CN112999182A - Metformin hydrochloride dual sustained and controlled release composition and preparation method and application thereof - Google Patents
Metformin hydrochloride dual sustained and controlled release composition and preparation method and application thereof Download PDFInfo
- Publication number
- CN112999182A CN112999182A CN202010837431.9A CN202010837431A CN112999182A CN 112999182 A CN112999182 A CN 112999182A CN 202010837431 A CN202010837431 A CN 202010837431A CN 112999182 A CN112999182 A CN 112999182A
- Authority
- CN
- China
- Prior art keywords
- release
- coating
- sustained
- metformin hydrochloride
- release material
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- 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
-
- 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
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention belongs to the field of pharmaceutical preparations, and discloses a metformin hydrochloride dual controlled-release composition which is prepared from a controlled-release coating film coated outside a metformin hydrochloride tablet core containing a sustained-release material, wherein the metformin hydrochloride tablet core containing the sustained-release material consists of metformin hydrochloride, a sustained-release material, a filler and an adhesive, the coating layer consists of a coating sustained-release material, a plasticizer and a pore-forming agent, the coating sustained-release material is cellulose acetate, the tablet core sustained-release material is a mixture of octadecanol and polyethylene oxide, and the coating sustained-release material is cellulose acetate. Compared with the traditional film-coated controlled release tablet, the film-controlled metformin hydrochloride dual controlled release composition has longer time for keeping stable release degree, more excellent storage stability, simple process, no need of expensive production equipment, low cost and easy industrialization.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, particularly relates to a controlled release preparation, and more particularly relates to a metformin hydrochloride controlled release tablet and a preparation method thereof.
Background
Diabetes, a serious non-infectious chronic disease, has become a "third killer" threatening humans after tumors and cardiovascular and cerebrovascular diseases. Metformin is a therapeutic agent against non-insulin-dependent diabetes mellitus, and chemically has a bisguanidine structure. Metformin controls glucose production in the gastrointestinal tract and increases glucose utilization in muscles, and thus has been used for the prevention and treatment of diabetes. In addition, metformin has an advantage of being capable of improving lipid metabolism to thereby prevent weight gain, and can be used for preventing and treating the occurrence and deterioration of diabetic complications (e.g., cardiovascular diseases, etc.). Metformin hydrochloride is a biguanide hypoglycemic medicament, is used for type II diabetes patients with unsatisfactory pure diet control, especially for obesity and hyperinsulinemia, and can also be used for insulin treatment patients to reduce the dosage of insulin. At present, the metformin hydrochloride sustained release tablet is a hypoglycemic drug which can be orally taken and widely applied, the clinical curative effect and the safety of the metformin hydrochloride sustained release tablet are continuously proved, and great gospel is brought to the treatment of patients with diabetes, especially patients with obesity, high plasma insulin, failure of secondary sulfonylureas and poor blood sugar control in the treatment of insulin type I diabetes.
Controlled release pharmaceutical formulations have many advantages over conventional pharmaceutical formulations, and the therapeutic advantages of sustained and controlled release formulations over conventional immediate release formulations are widely recognized, for example, sustained and controlled release formulations can maintain the desired blood levels for a longer period of time, while reducing peak-to-valley variations in blood levels and reducing the incidence and severity of toxic and side effects. The sustained-release preparation can also improve the compliance of patients by reducing the taking times. Due to the short half-life of metformin, the ordinary formulation needs to be taken 2 or 3 times a day. Therefore, the metformin sustained-release preparation 1 time in 1 day has important significance for clinical treatment of diabetic patients, and has wide demand in related patients. The metformin hydrochloride sustained release tablets currently commercialized under the FDA approval trade names of GLUCOPHAGE (developed by BRISTOL MYERS SQUIBB) and SALIX PHARMS INC adopt a skeleton (matrix) type sustained release tablet technology, a hydrophilic gel layer formed by the matrix in water is utilized to control the drug release, and the specification of the metformin hydrochloride sustained release preparation reaches 500mg to 1000mg, so that the individual difference can finally cause great drug effect difference
In recent years, the specific superiority of the multi-unit type drug delivery system represented by controlled release preparations has become one of the hot spots of the current slow controlled release preparations. However, despite prolonged drug release, the drug efficacy of some drugs (e.g., those with narrow absorption windows such as metformin) still fails to last long. .
The slow release mechanism of the metformin hydrochloride slow-release preparation on the market at present mainly comprises a skeleton slow-release mechanism, an osmotic pump slow-release mechanism, a membrane controlled slow-release mechanism and a pellet controlled slow-release mechanism. The sustained release tablet with the skeleton sustained release mechanism is great, and the patient has poor administration compliance.
The coating material of patent No. CN107049980A is a coating film formed by ethyl cellulose, polyethylene glycol 6000 and hexadecanol, and has poor toughness; the coating film can gradually generate fine cracks to reduce the stability of the coating film, and meanwhile, the slow release effect of the tablet core slow release agent carboxymethyl cellulose sodium is poor, and the release degree of a sample approaches the standard limit in long-term 30 months, so that the quality risk exists.
WO 1999/47128 discloses a technique of a prolonged biphasic controlled release formulation with gastric retention using an ionic polymer and a non-ionic polymer, which requires a large amount of sustained release agent, and the formulation is larger in size, resulting in a problem of deteriorated convenience of administration.
