CN111388438A - Metformin hydrochloride sustained release tablet and preparation method thereof - Google Patents
Metformin hydrochloride sustained release tablet and preparation method thereof Download PDFInfo
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- 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
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- 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
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- A—HUMAN NECESSITIES
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- 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
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Abstract
The invention belongs to the field of metformin hydrochloride sustained release agents, and particularly relates to a metformin hydrochloride sustained release tablet and a preparation method thereof.
Description
Technical Field
The invention belongs to the field of metformin hydrochloride sustained release agents, and particularly relates to a metformin hydrochloride sustained release tablet and a preparation method thereof.
Background
Metformin is a biguanide antidiabetic drug, mainly acts on the tissues outside the pancreatic islets, inhibits the intestinal absorption of glucose, increases the utilization and intake of glucose by peripheral tissues, reduces hepatic gluconeogenesis, thereby achieving the effect of reducing blood glucose, and simultaneously has the effect of reducing insulin resistance, is mainly used for obese diabetic patients clinically, metformin hydrochloride is less absorbed in vivo due to lower permeability in the intestinal tract, and most absorption parts are positioned at the upper end of the gastrointestinal tract (the absorption window is at the end of the small intestine). metformin hydrochloride oral bioavailability is about 40-60%, as the dosage is increased, absorption reaches saturation, and the time limit exists in the osmotic transport process, so the bioavailability is reduced, drugs with higher solubility in water (such as solubility more than 100mg/m L) are difficult to prepare into sustained-release preparations, metformin hydrochloride has better water solubility (such as 346mg/m L in water at 37 ℃, 355mg/m 2 in buffer, 333.2 mg/m) and is difficult to prepare into sustained-release preparations with the initial pH 35/333 mg/m and the initial pH of the sustained-release preparation.
In the prior art, various methods for preparing metformin hydrochloride sustained release agents exist, but drugs such as sustained release agents obtained by the methods have the problems of high organic solvent residue, slow preparation process, difficult industrialization and the like; or the preparation method has the problems of overlarge tablet volume, difficult water control, need of special equipment and the like.
For example, chinese patent application CN 102133204 a discloses a method for preparing a metformin osmotic pump controlled release tablet, wherein a pharmaceutically acceptable salt of metformin and a nonionic surfactant are added during the preparation of a tablet core to obtain a metformin osmotic pump controlled release tablet, and although the compliance and drug sustained release properties of the sustained release tablet prepared by the method are improved to a certain extent, laser drilling is required in the preparation process, and the requirement on equipment is high.
Secondly, the chinese patent application CN 102247370 a discloses a compound repaglinide-metformin hydrochloride controlled release preparation which is a compound three-layer osmotic pump controlled release tablet, wherein a tablet core consists of a boosting layer in the middle and an upper and a lower drug layers, the tablet core is coated with a semipermeable membrane, the upper and the lower drug layers are respectively provided with a drug release aperture, and the compound repaglinide-metformin hydrochloride controlled release preparation is prepared by the technologies of material mixing, tabletting and laser drilling, and the technology also has the defect of higher equipment requirements.
On the other hand, although the multiple-tone technology in the prior art is a sustained-release technology, sustained-release administration is not carried out in the actual administration process, and a patient still needs to take the medicine three times a day; therefore, the preparation has problems of poor compliance, inconvenience in administration, and the like.
Therefore, a metformin hydrochloride sustained-release preparation technology is needed to be provided, so that the bioavailability is improved, and the problems of slow preparation process, participation of organic solvents, special equipment requirements and the like are solved.
Disclosure of Invention
In order to overcome the technical problems, the invention provides a metformin hydrochloride sustained-release tablet and a preparation method thereof. The metformin hydrochloride sustained release tablet has the advantages of good bioavailability, good stability, simple preparation method and contribution to popularization and application.
In order to achieve the above purpose, the technical scheme provided by the invention is as follows:
a metformin hydrochloride sustained release tablet is prepared from tablet core and coating;
the preparation raw materials of the tablet core comprise: metformin hydrochloride, PVPK90, a penetration enhancer, an osmotically active substance;
preferably, the amount of the PVPK90 is 1-5% of the mass of the metformin hydrochloride, and is preferably 4%;
preferably, the osmotically active substance is a mixture of tragacanth, sulfobutyl ether- β -cyclodextrin, sulfobutyl ether- β -cyclodextrin;
preferably, the tragacanth gum is prepared from boat-fruited sterculia seed, and the preparation method comprises the following steps:
soaking semen Scaphii Lychnophori in hot water, expanding, removing outer skin and inner core, separating out middle skin part, drying, grinding into powder, and sieving to obtain tragacanth.
Preferably, the amount of the osmotically active substance is 0.5 to 5%, preferably 2 to 5%, of the total mass of the mixture of metformin hydrochloride and PVPK 90;
preferably, in the osmotically active substance, the mass ratio of the mixture of the tragacanth gum, the sulfobutyl ether- β -cyclodextrin and the sulfobutyl ether- β -cyclodextrin is 3-5:1-2: 1-2.
