CN113398097A - Dapagliflozin metformin sustained release preparation and preparation method thereof - Google Patents
Dapagliflozin metformin sustained release preparation and preparation method thereof Download PDFInfo
- Publication number
- CN113398097A CN113398097A CN202110794193.2A CN202110794193A CN113398097A CN 113398097 A CN113398097 A CN 113398097A CN 202110794193 A CN202110794193 A CN 202110794193A CN 113398097 A CN113398097 A CN 113398097A
- Authority
- CN
- China
- Prior art keywords
- release
- sustained
- dapagliflozin
- layer
- preparation
- 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.)
- Pending
Links
Images
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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5089—Processes
-
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5015—Organic compounds, e.g. fats, sugars
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Abstract
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a dapagliflozin metformin sustained-release preparation and a preparation method thereof. The dapagliflozin metformin sustained-release preparation consists of a metformin hydrochloride sustained-release pellet core, an isolating layer, a dapagliflozin quick-release coating layer and a protective layer. The metformin hydrochloride sustained-release pellet core mainly comprises 40-80% of metformin hydrochloride, 1-20% of diluent, 1-20% of adhesive and 10-40% of sustained-release material in percentage by weight. The preparation method of the dapagliflozin metformin sustained release preparation comprises the following steps: firstly, preparing a metformin hydrochloride pellet core by an extrusion rounding process; coating the isolating layer; ③ coating the dapagliflozin quick-release layer; and fourthly, coating a protective layer. The preparation process has the advantages of good stability, simple process and high production efficiency, and is suitable for industrial mass production.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a dapagliflozin metformin sustained-release preparation and a preparation method thereof.
Background
Dapagliflozin Propylene glycol monohydrate (Dapagliflozin Propylene glycol Hydrate), a sodium-glucose cotransporter 2(SGLT2) inhibitor, acts by inhibiting SGLT2, a protein in the kidney that reabsorbs glucose into the blood. This allows excess glucose to be removed from the body via the urine, thereby improving glycemic control without increasing insulin secretion.
Dapagliflozin propylene glycol monohydrate is white to pale yellowish white powder and odorless. It is soluble in methanol, ethanol, and N, N-dimethylacetamide, and slightly soluble in acetonitrile and water. The chemical name of the compound is (1S) -1, 5-anhydro-1-C- { 4-chloro-3- [ (4-ethoxyphenyl) methyl ] phenyl } -D-glucitol mono- (2S) -propane-1, 2-diol monohydrate, and the structural formula is shown as the following formula:
metformin Hydrochloride (Metformin Hydrochloride) reduces fasting and postprandial hyperglycemia in type 2 diabetics, and the mechanism may be: increasing the sensitivity of peripheral tissues to insulin and increasing insulin-mediated glucose utilization. ② increasing the utilization of glucose by non-insulin dependent tissues, such as brain, blood cells, kidney medulla, intestinal tract, skin, etc. And inhibiting liver gluconeogenesis and reducing hepatic glucose output. And fourthly, inhibiting the intestinal wall cells from taking glucose. Fifthly, inhibiting the biosynthesis and storage of cholesterol, and reducing the level of triglyceride and total cholesterol in blood. Unlike insulin, the product has no fat synthesis promoting effect, no obvious blood sugar lowering effect on normal people and no hypoglycemia caused by single application of type 2 diabetes.
The metformin hydrochloride is white crystal or crystalline powder and has no odor. It is soluble in water, soluble in methanol, slightly soluble in ethanol, and insoluble in chloroform or diethyl ether. The chemical name of the compound is 1, 1-dimethylbiguanide hydrochloride, and the structural formula is shown as the following formula:
the invention relates to a composition of dapagliflozin propylene glycol monohydrate and metformin hydrochloride, which can be used as an auxiliary means for improving and controlling the blood sugar of adults with type 2 diabetes besides diet and exercise, but is not used for patients with type 1 diabetes or diabetic ketoacidosis. After single oral administration: the dapagliflozin is absorbed quickly, the peak plasma concentration is achieved within 2 hours, and the clearing half-life period is about 12.9 hours. The metformin hydrochloride is slowly released, the peak concentration of blood plasma is reached within 4-8 hours, the metformin hydrochloride is mainly eliminated by urine in a prototype, and the elimination half-life period is about 17.6 hours.