The formulation for sustained release through the matrix has the following problems: firstly, the medicine release is uneven, and the phenomenon of burst release or no release exists; ② tablet with heavy weight, in the above patent, when the main component metformin hydrochloride is 500mg, the tablet weight is generally 800 mg-1000 mg. Fourthly, the in vitro release degree is low, the in vitro release time of the framework sustained release tablet generally can not reach 12 hours or more than 12 hours, and the final release value is 70 to 75 percent. Therefore, the existing metformin hydrochloride controlled release preparation still has the problems of high production cost, unsatisfactory release stability and oral compliance of patients. Production enterprises in the field of metformin hydrochloride sustained-release preparations still need to improve the production process, and obtain products with simplified production process, reduced production cost, stable release speed of medicinal components in stomach, long storage period without loss of medicament release degree and good oral compliance of patients.
Disclosure of Invention
The invention aims to provide an improved metformin hydrochloride dual controlled-release tablet composition aiming at the defects of the prior art, the prepared medicament has stable release, long-term storage resistance, no irritation to intestinal tracts, less administration times, easy swallowing, greatly improved patient compliance, simple production process and low cost.
The invention also aims to provide a preparation method of the metformin hydrochloride dual sustained and controlled release composition.
The purpose of the invention is realized by the following technical scheme:
the dual controlled release composition of metformin hydrochloride, wherein, the dual controlled release composition of metformin hydrochloride is prepared by controlled release coating film coated outside a tablet core containing the controlled release material of metformin hydrochloride, wherein:
the metformin hydrochloride tablet core containing the sustained-release material is composed of metformin hydrochloride, the sustained-release material, a filler and an adhesive, the coating layer is composed of a coating sustained-release material, a plasticizer and a pore-forming agent, wherein the coating sustained-release material is cellulose acetate, the tablet core sustained-release material is a mixture of octadecanol and polyethylene oxide, and the coating sustained-release material is cellulose acetate.
Preferably, the formula of the metformin hydrochloride tablet core containing the sustained-release material comprises the following raw materials in parts by weight: 75-100 parts of metformin hydrochloride, 8-16 parts of slow release material, 2-5 parts of filler and 0.1-1.5 parts of adhesive.
Preferably, in the mixture of the octadecanol serving as the core sustained-release material and the polyethylene oxide, the weight ratio of the octadecanol to the polyethylene oxide is 2-5: 1.
In some embodiments, the filler includes, but is not limited to, starch, lactose, dextrin, microcrystalline cellulose, pregelatinized starch,
in some embodiments, the binder includes, but is not limited to, hydroxypropylmethylcellulose, povidone K30, formulated as a 3% to 5% aqueous solution.
In some embodiments, the filler is selected from one or more of starch, lactose, dextrin, microcrystalline cellulose, pregelatinized starch.
In one embodiment, the filler is pregelatinized starch.
In one embodiment, the filler is lactose.
In one embodiment, the filler is microcrystalline cellulose.
In one embodiment, the filler is dextrin.
In some embodiments the binding is selected from one or more of hydroxypropyl methylcellulose, povidone K30, or hydroxypropyl cellulose, the binding agent being formulated as a 3% to 5% aqueous solution.
In one embodiment, the binder is hydroxypropyl methylcellulose.
In one embodiment, the binder is povidone K30.
In one embodiment, the binder is hydroxypropyl cellulose.
In some preferred embodiments, the polyethylene oxide has a molecular weight of 40 to 90 ten thousand.
Preferably, the weight part ratio of the coating sustained and controlled release material, the plasticizer and the pore-foaming agent is 2-5: 1.0-2.0: 1.5-2.0.
In some embodiments, the plasticizer is one or both of triethyl citrate and tributyl citrate.
In some embodiments, the porogen is one or both of povidone and hypromellose.
A preparation method of the metformin hydrochloride dual sustained-release composition comprises the following steps: 1 preparing a slow-release metformin hydrochloride tablet core, 2 preparing a coating solution with the solid content of 7-10%, 3 spraying the tablet core in the slow-release coating solution at high temperature for coating, and finishing coating and discharging when the weight is increased by 1-3%.
Wherein the step 1 of preparing the sustained-release metformin tablet core comprises the following steps: (1) weighing the metformin hydrochloride raw material, the tablet core slow-release material and the filler raw material according to the weight part ratio, crushing and sieving, (2) adding an adhesive to prepare a soft material, and performing wet granulation, (3) drying and granulating, and (4) tabletting;
the step 2 of preparing the sustained-release and controlled-release coating comprises the following steps:
(1) weighing solid substances for forming a coating solution according to the weight part ratio, wherein the solid formula of the coating solution comprises a coating sustained and controlled release material, a plasticizer and a pore-forming agent, (2) adding the solid substances weighed in the step (1) into a dispersion medium until the solid content is 5-12%, and thus obtaining the coating solution; (3) coating: placing the drug-containing sustained-release tablet obtained in the claim 9 into the coating liquid obtained in the step (2) for high-temperature spray coating;
the tablet core containing the metformin hydrochloride consists of the metformin hydrochloride, a mixture of sustained-release material octadecanol and polyethylene oxide, a filling agent and an adhesive, and the coating layer consists of a controlled-release material, a plasticizer and a pore-forming agent;
wherein the slow release material of the tablet core is a mixture of octadecanol and polyoxyethylene, and the slow release material of the coating layer is cellulose acetate.