Preferably, the penetration enhancer is a mixture of potassium gluconate sulfate, d-mannitol and urea;
preferably, the mass ratio of the potassium gluconate sulfate to the d-mannitol to the urea in the penetration enhancer is 3-5:1-2: 2-4;
preferably, the amount of the penetration enhancer is 1-3% of the total mass of the mixture of metformin hydrochloride and PVPK 90.
The preparation raw materials of the coating comprise: aqueous dispersions of polyvinyl acetate, polyvinylpyrrolidone and sodium dodecyl sulfate, pore-foaming agent and plasticizer;
preferably, the mass concentrations of the polyvinyl acetate, the polyvinylpyrrolidone and the sodium dodecyl sulfate in the aqueous dispersion are respectively 15-20%, 3-5% and 0.5-1%.
Preferably, the pore-forming agent is a mixture of polyethylene glycol (PEG800) and hydroxypropylmethylcellulose (HPMC-E5);
preferably, the amount of the pore-foaming agent is 10-30% of the total mass of the coating liquid;
preferably, the dosage ratio of the PEG800 to the HPMC-E5 is 2-5: 1.
Preferably, the plasticizer is: a mixture of triethyl citrate, triacetin, succinate, propylene glycol;
preferably, the amount of the plasticizer is 1-3% of the total mass of the coating solution;
preferably, the mass ratio of triethyl citrate, glyceryl triacetate, succinate and propylene glycol in the plasticizer is 1:2-3:1-2: 3-5.
Another objective of the present invention is to provide a preparation method of the metformin hydrochloride sustained release tablet, which comprises the following steps:
(1) preparation of a tablet core: mixing metformin hydrochloride with polyvinylpyrrolidone (PVP K-90), adding penetration enhancer and osmoactive substance, sieving, oven drying, adding sodium dodecyl sulfate, and tabletting to obtain metformin hydrochloride tablet core;
(2) preparing a coating solution: adding sodium dodecyl sulfate, polyvinyl acetate and polyvinylpyrrolidone (PVP K-30) into water in sequence to obtain aqueous dispersion, and adding a pore-forming agent and a plasticizer into the aqueous dispersion; preparing a coating solution;
(3) and (3) putting the metformin hydrochloride tablet core into a coating solution for coating treatment, and drying after the coating film reaches the thickness to obtain the metformin hydrochloride sustained release tablet.
Preferably, in the step (1), the drying temperature is 50-60 ℃;
preferably, in the step (1), the dosage of the sodium dodecyl sulfate is 1-3% of the total mass of the tablet core;
preferably, in the step (3), the thickness of the coating film is 200-300 μm;
preferably, in the step (3), the temperature of the coating treatment is 25-35 ℃;
preferably, in step (3), the temperature of the drying is 50-60 ℃.
Compared with the prior art, the invention has the technical advantages that:
(1) the metformin hydrochloride sustained release tablet prepared by the invention has stable drug release speed and large drug-loading rate, and is a dosage form which is more suitable for clinical needs; not only can take effect quickly, but also can maintain effective blood concentration;
(2) the metformin hydrochloride sustained release tablet prepared by the invention has better drug stability, and can still keep better drug effect after being stored indoors for more than 48 months at normal temperature.
(3) The potassium glucose sulfate, the d-mannitol and the urea which are added as penetration enhancers have better synergistic effect, can generate osmotic pressure and maintain the release of the medicament;
(4) the added osmotic active substances of the invention are the tragacanth mucilage, the sulfobutyl ether- β -cyclodextrin and the sulfobutyl ether- β -cyclodextrin, have better synergistic effect, can effectively promote the release of the medicine and effectively maintain the blood concentration.
Drawings
FIG. 1: the drug release profiles of examples 1-3 of the invention;
FIG. 2: the drug release profiles of comparative examples 1-6 of the present invention;
the invention will now be further illustrated with reference to the accompanying drawings and examples:
Detailed Description
The present invention will be described below with reference to specific examples to make the technical aspects of the present invention easier to understand and grasp, but the present invention is not limited thereto. The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.
Example 1
A metformin hydrochloride sustained release tablet is prepared from tablet core and coating;
the preparation raw materials of the tablet core comprise: metformin hydrochloride, PVPK90, a penetration enhancer, an osmotically active substance;
the dosage of the PVPK90 is 4% of the mass of the metformin hydrochloride;
the osmotic active substance is a mixture of the tragacanth gum, the sulfobutyl ether- β -cyclodextrin and the sulfobutyl ether- β -cyclodextrin, and the mass ratio of the mixture of the tragacanth gum, the sulfobutyl ether- β -cyclodextrin and the sulfobutyl ether- β -cyclodextrin is 4:1: 1.
The dosage of the penetration active substance is 2 percent of the total mass of the mixture of the metformin hydrochloride and the PVPK 90;
preferably, the tragacanth gum is prepared from boat-fruited sterculia seed, and the preparation method comprises the following steps:
soaking semen Scaphii Lychnophori in hot water, expanding, removing outer skin and inner core, separating out middle skin part, drying, grinding into powder, and sieving to obtain tragacanth.