The dapagliflozin metformin sustained release tablet is firstly developed by an Aslicon pharmaceutical company, and the main dosage form in the market at present is mainly a double-layer tablet coating. The original preparation dapagliflozin layer adopts a dry granulation preparation process, the metformin hydrochloride layer adopts a wet granulation preparation process, and the two layers of materials are pressed into a double-layer tablet and then subjected to a film coating process. The process flow is complicated, the requirements on the flowability and the compressibility of the granules are high, a dry granulator and a double-layer tablet press are required in the large-scale production, the industrial production difficulty is high, and the reproducibility is poor. In contrast, the process flow of directly coating the metformin hydrochloride layer after extrusion and spheronization to prepare the pellets is simpler, the production efficiency is high, the risk is lower, and the method is suitable for industrial mass production.
The pellet is a spherical solid body with the diameter less than 3mm and composed of medicine powder and auxiliary materials, and belongs to a dose dispersion type preparation in clinical effect. The medicine is prepared into pellets, and has more uniform size, smoother surface, smaller batch difference and better stability. After the patient takes the pellets, the medicine can be uniformly dispersed in the gastrointestinal tract, the gastrointestinal transportation and absorption are not influenced by the gastric emptying rate, and the difference between individuals is small; after a patient takes the pellet, the pellet can form the sum of the drug release behaviors of a plurality of small units of one dose, and the preparation defect of each small unit does not influence the drug release behavior of the whole preparation; after a patient takes the pellets, the contact area of the pellets and the mucous membrane of the gastrointestinal tract is increased, so that the bioavailability of the medicine can be improved, and the irritation of certain medicines to the gastrointestinal tract can be reduced and eliminated.
In the preparation process, the pellets are prepared by extrusion and rounding by an extrusion and rounding machine, the pellet weight and size can be accurately controlled, the reproducibility is good, the size and weight of each pellet unit are the same, and the drug content is the same. For the old and children with large individual difference, the pellet process can make the medicine taking more flexible, the dosage scheme can be adjusted according to individual requirements, and the pellets can be counted and taken.
Patent CN102711739A discloses a method for preparing a bilayer tablet, which comprises a first layer of metformin hydrochloride sustained release preparation, a second layer of SGLT2 inhibitory preparation and a film coating, and realizes the effects of long-acting sustained release and zero-order release. The process flow is complicated, the two parts need to be granulated by different processes separately, the requirements on the flowability and the compressibility of the granules are high, a dry granulator and a double-layer tablet machine are required in the large-scale production, the industrial production difficulty is high, and the reproducibility is poor.
The patent CN106924208A discloses a compound dapagliflozin metformin sustained release tablet and a preparation method thereof, wherein metformin hydrochloride is prepared into a sustained release tablet core, then dapagliflozin and an adhesive are prepared into solution or suspension for medicine coating, and finally film coating is carried out. The process flow is complex, the requirement on the tablet core is high due to the adoption of tablet core medicine application, the tablet core is required to have certain strength, the corner abrasion can be caused in the coating process due to the overlarge tablet core, the slow coating is required, the setting requirement on the coating process and parameters is high, and the whole production cost is increased.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a sustained-release preparation containing dapagliflozin and metformin hydrochloride, and a preparation method and application thereof.
The invention is realized by the following technical scheme.
The dapagliflozin metformin sustained-release preparation disclosed by the invention consists of a metformin hydrochloride sustained-release pellet core, an isolating layer, a dapagliflozin quick-release layer and a protective layer. The weight percentage of the metformin hydrochloride in the metformin hydrochloride sustained-release pellet core is 40-80%, the weight percentage of the diluent is 1-20%, the weight percentage of the adhesive is 1-20%, and the weight percentage of the sustained-release material is 10-40%.
The dapagliflozin metformin sustained release preparation is prepared by extruding and rounding a sustained release pellet core by an extruding and rounding machine, wherein the diameter of the sustained release pellet core is 0.8-3.0 mm, and preferably 1.5-2.5 mm.
The dapagliflozin metformin sustained-release preparation can be independently used as a novel preparation type (directly subpackaged by small bags) different from common tablets, the pellet preparation can be filled into capsules to be prepared into oral preparations in a capsule form, and the pellets are preferably independently used as the novel preparation type.
The dapagliflozin metformin sustained release preparation provided by the invention has the advantages that the diluent is selected from one or the combination of at least two of lactose, mannitol, microcrystalline cellulose and pregelatinized starch, and the dosage is 1-20% (w/w).