In some preferred embodiments, the weight ratio of the octadecanol to the polyoxyethylene is 2-5: 1. In some preferred embodiments, the polyethylene oxide has a molecular weight of 40 to 90 ten thousand.
In some embodiments, in step 1, the raw material is pulverized and sieved by pulverizing the metformin hydrochloride raw material, the filler and the sustained-release material and sieving the pulverized and sieved raw material with a sieve of 80-100 meshes;
in some embodiments, step 1 finds that the wet granulation is a 12-mesh swing granulation machine wet granulation with a frequency of 40-50 Hz;
in some embodiments, the drying in step 1 is 50-70 ℃ to a moisture content of 2-4%, in some embodiments the size stabilization is 16 mesh size stabilization at 30-40 Hz;
in some embodiments, the tabletting in the step 1 is uniformly mixed and tabletted, the pressure is 10-20 KN, the tabletting speed is 5-10 ten thousand tablets/h, and the tablet weight range is (+/-5%), and the friability is less than or equal to 1%, so that the tablet core containing the drug-sustained release agent is obtained.
In some embodiments, the weight ratio of the metformin hydrochloride, the mixture of the sustained-release material octadecanol and the polyethylene oxide, the filler and the binder in the tablet core containing the metformin hydrochloride in the step 2 is 75-100: 8-16: 2-5: 0.1-1.5.
In some embodiments, in the step 2, (2) the solid content weighed in the step (1) is added into a dispersion medium until the solid content is 5-12%, so as to obtain the coating solution; the dispersion medium includes, but is not limited to, ethanol, acetone.
In some embodiments, the dispersion medium is acetone.
In some embodiments, the dispersion medium is 95% ethanol.
In some embodiments, in the step (3) of coating in the step 2, the distance between the spray guns is adjusted to be 10-15 cm, the rotation speed of the liquid supply pump is 20-40 rpm, the rotation speed of the pot body is 3-10 rpm, the air inlet temperature is 30-50 ℃, the temperature of the tablet is controlled to be 30-40 ℃ and the atomization pressure is 0.25MPa, and coating is finished when the weight of the tablet is increased by 2-4% in a non-bonding state.
In some embodiments, the weight ratio of the sustained-release material, the plasticizer and the pore-forming agent in the solid content component of the prepared coating solution is 2-5: 1.0-1.8.
In some embodiments, the plasticizer is triethyl citrate.
In some implementations, the plasticizer is tributyl citrate.
In some embodiments, the porogen is povidone.
In some embodiments, the porogen is hypromellose.
The invention also provides application of the metformin hydrochloride dual sustained-release composition in preparing a pharmaceutical composition for treating diabetes.
In the present invention, the filler is not particularly limited as long as it is a substance for increasing the weight or volume of the tablet, facilitating molding or division, and reducing the variation in dosage of the main drug, and includes an absorbent and a diluent. Is preferably high
Specific examples of fillers include, but are not limited to, lactose, mannitol, sorbitol, starch, pregelatinized starch, powdered sugar, microcrystalline cellulose, dibasic calcium phosphate, magnesium oxide, and magnesium carbonate.
In the present invention, the binder is only required to be a substance that promotes the cohesion and agglomeration of the material powder particles to form granules and ensures the strength and density of the granules so as to facilitate the subsequent processes. That is, there is no particular limitation. Binders can be subdivided into wetting agents and binders according to the mechanism by which they function in the formulation. Specific examples include distilled water, ethanol, starch slurry, syrup, Hypromellose (HPMC), hydroxypropyl cellulose (HPC), sodium carboxymethyl cellulose (CMC-Na), methyl cellulose and ethyl cellulose, cellulose (CMC HPMC MC) mucilage, vinylpyrrolidone-vinylacetate copolymer (PVP/VA), gelatin mucilage, acacia mucilage water, ethanol. Hydroxypropyl methylcellulose, povidone K30 or hydroxypropyl cellulose are preferred.
In the present invention, the plasticizer is not particularly limited as long as it is a component for protecting the active ingredient in the tablet, and the core is isolated from the outside air and moisture, and includes diethyl phthalate (DEP), dimethyl phthalate (DMP), dibutyl phthalate (DBP), and the like, and may be selected from or a mixture thereof, preferably,
the action of the polymer that the mechanical property of the polymer is changed by adding a liquid substance of small molecules (Mr is about 300-500) which have high boiling point and low volatility and are miscible with the polymer or a solid substance with low melting point is called plasticization, the small molecule substance used is called plasticizer, and the plasticizer can increase the plasticity of the polymer. Plasticization can be divided into internal plasticization and external plasticization according to the manner and nature of the plasticizer. Internal plasticization is achieved by copolymerization; the external plasticization is to add a plasticizer to the coating solution or dispersion to change the properties of the coating film, and the plasticization of the coating film of the general preparation is the latter case, and the plasticizer is added to the coating material to make the polymer have the characteristics of softness, elasticity, adhesiveness and the like in the using temperature range.