The penetration enhancer is a mixture of potassium gluconate sulfate, d-mannitol and urea;
the mass ratio of the potassium gluconate sulfate to the d-mannitol to the urea in the penetration enhancer is 4:1: 3;
the dosage of the penetration enhancer is 2% of the total mass of the mixture of the metformin hydrochloride and the PVPK 90.
The preparation raw materials of the coating comprise: aqueous dispersions of polyvinyl acetate, polyvinylpyrrolidone and sodium dodecyl sulfate, pore-foaming agent and plasticizer;
in the water dispersion, the mass concentrations of polyvinyl acetate, polyvinylpyrrolidone and sodium dodecyl sulfate are respectively 18%, 4% and 0.75%.
The pore-foaming agent is a mixture of polyethylene glycol (PEG800) and hydroxypropyl methyl cellulose (HPMC-E5); the amount of the pore-foaming agent is 20 percent of the total mass of the coating liquid; the dosage ratio of the PEG800 to the HPMC-E5 is 3: 1.
The plasticizer is as follows: a mixture of triethyl citrate, triacetin, succinate, propylene glycol;
the amount of the plasticizer is 2% of the total mass of the coating liquid; the mass ratio of triethyl citrate, glyceryl triacetate, succinate and propylene glycol in the plasticizer is 1:2:1: 3.
The preparation method of the metformin hydrochloride sustained release tablet comprises the following steps:
(1) preparation of a tablet core: mixing metformin hydrochloride with PVP K-90, adding penetration enhancer and osmotically active substance, sieving, oven drying at 55 deg.C, adding 2% (by total mass of tablet core) sodium dodecyl sulfate, and tabletting to obtain metformin hydrochloride tablet core;
(2) preparing a coating solution: adding sodium dodecyl sulfate, polyvinyl acetate and PVP K-30 into water in sequence to prepare aqueous dispersion, and adding a pore-making agent and a plasticizer into the aqueous dispersion; preparing a coating solution;
(3) and (3) putting the metformin hydrochloride tablet core into a coating solution, coating at 30 ℃, drying at 55 ℃ after a coating film reaches the thickness of 250 mu m, and thus obtaining the metformin hydrochloride sustained release tablet.
Example 2
A metformin hydrochloride sustained release tablet is prepared from tablet core and coating;
the preparation raw materials of the tablet core comprise: metformin hydrochloride, PVPK90, a penetration enhancer, an osmotically active substance;
the dosage of the PVPK90 is 1 percent of the mass of the metformin hydrochloride;
the osmotic active substance is a mixture of the tragacanth gum, the sulfobutyl ether- β -cyclodextrin and the sulfobutyl ether- β -cyclodextrin, and the mass ratio of the mixture of the tragacanth gum, the sulfobutyl ether- β -cyclodextrin and the sulfobutyl ether- β -cyclodextrin is 3:1: 1.
The dosage of the penetration active substance is 0.5 percent of the total mass of the mixture of the metformin hydrochloride and the PVPK 90;
the tragacanth mucilage is prepared from boat-fruited sterculia seed, and the preparation method comprises the following steps:
soaking semen Scaphii Lychnophori in hot water, expanding, removing outer skin and inner core, separating out middle skin part, drying, grinding into powder, and sieving to obtain tragacanth.
The penetration enhancer is a mixture of potassium gluconate sulfate, d-mannitol and urea;
the mass ratio of the potassium gluconate sulfate to the d-mannitol to the urea in the penetration enhancer is 3:1: 2;
the dosage of the penetration enhancer is 1 percent of the total mass of the mixture of the metformin hydrochloride and the PVPK 90.
The preparation raw materials of the coating comprise: aqueous dispersions of polyvinyl acetate, polyvinylpyrrolidone and sodium dodecyl sulfate, pore-foaming agent and plasticizer;
in the water dispersion, the mass concentrations of polyvinyl acetate, polyvinylpyrrolidone and sodium dodecyl sulfate are respectively 15%, 3% and 1%.
The pore-foaming agent is a mixture of polyethylene glycol (PEG800) and hydroxypropyl methyl cellulose (HPMC-E5); the amount of the pore-foaming agent is 10 percent of the total mass of the coating liquid; the dosage ratio of the PEG800 to the HPMC-E5 is 2: 1.
The plasticizer is as follows: a mixture of triethyl citrate, triacetin, succinate, propylene glycol;
the amount of the plasticizer is 3% of the total mass of the coating liquid; the mass ratio of triethyl citrate, glyceryl triacetate, succinate and propylene glycol in the plasticizer is 1:2:1: 3.