The adhesive is selected from any one of hydroxypropyl methylcellulose, sodium carboxymethylcellulose, povidone or hydroxypropyl cellulose, preferably hydroxypropyl cellulose, and the using amount of the adhesive is 1-20% (w/w).
The dapagliflozin metformin sustained release preparation provided by the invention is characterized in that the sustained release material is selected from any one or the combination of at least two of hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, polyethylene oxide, sodium alginate and carbomer, and the dosage is 10-40% (w/w).
The coating materials of the isolating layer, the dapagliflozin quick-release layer and the protective layer are gastric-soluble coating materials, and preferably premixed opadry series gastric-soluble coating powder or easy-release beauty series gastric-soluble coating powder.
The weight of the isolating layer is 3-15% (w/w) of the weight of the pellet core, and the isolating coating material is selected from Opadry.
According to the dapagliflozin metformin sustained release preparation, the weight of the rapid release layer of the dapagliflozin is 1-10% (w/w) of the pill core, and the rapid release coating film material is selected from Opadry.
The dapagliflozin metformin sustained release preparation provided by the invention has the advantages that the dapagliflozin in the rapid release layer is 0.1-2% (w/w).
The stabilizing agent in the dapagliflozin quick-release layer comprises any one or combination of at least two of arginine, glycine or aspartic acid, and the using amount is 0-20% (w/w).
According to the dapagliflozin metformin sustained release preparation, the weight of the protective layer is 1-10% (w/w) of the pill core, and the quick release coating material is selected from Opadry.
The dapagliflozin metformin sustained release preparation provided by the invention comprises the following steps: firstly, preparing a metformin hydrochloride pellet core by an extrusion rounding process; coating the isolating layer; ③ coating the dapagliflozin quick-release layer; and fourthly, coating a protective layer.
The dapagliflozin metformin sustained release preparation provided by the invention has the following characteristics:
(1) the production process of the pellet is simple, the reproducibility is good, and the pellet prepared by adopting the extrusion and spheronization process has uniform size and complete and smooth surface.
(2) The content uniformity of the pellets is higher, the pellets are uniformly dispersed in the gastrointestinal tract after being taken by a patient, the irritation to the gastrointestinal tract is reduced, and the gastrointestinal transport and absorption of the medicine are not influenced by the emptying rate of the gastrointestinal tract, so that the individual difference is small.
(3) When the pellet is used, for the medicine with the dosage needing to be adjusted, an individual administration scheme can be set according to the needs of a patient, the pellets are counted and taken, and the dosage is more accurate.
(4) The pellet also overcomes the problem of poor compliance of medication, and can be directly taken without water for children and the elderly who have difficulty in taking medicine, or taken together with bread by adding jam.
The dapagliflozin metformin sustained release preparation has the characteristic of slow release, can be sustained for releasing medicine within 24 hours, thereby maintaining relatively stable blood concentration and longer action time, reducing the medicine taking times, improving the compliance of patients, and simultaneously has good stability of preparation process, simple process and high production efficiency, thereby being suitable for industrialized mass production.
Drawings
FIG. 1 is a drawing of a sustained release formulation of different types of fillers and filler compositions of the present invention with a commercially available dapagliflozin metformin sustained release tablet (trade name: Xigduo)
) The release curves of (c) are compared.
FIG. 2 is a graph of various types of binders and amounts of sustained release formulations of the present invention with commercially available dapagliflozin metformin sustained release tablets (trade name: Xigduo)
) The release curves of (c) are compared.
FIG. 3 shows the sustained release formulation of different types of sustained release materials of the present invention with a commercially available dapagliflozin metformin sustained release tablet (trade name: Xigduo)
) The release curves of (c) are compared.
FIG. 4 shows the sustained release formulations of hypromellose of different amounts of the present invention with the commercially available dapagliflozin metformin sustained release tablet (trade name: Xigduo)
) The release curves of (c) are compared.
Detailed Description
The present invention will be described in further detail with reference to specific embodiments. It should be emphasized that: the following description is merely exemplary in nature and is in no way intended to limit the scope of the invention or its application.