In the invention, the plasticizer is a component which can form a channel in the coating film and becomes a continuous phase in the channel, the plasticizer is added in the coating formula to improve the film forming capability of the coating material, enhance the flexibility and the strength of the coating film, improve the adhesion state of the coating film to a substrate, and even the release rate of the coating film can be adjusted by plasticizers with different properties, such as water-soluble, water-insoluble or water-insoluble plasticizers. The plasticizing effect of the plasticizer is due to its ability to intercalate between polymer chains, weakening the effect of the macromolecular chains to aggregate with each other, breaking the crosslinking junctions formed between the macromolecular chains, thereby extending and softening the polymer backbone, increasing mobility and flexibility. The plasticizer can increase the flexibility of the coating film and prevent the medicine from being released too quickly due to the fact that the stream of the tablet bursts. If the drug is more soluble in the plasticizer than in water, it is possible that the drug is preferentially released through this channel.
In the invention, the pore-forming agent is some water-soluble substances or insoluble solid components added in the slow-release coating layer and is widely distributed in the coating film in the form of extremely fine particles, and the pore-forming agent is dissolved or falls off after contacting with the water coating film, so that the coating film forms micropores or a sponge-like structure. The pore-forming agent is mainly some water-soluble substances such as PEG, PVP, sucrose, salts and other water-soluble film-forming materials such as HPMC, HPC, or part of the medicine is added into the coating solution to be used as the pore-forming agent, and the part of the medicine has the function of quick release. Insoluble solid components such as talc, magnesium stearate, silicon dioxide, titanium dioxide, etc. can be added into the coating liquid to act as pore-forming agent. These solid components may also act as anti-tack agents. When the slow release coating containing the pore-forming agent is contacted with water or digestive juice, the pore-forming agent on the coating film is partially dissolved or falls off, so that a micropore or sponge-like structure is formed, and the permeability of a medium and a medicament is increased.
In the present invention, the dispersion medium for preparing the coating solution is not particularly limited as long as it can dissolve the coating formulation components, and may be selected from organic solvents such as ethanol and acetone.
In the examples, the dispersion medium for the preparation of the coating is preferably acetone.
In some embodiments, the adhesive is formulated as a 3% to 5% aqueous solution.
In some embodiments the binder is formulated, preferably to 2-4%.
In some embodiments the polyoxyethylene has a molecular weight of from 30 to 50 ten thousand,
in some embodiments the polyoxyethylene preferably has a molecular weight of from 40 to 90 ten thousand.
In some embodiments, the weight ratio of the coating sustained-release material, the plasticizer and the pore-forming agent is 2-5: 1.0-1.8: 2.0-1.8.
In some embodiments, the coated sustained and controlled release material is cellulose acetate, the plasticizer is triethyl citrate, and the pore-forming agent is hypromellose.
In some embodiments, the coated sustained and controlled release material is cellulose acetate, the plasticizer is tributyl citrate, and the pore-forming agent is hypromellose.
In some embodiments, the coated sustained and controlled release material is cellulose acetate, the plasticizer is triethyl citrate, and the pore-forming agent is hypromellose.
The invention has the advantages that
The invention adopts the dual controlled release technology of tablet core slow release and film controlled coating, the release rate in the 2 nd hour in the in vitro release rate test is 10-35%, the release rate in the 6 th hour is 40-70% and the release rate in the 12 th hour is more than 80%, and the release rate has no obvious change within 30 months for a long time.
The metformin hydrochloride controlled release tablet prepared by the invention has the specification of 500mg, is small in tablet weight of 580 mg-590 mg, is easy to swallow, and improves the compliance of patients.
The invention does not need expensive production equipment, has low production cost and has commercial advantage of large-scale production.
Detailed Description
The present invention will be further described with reference to the following examples, to which the present invention is not limited.
Example 1 preparation method of a membrane-controlled metformin dual controlled-release tablet
Firstly, weighing the components according to the formula of a tablet core and the formula of a coating solution respectively
TABLE 1 weight ratio table of components of film-controlled metformin dual controlled-release tablet
Secondly, the preparation step
1. Preparation of extended Release metformin hydrochloride core
(1) Grinding the metformin hydrochloride raw material, lactose, octadecanol and polyoxyethylene and sieving by a 100-mesh sieve;
(2) adding the powder sieve obtained in the step (1) into a wet granulating machine, uniformly stirring at a low speed, adding 5% of polyvidone K30 aqueous solution to prepare a soft material, and granulating at the frequency of 40-50 Hz by using a 12-mesh swing type granulator;
(3) drying the wet granules at 60 ℃, controlling the moisture to be 2.5-3.5%, taking out, and finishing granules in a 16-mesh swing type granulator at the frequency of 30-40 Hz;
(4) mixing uniformly and tabletting, controlling the tabletting pressure to be 10-20 KN and the tabletting speed to be 5-10 ten thousand tablets/h until the tablet weight range is +/-5 percent and the friability is less than or equal to 1 percent.
2. Preparing a coating solution with solid content of 8 percent: adding cellulose acetate, triethyl citrate and hypromellose (E3) into acetone, and stirring to dissolve.
3. High-temperature spray coating: and (3) preheating the plain tablets for 3-5 minutes, adjusting the distance between spray guns to be 10-15 cm, spraying at the liquid feed pump rotating speed of 20-40 rpm, the pot rotating speed of 3-10 rpm, the air inlet temperature of 30-50 ℃, the tablet temperature of 30-40 ℃ and the pressure of 0.25MPa until the plain tablets are not adhered and the weight is increased by 2-4%, and finishing coating and discharging to obtain the membrane-controlled metformin dual controlled-release tablet.