The preparation method of the metformin hydrochloride sustained release tablet comprises the following steps:
(1) preparation of a tablet core: mixing metformin hydrochloride with PVP K-90, adding penetration enhancer and osmotically active substance, sieving, oven drying at 50 deg.C, adding 1% (based on total mass of tablet core) sodium dodecyl sulfate, and tabletting to obtain metformin hydrochloride tablet core;
(2) preparing a coating solution: adding sodium dodecyl sulfate, polyvinyl acetate and PVP K-30 into water in sequence to prepare aqueous dispersion, and adding a pore-making agent and a plasticizer into the aqueous dispersion; preparing a coating solution;
(3) putting the metformin hydrochloride tablet core into a coating solution, carrying out coating treatment at 25 ℃, drying at 50 ℃ after the coating film reaches the thickness of 200 mu m, and obtaining the metformin hydrochloride sustained release tablet.
Example 3
A metformin hydrochloride sustained release tablet is prepared from tablet core and coating;
the preparation raw materials of the tablet core comprise: metformin hydrochloride, PVPK90, a penetration enhancer, an osmotically active substance;
the dosage of the PVPK90 is 5 percent of the mass of the metformin hydrochloride;
the osmotic active substance is a mixture of the tragacanth gum, the sulfobutyl ether- β -cyclodextrin and the sulfobutyl ether- β -cyclodextrin, and the mass ratio of the mixture of the tragacanth gum, the sulfobutyl ether- β -cyclodextrin and the sulfobutyl ether- β -cyclodextrin is 5:2: 2.
The dosage of the penetration active substance is 5 percent of the total mass of the mixture of the metformin hydrochloride and the PVPK 90;
the tragacanth mucilage is prepared from boat-fruited sterculia seed, and the preparation method comprises the following steps:
soaking semen Scaphii Lychnophori in hot water, expanding, removing outer skin and inner core, separating out middle skin part, drying, grinding into powder, and sieving to obtain tragacanth.
The penetration enhancer is a mixture of potassium gluconate sulfate, d-mannitol and urea;
the mass ratio of the potassium gluconate sulfate to the d-mannitol to the urea in the penetration enhancer is 5:2: 4;
the dosage of the penetration enhancer is 3 percent of the total mass of the mixture of the metformin hydrochloride and the PVPK 90.
The preparation raw materials of the coating comprise: aqueous dispersions of polyvinyl acetate, polyvinylpyrrolidone and sodium dodecyl sulfate, pore-foaming agent and plasticizer;
in the water dispersion, the mass concentrations of polyvinyl acetate, polyvinylpyrrolidone and sodium dodecyl sulfate are respectively 20%, 5% and 0.5%.
The pore-foaming agent is a mixture of polyethylene glycol (PEG800) and hydroxypropyl methyl cellulose (HPMC-E5); the amount of the pore-foaming agent is 30 percent of the total mass of the coating liquid; the dosage ratio of the PEG800 to the HPMC-E5 is 5: 1.
The plasticizer is as follows: a mixture of triethyl citrate, triacetin, succinate, propylene glycol;
the amount of the plasticizer is 1 percent of the total mass of the coating liquid; the mass ratio of triethyl citrate, glyceryl triacetate, succinate and propylene glycol in the plasticizer is 1:3:2: 5.
The preparation method of the metformin hydrochloride sustained release tablet comprises the following steps:
(1) preparation of a tablet core: mixing metformin hydrochloride with PVP K-90, adding penetration enhancer and osmotically active substance, sieving, oven drying at 60 deg.C, adding 3% (based on total mass of tablet core) of sodium dodecyl sulfate, and tabletting to obtain metformin hydrochloride tablet core;
(2) preparing a coating solution: adding sodium dodecyl sulfate, polyvinyl acetate and PVP K-30 into water in sequence to prepare aqueous dispersion, and adding a pore-making agent and a plasticizer into the aqueous dispersion; preparing a coating solution;
(3) and (3) putting the metformin hydrochloride tablet core into a coating solution, coating at 35 ℃, drying at 60 ℃ after the coating film reaches the thickness of 300 mu m, and thus obtaining the metformin hydrochloride sustained release tablet.
Comparative example 1
The composition of the penetration enhancer was different compared to example 1, using sodium chloride instead of d-mannitol.
A metformin hydrochloride sustained release tablet is prepared from tablet core and coating;
the preparation raw materials of the tablet core comprise: metformin hydrochloride, PVPK90, a penetration enhancer, an osmotically active substance;
the dosage of the PVPK90 is 4% of the mass of the metformin hydrochloride;
the osmotic active substance is a mixture of the tragacanth gum, the sulfobutyl ether- β -cyclodextrin and the sulfobutyl ether- β -cyclodextrin, and the mass ratio of the mixture of the tragacanth gum, the sulfobutyl ether- β -cyclodextrin and the sulfobutyl ether- β -cyclodextrin is 4:1: 1.
The dosage of the penetration active substance is 2 percent of the total mass of the mixture of the metformin hydrochloride and the PVPK 90;
the tragacanth mucilage is prepared from boat-fruited sterculia seed, and the preparation method comprises the following steps:
soaking semen Scaphii Lychnophori in hot water, expanding, removing outer skin and inner core, separating out middle skin part, drying, grinding into powder, and sieving to obtain tragacanth.