Example 1
The preparation process comprises the following steps:
a. metformin hydrochloride sustained-release pellets: uniformly mixing metformin hydrochloride, microcrystalline cellulose 101, hydroxypropyl methylcellulose E5LV and hydroxypropyl methylcellulose K100M, and uniformly spraying water serving as a wetting agent into the mixed powder to prepare a soft material with moderate humidity. Extruding the soft material into strips through a sieve plate of an extruder, adjusting proper rounding speed and rounding time, putting the extruded material into a rounding barrel, taking out the extruded material after the extruded material has certain hardness and roundness, and drying the extruded material in an oven at 50 ℃ for 4 hours;
b. isolation layer: dispersing the Opadry coating powder in purified water, uniformly mixing to obtain a coating solution, and coating the metformin sustained-release pellet core, wherein the weight gain is 10% of the weight of the sustained-release pellet core;
c. a dapagliflozin medicine application layer: dispersing dapagliflozin, opadry coating powder and arginine in purified water, uniformly mixing to obtain a coating solution, and coating the sustained-release pill core coated with the isolation layer with the medicine;
d. protective layer: dispersing the Opadry coating powder in purified water, uniformly mixing to obtain a coating solution, and coating the sustained-release pellet core, wherein the weight gain is 5% of the weight of the sustained-release pellet core.
Example 2
The filling agent adopts lactose G200, and the other prescription compositions and preparation processes are the same as example 1.
Example 3
The filler adopts microcrystalline cellulose and pregelatinized starch, and the other prescription components and preparation process are the same as those in example 1.
Example 4
The adhesive adopts povidone K30, and the other prescription components and the preparation process are the same as those of the example 1.
Example 5
The adhesive adopts hydroxypropyl cellulose, and the other formula components and the preparation process are the same as the example 1.
Example 6
The adhesive adopts hydroxypropyl methylcellulose, the dosage is adjusted to 50 mg/tablet, and the other prescription components and the preparation process are the same as the embodiment 1.
Example 7
The slow release material adopts polyethylene oxide 303, and the other prescription components and the preparation process are the same as those of the example 1.
Example 8
The slow release material adopts sodium alginate, and the other prescription components and the preparation process are the same as the example 1.
Example 9
The slow release material adopts carbomer, and the other prescription components and the preparation process are the same as the example 1.
Example 10
The sustained-release material adopts hydroxypropyl methylcellulose, the dosage is adjusted to 120 mg/tablet, and the other prescription components and the preparation process are the same as the embodiment 1.
Example 11
The sustained-release material adopts hydroxypropyl methylcellulose, the dosage is adjusted to 180 mg/tablet, and the other prescription components and the preparation process are the same as the embodiment 1.
Example 12
Extruding and rounding the soft material with different screens (0.5mm, 1.0mm, 1.5mm, 2.0mm and 2.5mm) to obtain pellet, and making into other prescription components and preparation process the same as example 1.
Test example 1: comparison of examples 1 to 3
The results show (table 1) that the metformin hydrochloride pellet cores respectively used different types and combinations of fillers had no significant effect on the properties of the granules, and the release profiles in the phosphate buffer at ph6.8 were not significantly different.
Table 1 release profile of sustained release formulations of different types of bulking agents and bulking agent compositions in phosphate buffer ph6.8 (n ═ 6)
Test example 2: comparison of examples 1, 4, 5 and 6
The results show (table 2) that the cores of metformin hydrochloride pellet pellets of examples 1, 4 and 5 respectively adopt different types of materials as binders, which have no significant influence on the moldability of the pellets and no significant difference in the release curves in the phosphate buffer at ph 6.8; the cores of the metformin hydrochloride pellet pills in the examples 1 and 6 adopt the same adhesive, but the formulation dosage proportion has no remarkable influence on the formability of the granules, and the release curve in phosphate buffer solution with pH6.8 has a slightly slow trend.
Table 2 release profile of different types of binders and amounts of sustained release formulations in ph6.8 phosphate buffer (n ═ 6)
Test example 3: comparison of examples 1, 7, 8 and 9
The results show (table 3) that the cores of the metformin hydrochloride pellet pills of examples 1, 7, 8 and 9 respectively adopt different types of sustained-release materials, the release curves in phosphate buffer solution with pH6.8 are obviously different, the release curve adopting polyethylene oxide as the sustained-release material is the slowest, the release curve adopting carbomer as the sustained-release material is the fastest, and the other different types of sustained-release materials are not obviously different.
Table 3 release profiles of sustained release formulations of different types of sustained release materials in ph6.8 phosphate buffer (n ═ 6)
Test example 4: comparison of examples 1, 9 and 10
The results show (table 4) that the release profiles in phosphate buffer at ph6.8 with different stabilizers used in the drug-loaded layers of the metformin hydrochloride sustained release pellet cores of examples 1, 9 and 10 were not significantly different.