Embodiment 2. preparation method of membrane-controlled metformin dual controlled-release tablet
Firstly, weighing the components according to the formula of a tablet core and the formula of a coating solution respectively
TABLE 2 weight ratio table of components of film-controlled metformin dual controlled-release tablet
Secondly, the preparation step
1. Preparation of extended Release metformin hydrochloride core
(1) Grinding the metformin hydrochloride raw material, lactose, octadecanol and polyoxyethylene and sieving by a 80-mesh sieve;
(2) adding the powder sieve obtained in the step (1) into a wet granulating machine, uniformly stirring at a low speed, adding a 3% hydroxypropyl methylcellulose water solution to prepare a soft material, and granulating by using a 12-mesh swing granulator at the frequency of 40-50 Hz;
(3) drying the wet granules at 60 ℃, controlling the moisture to be 2.5-3.5%, taking out, and finishing granules in a 16-mesh swing type granulator at the frequency of 30-40 Hz;
(4) mixing uniformly and tabletting, controlling the tabletting pressure to be 10-20 KN and the tabletting speed to be 5-10 ten thousand tablets/h until the tablet weight range is +/-3 percent and the friability is less than or equal to 1 percent.
2. Preparing a coating solution with solid content of 8 percent: adding cellulose acetate, triethyl citrate and povidone into acetone, and stirring to dissolve.
3. High-temperature spray coating: and (3) preheating the plain tablets for 3-5 minutes, adjusting the distance between spray guns to be 10-15 cm, spraying at the liquid feed pump rotating speed of 20-40 rpm, the pot rotating speed of 3-10 rpm, the air inlet temperature of 30-50 ℃, the tablet temperature of 30-40 ℃ and the pressure of 0.25MPa until the plain tablets are not adhered and the weight is increased by 2-4%, and finishing coating and discharging to obtain the membrane-controlled metformin dual controlled-release tablet.
Example 3 preparation method of a membrane-controlled metformin dual controlled-release tablet
Firstly, weighing the components according to the formula of a tablet core and the formula of a coating solution respectively
TABLE 3 weight ratio table of components of film-controlled metformin dual controlled-release tablet
Secondly, the preparation step
1. Preparation of extended Release metformin hydrochloride core
(1) Grinding the metformin hydrochloride raw material, lactose, octadecanol and polyoxyethylene and sieving by a 120-mesh sieve;
(2) adding the powder sieve obtained in the step (1) into a wet granulating machine, uniformly stirring at a low speed, adding a 3% hydroxypropyl methylcellulose aqueous solution, uniformly mixing the powder sieve, adding an adhesive to prepare a soft material, and granulating by using a 12-mesh swing granulator at the frequency of 40-50 Hz;
(3) drying the wet granules at 60 ℃, controlling the moisture content to be 1.5-4.0%, taking out, and finishing granules in a 16-mesh swing type granulator at the frequency of 35 Hz;
(4) mixing uniformly and tabletting, controlling the tabletting pressure to be 10-20 KN and the tabletting speed to be 5-10 ten thousand tablets/h until the tablet weight range (plus or minus 4 percent) and the friability (less than or equal to 1 percent).
2. Preparing a coating solution with solid content of 8 percent: adding cellulose acetate, triethyl citrate and hypromellose (E3) into acetone, and stirring to dissolve.
3. High-temperature spray coating: and (3) preheating the plain tablets for 4 minutes, adjusting the distance between spray guns to be 10-15 cm, spraying at the liquid feed pump rotating speed of 20-40 rpm, the pot rotating speed of 3-10 rpm, the air inlet temperature of 30-50 ℃, the tablet temperature of 50 ℃ and the pressure of 0.25MPa until the plain tablets are not bonded and the weight of the plain tablets is increased by 4%, and finishing coating and discharging to obtain the membrane-controlled metformin dual controlled-release tablet.
Comparative example preparation of conventional metformin coated tablet
TABLE 4 preparation method of conventional metformin-coated tablet with ratio of ingredients
Secondly, the preparation steps are as follows:
1. preparation of metformin tablet core
(1) The metformin hydrochloride, the sodium carboxymethyl cellulose and the pregelatinized starch are crushed, mixed and sieved by a sieve with 85 meshes;
(2) preparing a hydroxypropyl methyl cellulose aqueous solution with the concentration of 5%, uniformly mixing powder and a sieve, adding an adhesive to prepare a soft material, and sieving by a 14-mesh sieve to granulate;
(3) drying the wet granules at 55-65 ℃, wherein the moisture is 2.8-3.0%, and the granules are granulated by a granulator with 16 meshes at the frequency of 15 Hz;
(4) mixing uniformly and tabletting, wherein the tabletting weight range is +/-5 percent, and the friability is less than or equal to 1 percent;
2. preparing a coating solution: adding ethanol into the weighed ethyl cellulose, polyethylene glycol 6000 and hexadecanol until the concentration of the coating liquid is 10%
3. Coating:
adjusting the height of a spray gun to be 17cm, putting the tablets into the spray gun for preheating for 3-5 minutes, adjusting the flow rate to be 200-250 ml/min, the rotating speed to be 4-6 r/min and the hot air temperature to be 30-40 ℃, continuously spraying under the condition that the plain tablets are not bonded, and discharging after coating.