The penetration enhancer is a mixture of potassium gluconate sulfate, sodium chloride and urea;
the mass ratio of the potassium glucose sulfate, the sodium chloride and the urea in the penetration enhancer is 4:1: 3;
the dosage of the penetration enhancer is 2% of the total mass of the mixture of the metformin hydrochloride and the PVPK 90.
The preparation raw materials of the coating comprise: aqueous dispersions of polyvinyl acetate, polyvinylpyrrolidone and sodium dodecyl sulfate, pore-foaming agent and plasticizer;
in the water dispersion, the mass concentrations of polyvinyl acetate, polyvinylpyrrolidone and sodium dodecyl sulfate are respectively 18%, 4% and 0.75%.
The pore-foaming agent is a mixture of polyethylene glycol (PEG800) and hydroxypropyl methyl cellulose (HPMC-E5); the amount of the pore-foaming agent is 20 percent of the total mass of the coating liquid; the dosage ratio of the PEG800 to the HPMC-E5 is 3: 1.
The plasticizer is as follows: a mixture of triethyl citrate, triacetin, succinate, propylene glycol;
the amount of the plasticizer is 2% of the total mass of the coating liquid; the mass ratio of triethyl citrate, glyceryl triacetate, succinate and propylene glycol in the plasticizer is 1:2:1: 3.
The preparation method of the metformin hydrochloride sustained release tablet has the same steps as the example 1.
Comparative example 2
The composition of the permeation enhancer was different from that of example 1, and sodium chloride was used instead of potassium gluconate sulfate.
A metformin hydrochloride sustained release tablet is prepared from tablet core and coating;
the preparation raw materials of the tablet core comprise: metformin hydrochloride, PVPK90, a penetration enhancer, an osmotically active substance;
the dosage of the PVPK90 is 4% of the mass of the metformin hydrochloride;
the osmotic active substance is a mixture of the tragacanth gum, the sulfobutyl ether- β -cyclodextrin and the sulfobutyl ether- β -cyclodextrin, and the mass ratio of the mixture of the tragacanth gum, the sulfobutyl ether- β -cyclodextrin and the sulfobutyl ether- β -cyclodextrin is 4:1: 1.
The dosage of the penetration active substance is 2 percent of the total mass of the mixture of the metformin hydrochloride and the PVPK 90;
the tragacanth mucilage is prepared from boat-fruited sterculia seed, and the preparation method comprises the following steps:
soaking semen Scaphii Lychnophori in hot water, expanding, removing outer skin and inner core, separating out middle skin part, drying, grinding into powder, and sieving to obtain tragacanth.
The penetration enhancer is a mixture of sodium chloride, d-mannitol and urea;
the mass ratio of sodium chloride, d-mannitol and urea in the penetration enhancer is 4:1: 3;
the dosage of the penetration enhancer is 2% of the total mass of the mixture of the metformin hydrochloride and the PVPK 90.
The preparation raw materials of the coating comprise: aqueous dispersions of polyvinyl acetate, polyvinylpyrrolidone and sodium dodecyl sulfate, pore-foaming agent and plasticizer;
in the water dispersion, the mass concentrations of polyvinyl acetate, polyvinylpyrrolidone and sodium dodecyl sulfate are respectively 18%, 4% and 0.75%.
The pore-foaming agent is a mixture of polyethylene glycol (PEG800) and hydroxypropyl methyl cellulose (HPMC-E5); the amount of the pore-foaming agent is 20 percent of the total mass of the coating liquid; the dosage ratio of the PEG800 to the HPMC-E5 is 3: 1.
The plasticizer is as follows: a mixture of triethyl citrate, triacetin, succinate, propylene glycol;
the amount of the plasticizer is 2% of the total mass of the coating liquid; the mass ratio of triethyl citrate, glyceryl triacetate, succinate and propylene glycol in the plasticizer is 1:2:1: 3.
The preparation method of the metformin hydrochloride sustained release tablet has the same steps as the example 1.
Comparative example 3
Compared with example 1, the penetration-promoting active substance has a different composition, and lactose is used instead of tragacanth.
A metformin hydrochloride sustained release tablet is prepared from tablet core and coating;
the preparation raw materials of the tablet core comprise: metformin hydrochloride, PVPK90, a penetration enhancer, an osmotically active substance;
the dosage of the PVPK90 is 4% of the mass of the metformin hydrochloride;
the osmotic active substance is a mixture of lactose, sulfobutyl ether- β -cyclodextrin and sulfobutyl ether- β -cyclodextrin, and the mass ratio of the mixture of the lactose, the sulfobutyl ether- β -cyclodextrin and the sulfobutyl ether- β -cyclodextrin in the osmotic active substance is 4:1: 1.