Table 4 release profiles of sustained release formulations of hypromellose at different dosages in phosphate buffer ph6.8 (n ═ 6)
Test example 5: the results of the powder properties of the metformin hydrochloride pellet core and the content uniformity of the pellets are compared after extrusion and rounding by different screen meshes
The results show that the mesh number of the screen is controlled between 0.5mm and 2.5mm, particles with good fluidity can be obtained, the content uniformity of the pellets meets the requirement, and the screen with the aperture of 1.5mm to 2.5mm is preferably used for extrusion and spheronization.
TABLE 5 comparison of the powder properties of metformin hydrochloride pellets after extrusion rounding with different mesh sizes
| Mesh aperture | Bulk density/g/ml | Tap density/g/ml | Karl index | Angle of repose/° | D90Micron/micron |
| 0.5mm | 0.612 | 0.710 | 0.14 | 35.6 | 78 |
| 1.0mm | 0.609 | 0.703 | 0.13 | 35.8 | 161 |
| 1.5mm | 0.588 | 0.696 | 0.16 | 36.5 | 203 |
| 2.0mm | 0.562 | 0.688 | 0.18 | 36.6 | 310 |
| 2.5mm | 0.551 | 0.677 | 0.19 | 36.9 | 356 |
TABLE 6 comparison of pellet content uniformity after extrusion and spheronization through different mesh sizes
Finally, the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting, although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all the technical solutions of the present invention should be covered in the claims of the present invention.
Claims (10)
1. A sustained-release preparation containing dapagliflozin and metformin hydrochloride is characterized by sequentially consisting of a metformin hydrochloride sustained-release pellet core, an isolating layer, a dapagliflozin quick-release layer and a protective layer from inside to outside.
2. The sustained-release preparation of claim 1, wherein the metformin hydrochloride sustained-release pellet core comprises the following components in percentage by weight: 40-80% of metformin hydrochloride, 1-20% of diluent, 1-20% of adhesive and 10-40% of slow-release material.
3. The sustained-release preparation according to claim 2, wherein the metformin hydrochloride sustained-release pellet core is formed by extrusion and spheronization by an extrusion spheronizer, and the diameter of the sustained-release pellet core is 0.8-3.0 mm, preferably 1.5-2.5 mm.
4. The sustained-release preparation according to claim 2, wherein the diluent is selected from one or a combination of at least two of lactose, mannitol, microcrystalline cellulose and pregelatinized starch, and the amount of the diluent is 1-20%.
The adhesive is selected from any one of hydroxypropyl methylcellulose, sodium carboxymethylcellulose, povidone or hydroxypropyl cellulose; preferably, the hydroxypropyl cellulose is used in an amount of 1-20%.
The slow release material is selected from any one or a combination of at least two of hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, polyethylene oxide, sodium alginate and carbomer, and the using amount of the slow release material is 10-40%.
5. The sustained-release preparation according to claim 1, wherein the coating material of the isolation layer is a gastric-soluble coating material, the weight of the coating material is 3-15% of the weight of the pellet core, and the gastric-soluble coating powder or the enteric-soluble coating powder is preferably premixed type Opadry series; more preferably, the Opadry series gastric soluble coating powder.
6. The sustained-release preparation according to claim 1, wherein the weight of the dapagliflozin quick-release layer is increased by 1-10% of the weight of the pellet core, and the coating material is a gastric-soluble coating material, preferably a premixed type stomach-soluble coating powder of the Opadry series or a stomach-soluble coating powder of the easy-release series; more preferably, the Opadry series gastric soluble coating powder.
7. The sustained-release preparation according to claim 1, wherein the content of dapagliflozin in the rapid-release layer of dapagliflozin is 0.1-2%.
8. The sustained-release preparation of claim 1, wherein the stabilizer in the immediate-release dapagliflozin layer comprises one or a combination of at least two of arginine, glycine and aspartic acid, and the dosage of the stabilizer is 0-20%.
9. The sustained-release preparation according to claim 1, wherein the weight of the protective layer is 1-10% of the weight of the pellet core, and the coating material is a gastric-soluble coating material, preferably a premixed stomach-soluble coating powder of the Opadry series or a stomach-soluble coating powder of the easy-release series; more preferably, the Opadry series gastric soluble coating powder.