Example 5 comparative and Experimental drug Release data
1. And (3) release curve determination:
the determination method comprises the following steps: release test standard procedure the first method, using 1000ml of pH6.8 phosphate buffer solution as release medium, rotating speed 100 rpm, operating according to the method, taking 5ml of solution after 2 hours, 6 hours and 12 hours, filtering, and instantly supplementing 5ml of pH6.8 phosphate buffer solution with the same temperature in a dissolution cup; accurately weighing 1ml of each of the subsequent filtrates, placing into a 100ml measuring flask, diluting with phosphate buffer solution with pH of 6.8 to scale, and shaking.
TABLE 5 Release data for comparative and example
Release data for comparative and example
Table 5 shows that the release of the product increases with time during storage at various time points, with a more pronounced increase at 2h and 6 h. The product obtained in the embodiment 1, the embodiment 2 and the embodiment 3 is increased by about 2-5% in 2h, 6h and 12h, the comparative example is worth that the product is increased by about 9% in 2h and 6h, after the product is placed for 30 months for a long time, the release degrees of the products in the embodiments 1-3 are all in a standard range, the release degrees of the comparative example are close to a standard limit, and the quality risk exists.
Therefore, compared with the traditional film-coated controlled release tablet, the film-controlled metformin hydrochloride dual controlled release composition has longer time for keeping stable release degree and more excellent storage stability.
The tablet weight is smaller, and the oral compliance of patients is improved, so that supplementary experimental examples are needed.
Claims (10)
1. The metformin hydrochloride dual controlled release composition is prepared from a controlled release coating film coated outside a tablet core containing a sustained release material metformin hydrochloride, and is characterized in that: the metformin hydrochloride tablet core containing the sustained-release material is composed of metformin hydrochloride, the sustained-release material, a filler and an adhesive, the coating layer is composed of a coating sustained-release material, a plasticizer and a pore-forming agent, wherein the coating sustained-release material is cellulose acetate, the tablet core sustained-release material is a mixture of octadecanol and polyethylene oxide, and the coating sustained-release material is cellulose acetate.
2. The metformin hydrochloride dual sustained and controlled release composition according to claim 1, wherein the formula of the tablet core containing metformin hydrochloride comprises the following raw materials in weight ratio: 75-100 parts of metformin hydrochloride, 8-16 parts of a mixture of sustained-release material octadecanol and polyethylene oxide, 2-5 parts of a filler and 0.1-1.5 parts of an adhesive.
3. The dual controlled release composition of metformin hydrochloride according to claim 1 or 2, wherein the ratio of octadecanol: the weight ratio of polyoxyethylene is 2-5: 1.
4. The metformin hydrochloride dual controlled-release composition according to claim 1, wherein the filler includes but is not limited to starch, lactose, dextrin, microcrystalline cellulose, pregelatinized starch, the binder includes but is not limited to hydroxypropylmethyl cellulose, povidone K30 and hydroxypropylcellulose, the binder is formulated into 3-5% aqueous solution;
or the filler is selected from one or more of starch, lactose, dextrin, microcrystalline cellulose and pregelatinized starch, the adhesive is selected from one or more of hydroxypropyl methyl cellulose, povidone K30 or hydroxypropyl cellulose, and the adhesive is prepared into 3-5% aqueous solution.
5. The metformin hydrochloride dual sustained-release composition according to claim 1 or 2, wherein the polyethylene oxide has a molecular weight of 40 to 90 ten thousand.
6. The metformin hydrochloride dual controlled-release composition according to claim 2, wherein in the controlled-release coating film coated outside the tablet core, the weight ratio of the coating controlled-release material cellulose acetate, the plasticizer and the pore-forming agent is 4: 1.0-2.0: 1.5 to 2.0.
7. The metformin hydrochloride dual controlled-release composition according to claim 6, wherein the plasticizer is one or both of triethyl citrate and tributyl citrate, and the pore-forming agent is one or both of povidone and hypromellose.