The dosage of the penetration active substance is 2 percent of the total mass of the mixture of the metformin hydrochloride and the PVPK 90;
the penetration enhancer is a mixture of potassium gluconate sulfate, d-mannitol and urea;
the mass ratio of the potassium gluconate sulfate to the d-mannitol to the urea in the penetration enhancer is 4:1: 3;
the dosage of the penetration enhancer is 2% of the total mass of the mixture of the metformin hydrochloride and the PVPK 90.
The preparation raw materials of the coating comprise: aqueous dispersions of polyvinyl acetate, polyvinylpyrrolidone and sodium dodecyl sulfate, pore-foaming agent and plasticizer;
in the water dispersion, the mass concentrations of polyvinyl acetate, polyvinylpyrrolidone and sodium dodecyl sulfate are respectively 18%, 4% and 0.75%.
The pore-foaming agent is a mixture of polyethylene glycol (PEG800) and hydroxypropyl methyl cellulose (HPMC-E5); the amount of the pore-foaming agent is 20 percent of the total mass of the coating liquid; the dosage ratio of the PEG800 to the HPMC-E5 is 3: 1.
The plasticizer is as follows: a mixture of triethyl citrate, triacetin, succinate, propylene glycol;
the amount of the plasticizer is 2% of the total mass of the coating liquid; the mass ratio of triethyl citrate, glyceryl triacetate, succinate and propylene glycol in the plasticizer is 1:2:1: 3.
The preparation method of the metformin hydrochloride sustained release tablet has the same steps as the example 1.
Comparative example 4
Compared to example 1, the composition of the porogen is different, using PEG400 instead of PEG 800.
A metformin hydrochloride sustained release tablet is prepared from tablet core and coating;
the preparation raw materials of the tablet core comprise: metformin hydrochloride, PVPK90, a penetration enhancer, an osmotically active substance;
the dosage of the PVPK90 is 4% of the mass of the metformin hydrochloride;
the osmotic active substance is a mixture of the tragacanth gum, the sulfobutyl ether- β -cyclodextrin and the sulfobutyl ether- β -cyclodextrin, and the mass ratio of the mixture of the tragacanth gum, the sulfobutyl ether- β -cyclodextrin and the sulfobutyl ether- β -cyclodextrin is 4:1: 1.
The dosage of the penetration active substance is 2 percent of the total mass of the mixture of the metformin hydrochloride and the PVPK 90;
the tragacanth mucilage is prepared from boat-fruited sterculia seed, and the preparation method comprises the following steps:
soaking semen Scaphii Lychnophori in hot water, expanding, removing outer skin and inner core, separating out middle skin part, drying, grinding into powder, and sieving to obtain tragacanth.
The penetration enhancer is a mixture of potassium gluconate sulfate, d-mannitol and urea;
the mass ratio of the potassium gluconate sulfate to the d-mannitol to the urea in the penetration enhancer is 4:1: 3;
the dosage of the penetration enhancer is 2% of the total mass of the mixture of the metformin hydrochloride and the PVPK 90.
The preparation raw materials of the coating comprise: aqueous dispersions of polyvinyl acetate, polyvinylpyrrolidone and sodium dodecyl sulfate, pore-foaming agent and plasticizer;
in the water dispersion, the mass concentrations of polyvinyl acetate, polyvinylpyrrolidone and sodium dodecyl sulfate are respectively 18%, 4% and 0.75%.
The pore-foaming agent is a mixture of polyethylene glycol (PEG400) and hydroxypropyl methyl cellulose (HPMC-E5); the amount of the pore-foaming agent is 20 percent of the total mass of the coating liquid; the dosage ratio of the PEG800 to the HPMC-E5 is 3: 1.
The plasticizer is as follows: a mixture of triethyl citrate, triacetin, succinate, propylene glycol;
the amount of the plasticizer is 2% of the total mass of the coating liquid; the mass ratio of triethyl citrate, glyceryl triacetate, succinate and propylene glycol in the plasticizer is 1:2:1: 3.
The preparation method of the metformin hydrochloride sustained release tablet has the same steps as the example 1.
Comparative example 5
Compared to example 1, the composition of the plasticizer was different, triacetin replacing triethyl citrate.
A metformin hydrochloride sustained release tablet is prepared from tablet core and coating;
the preparation raw materials of the tablet core comprise: metformin hydrochloride, PVPK90, a penetration enhancer, an osmotically active substance;
the dosage of the PVPK90 is 4% of the mass of the metformin hydrochloride;
the osmotic active substance is a mixture of the tragacanth gum, the sulfobutyl ether- β -cyclodextrin and the sulfobutyl ether- β -cyclodextrin, and the mass ratio of the mixture of the tragacanth gum, the sulfobutyl ether- β -cyclodextrin and the sulfobutyl ether- β -cyclodextrin is 4:1: 1.
The dosage of the penetration active substance is 2 percent of the total mass of the mixture of the metformin hydrochloride and the PVPK 90;
the tragacanth mucilage is prepared from boat-fruited sterculia seed, and the preparation method comprises the following steps:
soaking semen Scaphii Lychnophori in hot water, expanding, removing outer skin and inner core, separating out middle skin part, drying, grinding into powder, and sieving to obtain tragacanth.
