule;
(5) tabletting.
10. preparation method according to claim 9, it is characterised in that described microcrystalline cellulose crude granule adopts following methods to prepare: be sequentially added in granulation pot by microcrystalline Cellulose and PVP K30, mixes 10min; Slowly add water in stirring simultaneously, soft material processed; Being extruded by the soft material extruder of preparation, hole diameter of sieve (perforated) plate is 0.8mm, the material of extrusion is proceeded to spheronizator and carries out round as a ball, rotating speed 160～300rpm;Round as a ball material is proceeded to drying machine, and inlet temperature is set to 50～70 DEG C, when moisture is 2%～8%, stops dry; The dried granule screen cloth of 40～60 orders is sieved, obtains microcrystalline cellulose crude granule.
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CN106109428A (en) * 2016-07-22 2016-11-16 江苏豪森药业集团有限公司 The preparation process of repaglinide metformin
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