8. The method for preparing a metformin hydrochloride dual controlled-release composition according to any one of claims 1 to 7, comprising the steps of: 1, preparing a slow-release metformin tablet core, 2, preparing a coating solution with the solid content of 7-10%, 3, spraying and coating the plain tablet in the slow-release coating solution at a high temperature until the weight is increased by 1.5-5%, and finishing coating and discharging;
wherein the step 1 of preparing the sustained-release metformin tablet core comprises the following steps: (1) weighing metformin hydrochloride raw materials, tablet core slow-release materials and filler raw materials according to the weight part ratio, crushing and sieving, (2) adding an adhesive to prepare a soft material, and performing wet granulation, (3) drying and granulating, and (4) tabletting; wherein
(1) The crushing and sieving is to pass through a sieve of 80-100 meshes;
(2) the wet granulation is to prepare wet granules by sieving with a 12-mesh sieve with the frequency of 40-50 Hz;
(3) the drying temperature is 50-70 ℃, the moisture content after drying is 2-4%, and the whole grain is a 16-mesh granulator with the frequency of 30-40 Hz;
(4) the tablet pressing is carried out under the pressure of 10-20 KN, the pressing speed is 5-10 ten thousand tablets/h, and the tablet is pressed to the weight range (+/-5%) and the friability is not more than 1%, so that the tablet core containing the medicine sustained-release extract is obtained; the above-mentioned
The step 2 of preparing the controlled release coating comprises the following steps:
(1) weighing solid substances for forming the coating solution according to the weight part ratio, wherein the solid formula of the coating solution comprises a coating sustained and controlled release material, a plasticizer and a pore-forming agent, and the coating sustained and controlled release material is cellulose acetate
(2) Adding the solid content weighed in the step (1) into a dispersion medium until the solid content is 5-12% to obtain the coating liquid;
(3) coating: placing the drug-containing sustained-release tablet obtained in the claim 9 into the coating liquid obtained in the step (2) for high-temperature spray coating;
the coating step (3) is to adjust the distance of a spray gun to 10-15 cm, adjust the rotation speed of a liquid supply pump to 20-40 rpm, adjust the rotation speed of a pot body to 3-10 rpm, control the temperature of inlet air to 30-50 ℃, control the temperature of tablets to 30-40 ℃ and the atomization pressure to 0.25MPa, and finish the coating and discharging when the weight of the plain tablets is increased by 2-4% in a non-bonding state;
wherein the slow release material of the tablet core is a mixture of octadecanol and polyoxyethylene, and the slow release material of the coating layer is cellulose acetate.
9. The preparation method of the metformin hydrochloride dual sustained and controlled release composition according to claim 8, wherein the tablet core containing metformin hydrochloride comprises metformin hydrochloride, a mixture of sustained release material octadecanol and polyethylene oxide, a filling agent and an adhesive, and the weight parts of the metformin hydrochloride, the mixture of sustained release material octadecanol and polyethylene oxide, the filling agent and the adhesive in the tablet core containing metformin hydrochloride are 75-100: 8-16: 2-5: 0.1 to 1.5;
the slow release material in the tablet core is a mixture of octadecanol and polyoxyethylene, the proportion of octadecanol and polyoxyethylene in the mixture of octadecanol and polyoxyethylene is 2-5: 1, the solid formula of the coating liquid comprises a coating slow/controlled release material, a plasticizer and a pore-foaming agent, and the coating slow/controlled release material, the plasticizer and the pore-foaming agent are mixed according to the weight proportion of 2-5: 1.0-2.0: 1.0-2.0, wherein the coating slow-release material is cellulose acetate.
10. Use of a dual sustained release composition comprising metformin hydrochloride according to any one of claims 1 to 7 in the preparation of a pharmaceutical composition for the treatment of diabetes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010837431.9A CN112999182B (en) | 2020-08-19 | 2020-08-19 | Metformin hydrochloride dual sustained and controlled release composition and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010837431.9A CN112999182B (en) | 2020-08-19 | 2020-08-19 | Metformin hydrochloride dual sustained and controlled release composition and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112999182A true CN112999182A (en) | 2021-06-22 |
| CN112999182B CN112999182B (en) | 2023-04-07 |
Family
ID=76383551
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010837431.9A Active CN112999182B (en) | 2020-08-19 | 2020-08-19 | Metformin hydrochloride dual sustained and controlled release composition and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112999182B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115227660A (en) * | 2022-09-21 | 2022-10-25 | 北京惠之衡生物科技有限公司 | Metformin hydrochloride sustained release tablet and preparation method thereof |
Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030104053A1 (en) * | 2001-10-25 | 2003-06-05 | Depomed, Inc. | Optimal polymer mixtures for gastric retentive tablets |
| US20070275061A1 (en) * | 2006-05-23 | 2007-11-29 | Young Gwan Jo | Pharmaceutical compositions and formulations of metformin extended release tablets |
| CN101536989A (en) * | 2008-03-18 | 2009-09-23 | 杭州容立医药科技有限公司 | Metformin hydrochloride intragastric floating sustained-release tablet and preparation method thereof |
| CN101579325A (en) * | 2009-06-16 | 2009-11-18 | 重庆康刻尔制药有限公司 | Metformin hydrochloride controlled-release tablet and preparation method thereof |
| CN101912375A (en) * | 2010-08-26 | 2010-12-15 | 冯岩 | Metformin controlled release tablet |