The penetration enhancer is a mixture of potassium gluconate sulfate, d-mannitol and urea;
the mass ratio of the potassium gluconate sulfate to the d-mannitol to the urea in the penetration enhancer is 4:1: 3;
the dosage of the penetration enhancer is 2% of the total mass of the mixture of the metformin hydrochloride and the PVPK 90.
The preparation raw materials of the coating comprise: aqueous dispersions of polyvinyl acetate, polyvinylpyrrolidone and sodium dodecyl sulfate, pore-foaming agent and plasticizer;
in the water dispersion, the mass concentrations of polyvinyl acetate, polyvinylpyrrolidone and sodium dodecyl sulfate are respectively 18%, 4% and 0.75%.
The pore-foaming agent is a mixture of polyethylene glycol (PEG800) and hydroxypropyl methyl cellulose (HPMC-E5); the amount of the pore-foaming agent is 20 percent of the total mass of the coating liquid; the dosage ratio of the PEG800 to the HPMC-E5 is 3: 1.
The plasticizer is as follows: mixtures of glyceryl triacetate, succinate, propylene glycol;
the amount of the plasticizer is 2% of the total mass of the coating liquid; the mass ratio of the glyceryl triacetate to the succinate to the propylene glycol in the plasticizer is 3:1: 3.
The preparation method of the metformin hydrochloride sustained release tablet has the same steps as the example 1.
Comparative example 6
Compared with the example 1, the preparation method of the metformin hydrochloride sustained-release tablet is different.
A metformin hydrochloride sustained release tablet has the same composition as that of example 1.
The preparation method of the metformin hydrochloride sustained release tablet comprises the following steps:
(1) preparation of a tablet core: mixing metformin hydrochloride with PVP K-90, adding penetration enhancer and osmotically active substance, sieving, oven drying at 55 deg.C, and tabletting to obtain metformin hydrochloride tablet core;
(2) preparing a coating solution: adding sodium dodecyl sulfate, polyvinyl acetate and PVP K-30 into water in sequence to prepare aqueous dispersion, and adding a pore-making agent and a plasticizer into the aqueous dispersion; preparing a coating solution;
(3) and (3) putting the metformin hydrochloride tablet core into a coating solution, coating at 30 ℃, drying at 55 ℃ after a coating film reaches the thickness of 250 mu m, and thus obtaining the metformin hydrochloride sustained release tablet.
Examples of effects
The metformin hydrochloride sustained-release tablets in examples 1 to 3 and comparative examples 1 to 6 were prepared into products having an effective content of 500 mg/tablet, and effect tests were conducted.
1. Release test of metformin hydrochloride sustained-release tablets
Measuring the release rate according to a release rate measuring method (a first method of 0931 of the general rules of the Chinese pharmacopoeia 2015 edition), namely measuring the release rate by adopting a first method in the dissolution rate measuring method, taking a phosphate buffer solution (pH6.8) of 1000m L as a dissolving medium, operating at a rotating speed of 100rmp according to the method, taking 10m L of the solution at each time point when dissolving for 1h, 3h, 5h, 7h, 10h and 12h respectively, filtering, precisely measuring 1m L of a subsequent filtrate, respectively placing the subsequent filtrate in measuring bottles of 25m L, 50m L, 100m L, 100ml and 100ml, adding the phosphate buffer solution (pH6.8) to dilute to a scale, and shaking uniformly to obtain a sample solution;
an appropriate amount of metformin hydrochloride control (source: China institute for food and drug testing) was precisely weighed, dissolved in phosphate buffer (pH6.8), and quantitatively diluted to a solution containing 5 μ g of metformin hydrochloride per 1m of L to obtain a control solution.
Finally, the absorbance of the test solution and the absorbance of the control solution are respectively measured at the wavelength of 232nm by an ultraviolet-visible spectrophotometry (four parts general rule 0401 of Chinese pharmacopoeia 2015 edition), and the cumulative release amount of the metformin hydrochloride in different time periods is calculated. The results are shown in Table 1 and FIGS. 1-2.
TABLE 1 Release test of metformin hydrochloride sustained-release tablets
Therefore, the metformin hydrochloride sustained release tablet provided by the invention has a good sustained release effect, so that the blood concentration of metformin hydrochloride reaches a treatment concentration in a short time; the sustained-release tablet slowly and stably releases the medicament without burst release, so that the blood concentration of the metformin hydrochloride can be kept at the treatment concentration for a long time, and the curative effect is improved.
Meanwhile, the formulation composition and the preparation method of the metformin hydrochloride sustained-release tablet have important influence on the release effect, the release stability is poor when the composition is changed or the preparation method is changed, and meanwhile, the burst release phenomenon occurs in the release process of partial products.
2. Stability test
The metformin hydrochloride sustained-release tablets were subjected to an accelerated stability test at a temperature of 40 ℃ and a relative humidity of 75%. The tablets are taken out at 1 month, 2 months and 3 months respectively, the change condition of the content is measured by referring to the measuring method of the metformin hydrochloride tablets in the second part of the Chinese pharmacopoeia 2015 edition, the release rates of the metformin hydrochloride sustained release tablets at 1h, 3h and 10h after 3 months are detected, and the results are shown in table 2.
TABLE 2 stability test
Therefore, the results of the stability acceleration test of the metformin hydrochloride sustained release tablet show that the metformin hydrochloride sustained release tablet provided by the invention has better stability, and the quality of the metformin hydrochloride sustained release tablet is not obviously changed within 3 months. Meanwhile, the formula composition and the preparation method of the metformin hydrochloride sustained-release tablet have important influence on the stability effect, and the stability change is obvious when the composition is changed or the preparation method is changed.
The above detailed description is specific to one possible embodiment of the present invention, and the embodiment is not intended to limit the scope of the present invention, and all equivalent implementations or modifications without departing from the scope of the present invention should be included in the technical scope of the present invention.
Claims (10)
1. A metformin hydrochloride sustained release tablet is prepared from tablet core and coating;
the preparation raw materials of the tablet core comprise: metformin hydrochloride, PVPK90, a permeation enhancer and an osmotically active substance;
the osmotic active substance is a mixture of tragacanth, sulfobutyl ether- β -cyclodextrin and sulfobutyl ether- β -cyclodextrin.
2. The metformin hydrochloride sustained-release tablet according to claim 1, wherein the tragacanth gum is prepared from boat-fruited sterculia seed by the following steps: soaking semen Scaphii Lychnophori in hot water, expanding, removing outer skin and inner core, separating out middle skin part, drying, grinding into powder, and sieving to obtain tragacanth.
3. The metformin hydrochloride sustained-release tablet according to claim 1, wherein the amount of the osmotically active substance is 0.5 to 5% by mass based on the total mass of the mixture of metformin hydrochloride and PVPK 90.
4. The metformin hydrochloride sustained-release tablet according to claim 1, wherein the mixture of the tragacanth gum, the sulfobutyl ether- β -cyclodextrin and the sulfobutyl ether- β -cyclodextrin is contained in the osmotically active substance in a mass ratio of 3-5:1-2: 1-2.
5. The metformin hydrochloride sustained-release tablet according to claim 1, wherein the permeation enhancer is a mixture of potassium gluconate sulfate, d-mannitol and urea; the mass ratio of the potassium gluconate sulfate to the d-mannitol to the urea in the penetration enhancer is 3-5:1-2: 2-4; the dosage of the penetration enhancer is 1-3% of the total mass of the mixture of the metformin hydrochloride and the PVPK 90.
6. The metformin hydrochloride sustained-release tablet according to claim 1, wherein the coating is prepared from the following raw materials: aqueous dispersions of polyvinyl acetate, polyvinylpyrrolidone and sodium dodecyl sulfate, pore-foaming agent and plasticizer; in the water dispersion, the mass concentrations of polyvinyl acetate, polyvinylpyrrolidone and sodium dodecyl sulfate are respectively 15-20%, 3-5% and 0.5-1%.
7. The metformin hydrochloride sustained-release tablet according to claim 6, wherein the pore-forming agent is a mixture of PEG800 and HPMC-E5; the amount of the pore-foaming agent is 10-30% of the total mass of the coating liquid; the dosage ratio of the PEG800 to the HPMC-E5 is 2-5: 1.
8. The metformin hydrochloride sustained-release tablet according to claim 6, wherein the plasticizer is: a mixture of triethyl citrate, triacetin, succinate, propylene glycol; the amount of the plasticizer is 1-3% of the total mass of the coating liquid; the mass ratio of triethyl citrate, glyceryl triacetate, succinate and propylene glycol in the plasticizer is 1:2-3:1-2: 3-5.
9. The process for the preparation of the metformin hydrochloride sustained release tablets according to any one of claims 1 to 8, wherein the process comprises the steps of:
(1) preparation of a tablet core: mixing metformin hydrochloride with PVP K-90, adding penetration enhancer and osmotically active substance, sieving, oven drying, adding sodium dodecyl sulfate, and tabletting to obtain metformin hydrochloride tablet core;
(2) preparing a coating solution: adding sodium dodecyl sulfate, polyvinyl acetate and PVP K-30 into water in sequence to prepare aqueous dispersion, and adding a pore-making agent and a plasticizer into the aqueous dispersion; preparing a coating solution;
(3) and (3) putting the metformin hydrochloride tablet core into a coating solution for coating treatment, and drying after the coating film reaches the thickness to obtain the metformin hydrochloride sustained release tablet.
10. The method for preparing the metformin hydrochloride sustained release tablet according to claim 9, wherein in the step (1), the drying temperature is 50 to 60 ℃; the dosage of the sodium dodecyl sulfate is 1-3% of the total mass of the tablet core; in the step (3), the thickness of the coating film is 200-300 μm; the temperature of the coating treatment is 25-35 ℃; the drying temperature is 50-60 ℃.
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