10. A method of preparing a sustained release formulation as claimed in any one of claims 1 to 9, comprising the steps of: firstly, preparing a metformin hydrochloride pellet core by an extrusion rounding process; coating the isolating layer; ③ coating the dapagliflozin quick-release layer; and fourthly, coating a protective layer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110794193.2A CN113398097A (en) | 2021-07-14 | 2021-07-14 | Dapagliflozin metformin sustained release preparation and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110794193.2A CN113398097A (en) | 2021-07-14 | 2021-07-14 | Dapagliflozin metformin sustained release preparation and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113398097A true CN113398097A (en) | 2021-09-17 |
Family
ID=77686326
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110794193.2A Pending CN113398097A (en) | 2021-07-14 | 2021-07-14 | Dapagliflozin metformin sustained release preparation and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113398097A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116370430A (en) * | 2023-05-11 | 2023-07-04 | 泊诺(天津)创新医药研究有限公司 | Dapagliflozin and metformin sustained release tablet and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1726912A (en) * | 2005-07-25 | 2006-02-01 | 天津药物研究院 | Slow release capsule of compound metformin pyrrolidone and preparation method |
| CN103417496A (en) * | 2013-08-26 | 2013-12-04 | 中国人民解放军第150中心医院 | Method for preparing metformin hydrochloride controlled-release pellet preparation |
| CN106924208A (en) * | 2015-12-30 | 2017-07-07 | 深圳翰宇药业股份有限公司 | A kind of compound Dapagliflozin Metformin Extended-release Tablets and preparation method thereof |
-
2021
- 2021-07-14 CN CN202110794193.2A patent/CN113398097A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1726912A (en) * | 2005-07-25 | 2006-02-01 | 天津药物研究院 | Slow release capsule of compound metformin pyrrolidone and preparation method |
| CN103417496A (en) * | 2013-08-26 | 2013-12-04 | 中国人民解放军第150中心医院 | Method for preparing metformin hydrochloride controlled-release pellet preparation |
| CN106924208A (en) * | 2015-12-30 | 2017-07-07 | 深圳翰宇药业股份有限公司 | A kind of compound Dapagliflozin Metformin Extended-release Tablets and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116370430A (en) * | 2023-05-11 | 2023-07-04 | 泊诺(天津)创新医药研究有限公司 | Dapagliflozin and metformin sustained release tablet and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102258492B (en) | Neostigmine bromide slow release preparation and its preparation method | |
| CN101002737A (en) | Slow release preparation of Kui-Liu-Ping | |
| EP4082534A1 (en) | Solid preparation, and preparation method therefor and use thereof | |
| CN113616624B (en) | Empagliflozin metformin sustained release preparation and preparation method thereof | |
| CN112137990A (en) | Epalrestat sustained-release preparation and preparation method thereof | |
| CN113398097A (en) | Dapagliflozin metformin sustained release preparation and preparation method thereof | |
| CN103251594B (en) | Repaglinide/metformin combo tablet | |
| CN101990427A (en) | Combination of mitiglinide and metformin and process for preparing same | |
| EP4082532A1 (en) | Complex formulation comprising sitagliptin and dapagliflozin, and preparation method therefor | |
| GR1009644B (en) | Pharmaceutical composition comprising vildagliptin and metformin and method of preparation thereof | |
| CN101002744A (en) | Slow release preparation of cefalexin | |
| CN101002747A (en) | Slow release preparation of cefaclor | |
| CN101011364A (en) | Slow release preparation of metformin rosiglitazone | |
| CN112057429B (en) | Lei Xina Deg controlled release pharmaceutical composition | |
| CN114306267A (en) | Sitagliptin and metformin tablet preparation and preparation method thereof | |
| CN101015530A (en) | Sustained release preparation of doxepin | |
| EP4162929A1 (en) | Composite formulation comprising sitagliptin and dapagliflozin and preparation method therefor | |
| CN112315942B (en) | Trimetazidine hydrochloride sustained release preparation and preparation method thereof | |
| CN114903863B (en) | Sitagliptin and metformin hydrochloride sustained-release tablet and preparation method thereof | |
| CN101002746A (en) | Slow release preparation of cefuroxime axetil | |
| CN116440103A (en) | Saxagliptin metformin sustained release preparation and preparation method thereof | |
| CN101011368A (en) | Slow release tablet of troxerutin | |
| CN101002739A (en) | Slow release preparation of ranitidine | |
| CN101002740A (en) | Slow release preparation of compactin | |
| CN101015534A (en) | Sustained release preparation of phenprobamate |
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 |