| CN105878204A (en) * | 2014-12-16 | 2016-08-24 | 合肥立方制药股份有限公司 | Metformin hydrochloride osmotic pump controlled release tablet and preparation method thereof |
| CN106727404A (en) * | 2017-03-27 | 2017-05-31 | 华益药业科技(安徽)有限公司 | Diabecron sustained-release tablet and preparation method thereof |
| CN107049980A (en) * | 2017-04-01 | 2017-08-18 | 重庆康刻尔制药有限公司 | A kind of diabecron sustained-release tablet and preparation method thereof |
| CN107260697A (en) * | 2017-05-26 | 2017-10-20 | 合肥华方医药科技有限公司 | A kind of Metformin hydrochloride controlled release tablet and preparation method thereof |
| CN108969501A (en) * | 2018-08-20 | 2018-12-11 | 奕利制药有限公司 | A kind of Metformin hydrochloride intragastric floating tablets and preparation method thereof |
| CN110693845A (en) * | 2019-12-01 | 2020-01-17 | 仁和堂药业有限公司 | Preparation process of metformin hydrochloride sustained-release tablet |
| CN111840242A (en) * | 2020-08-05 | 2020-10-30 | 重庆康刻尔制药有限公司 | Metformin hydrochloride controlled release tablet and preparation method thereof |
-
2020
- 2020-08-19 CN CN202010837431.9A patent/CN112999182B/en active Active
Patent Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030104053A1 (en) * | 2001-10-25 | 2003-06-05 | Depomed, Inc. | Optimal polymer mixtures for gastric retentive tablets |
| US20070275061A1 (en) * | 2006-05-23 | 2007-11-29 | Young Gwan Jo | Pharmaceutical compositions and formulations of metformin extended release tablets |
| CN101536989A (en) * | 2008-03-18 | 2009-09-23 | 杭州容立医药科技有限公司 | Metformin hydrochloride intragastric floating sustained-release tablet and preparation method thereof |
| CN101579325A (en) * | 2009-06-16 | 2009-11-18 | 重庆康刻尔制药有限公司 | Metformin hydrochloride controlled-release tablet and preparation method thereof |
| CN101912375A (en) * | 2010-08-26 | 2010-12-15 | 冯岩 | Metformin controlled release tablet |
| CN105878204A (en) * | 2014-12-16 | 2016-08-24 | 合肥立方制药股份有限公司 | Metformin hydrochloride osmotic pump controlled release tablet and preparation method thereof |
| CN106727404A (en) * | 2017-03-27 | 2017-05-31 | 华益药业科技(安徽)有限公司 | Diabecron sustained-release tablet and preparation method thereof |
| CN107049980A (en) * | 2017-04-01 | 2017-08-18 | 重庆康刻尔制药有限公司 | A kind of diabecron sustained-release tablet and preparation method thereof |
| CN107260697A (en) * | 2017-05-26 | 2017-10-20 | 合肥华方医药科技有限公司 | A kind of Metformin hydrochloride controlled release tablet and preparation method thereof |
| CN108969501A (en) * | 2018-08-20 | 2018-12-11 | 奕利制药有限公司 | A kind of Metformin hydrochloride intragastric floating tablets and preparation method thereof |
| CN110693845A (en) * | 2019-12-01 | 2020-01-17 | 仁和堂药业有限公司 | Preparation process of metformin hydrochloride sustained-release tablet |
| CN111840242A (en) * | 2020-08-05 | 2020-10-30 | 重庆康刻尔制药有限公司 | Metformin hydrochloride controlled release tablet and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115227660A (en) * | 2022-09-21 | 2022-10-25 | 北京惠之衡生物科技有限公司 | Metformin hydrochloride sustained release tablet and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112999182B (en) | 2023-04-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1842534B1 (en) | Metoprolol succinate extended release tablets and methods for their preparation | |
| TW200942273A (en) | Drug delivery systems comprising weakly basic drugs and organic acids | |
| WO2022012172A1 (en) | Oral sustained-release composition for insoluble drug, and preparation method thereof | |
| US20080279938A1 (en) | Zaltoprofen-containing sustained release tablet and process for the preparation thereof | |
| WO2005123134A2 (en) | A controlled release delivery system for metformin | |
| CN112999182B (en) | Metformin hydrochloride dual sustained and controlled release composition and preparation method and application thereof | |
| JP6915258B2 (en) | Pharmaceutical composition particles, orally disintegrating preparation containing them, method for producing pharmaceutical composition particles | |
| CN113616624B (en) | Empagliflozin metformin sustained release preparation and preparation method thereof | |
| CN112315927A (en) | Paliperidone sustained-release orally disintegrating tablet and preparation method thereof | |
| CN109646417B (en) | Trimetazidine sustained release tablet and preparation method thereof | |
| WO2005077357A1 (en) | Pharmaceutical composition containing platinum complex as active substance and method of manufacturing thereof | |
| CN106620715B (en) | A Chinese medicinal composition for treating diabetes, and its preparation method | |
| WO2021060304A1 (en) | Granule having masked unpleasant taste and method for producing same | |
| RU2435584C2 (en) | Prolonged pharmaceutical composition drug form and method of its production (versions) | |
| EP3995136A1 (en) | Pharmaceutical composition containing tamsulosin or hydrochloride thereof and preparation method therefor | |
| CN112057429B (en) | Lei Xina Deg controlled release pharmaceutical composition | |
| CN111840242A (en) | Metformin hydrochloride controlled release tablet and preparation method thereof | |
| CN106606496A (en) | Naproxen and esomeprazole magnesium compound enteric coated tablets and preparation method thereof | |
| KR20080009016A (en) | Gastric retention-type pellet and the preparation method thereof | |
| KR20210054137A (en) | Sustained-release pharmaceutical compositions for oral administration comprising rebamipide or pharmaceutically acceptable salt thereof | |
| CN115252574B (en) | Telmisartan pellets, preparation method thereof and pharmaceutical preparation | |
| US20090068260A1 (en) | Beta-1-selective adrenoceptor blocking agent compositions and methods for their preparation | |
| JPH0774166B2 (en) | Method for producing sustained-release coated drug | |
| KR20210147955A (en) | Sustained release metformin coated tablets controlled by osmotic pressure and preparation method thereof | |
| CN111870585A (en) | Metformin hydrochloride controlled release tablet and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |