CN113616624A - Empagliflozin metformin sustained release preparation and preparation method thereof - Google Patents
Empagliflozin metformin sustained release preparation and preparation method thereof Download PDFInfo
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- 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
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- 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
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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
- A61K9/48—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
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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 medicinal preparations, and particularly relates to an engeletin metformin sustained-release preparation and a preparation method thereof, wherein an engeletin pellet core is a quick-release part, a metformin hydrochloride pellet core is a sustained-release part, two parts of pellet cores are respectively subjected to isolated layer coating, and then two parts of drug-loaded pellets are mixed and filled into a capsule. The invention also discloses a preparation method of the empagliflozin metformin sustained release preparation, which comprises the following steps: firstly, preparing a metformin hydrochloride sustained-release pill core by an extrusion rounding process; secondly, preparing an Engelliflozin quick-release pill core by an extrusion rounding process; thirdly, coating the two drug-loaded pill cores with an isolating layer respectively; and fourthly, filling the two drug-loaded pellets into capsules according to a certain proportion. 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 an empagliflozin metformin sustained-release preparation and a preparation method thereof.
Background
Empagliflozin (Empagliflozin), a sodium glucose co-transporter 2(SGLT-2) inhibitor, reabsorbs glucose in glomerular filtrate into the main transporter in blood circulation, lowers the renal glucose threshold by reducing glucose reabsorption in the kidney, and promotes glucose excretion from the urine. Engagliflozin is a white to pale yellow non-hygroscopic powder. Very slightly soluble in water, slightly soluble in methanol, ethanol and acetonitrile, soluble in 50% acetonitrile/water, and practically insoluble in toluene. The chemical name of the compound is (1S) -1, 5-anhydro-1- (4-chloro-3- {4- [ (3S) -tetrahydrofuran-3-oxy ] benzyl } phenyl ] -D-glucitol, and the structural formula is shown as follows:
the metformin hydrochloride is used for patients with type II diabetes mellitus with unsatisfactory simple diet control, especially for obesity and people with hyperinsulinemia, and has the effects of reducing blood sugar and possibly reducing weight and hyperinsulinemia. Can be used for treating patients with poor curative effect of some sulfonylureas, such as sulfonylureas, small intestine glycosidase inhibitor or thiazolidinedione hypoglycemic agent, which has better effect than single use. Can also be used for patients with insulin therapy to reduce insulin dosage. 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 follows:
the compound single tablet consisting of the empagliflozin and the metformin hydrochloride has two unique sugar-reducing mechanisms. The engeletin belongs to a novel sodium-glucose cotransporter-2 (SGLT-2) inhibitor hypoglycemic agent, can block the reabsorption of glucose in the kidney, excretes excessive glucose in vitro and achieves the hypoglycemic effect, and the hypoglycemic effect is independent of beta cell function and insulin resistance. Metformin hydrochloride is a common initial therapeutic agent for type 2 diabetes, reduces hepatic glucose production, decreases glucose absorption in the small intestine, and increases insulin sensitivity by increasing glucose uptake and utilization in peripheral tissues. Can be used as auxiliary means for diet and exercise, can improve blood sugar control of adult type 2 diabetes patients, and is suitable for patients with the combination of empagliflozin and metformin. The compound preparation has the indications of being combined with diet and exercise, is used for improving the blood sugar control of the type 2 diabetes adult patients, and is suitable for the following people: (1) type 2 diabetic patients who have failed to adequately control blood glucose levels with either empagliflozin or metformin regimens; (2) a type 2 diabetic patient undergoing a combination treatment of empagliflozin and metformin.
The empagliflozin metformin sustained release tablet is cooperatively developed by Boringer Yiger-Li, and the main dosage form in the market at present is mainly coated by a single-layer tablet. The metformin hydrochloride layer in the original preparation adopts a wet granulation process, the Empagliflol clear layer adopts a medicine coating preparation process, the process flow is complicated, the requirement on the compressibility of the tablet core of the biguanide layer is high, the risk of the subsequent medicine coating process is high, the industrial production is difficult, and the loss of raw materials in the coating process can cause the increase of the production cost. In contrast, the metformin hydrochloride layer and the engelist layer are respectively extruded and rounded to prepare the pellets, and then the pellets are coated by the isolating layer.
In 1964, Nakahara originally invented the extrusion spheronization pelleting technology, and Reynolds and Conine, etc. introduced this method first and applied it in pharmacy field. Currently, the extrusion spheronization method is one of the most widely used techniques in pellet preparation. The extrusion spheronization method comprises the basic steps of adding the adhesive into the medicine and auxiliary material powder, uniformly mixing, extruding into a strip column shape through an extruder, cutting and rolling into spheres with uniform sizes in a spheronization machine, and finally drying. The process can be summarized as mixing, soft mass making, extrusion, spheronization and drying steps.
The pellet (pellet) is a spherical or spheroidal solid dosage form having a diameter generally in the range of 0.25 to 2.5mm, and may also be encapsulated, compressed into tablets, or made into other formulations. Pellets are a multi-unit oral dosage form, usually consisting of tens to hundreds of pellets for a single administration. The micro-pills can be divided into quick-release micro-pills, slow-release micro-pills and controlled-release micro-pills according to different drug release rates. The quick release pellet can be quickly disintegrated and dissolved in vivo, the drug release speed is high, and generally the drug release speed is not less than 70% within 3 min. The sustained-release pellets and the controlled-release pellets can ensure that the medicine is slowly released according to a certain rule, the peak valley phenomenon of the blood concentration is reduced, and the cumulative medicine release percentage is higher than 90 percent within the interval time (12 hours or 24 hours) of taking. In recent years, the pellets are increasingly paid more attention by people and become a great trend of the development of sustained and controlled release preparations, and a plurality of companies at home and abroad are in the shape of the preparation.
The common method for preparing the pellets is an extrusion spheronization method, and compared with pellets prepared by other technologies, the pellets prepared by the method have unique advantages in the aspects of physicochemical and mechanical properties, drug release behavior, in-vivo process, formulation of a preparation, process control and the like of finished pellets: the pellet has better roundness and fluidity; secondly, the shape and the size are uniform, and the particle size distribution is more concentrated; thirdly, the micro-pill has high hardness, high density and small friability; fourthly, the yield is high, the production efficiency is high, the labor intensity is low, and the process reproducibility is good; and fifthly, the technological process is parameterized, easy to control and convenient for scientific management.
Patent CN106924237A discloses a pharmaceutical composition containing englipin and metformin hydrochloride, the method for preparing the composition is: mixing metformin hydrochloride, engeletin and microcrystalline cellulose, placing the mixture into a fluidized bed granulator, spraying a binding agent into the mixture to prepare granules, adding a flow aid and a lubricant, mixing and tabletting. The process is relatively simple, but because the metformin hydrochloride and the engagliflozin are mixed and then granulated, the problem of stability of the medicine in the standing process can occur, and because the fluidized bed granulation is adopted, the dosage of the engagliflozin is low, the content uniformity is not in accordance with the specification, and the amplification operability and the repeatability are poor.
Patent CN107432869A discloses a bilayer tablet containing metformin hydrochloride and engletin and a preparation method thereof, wherein metformin hydrochloride is prepared into slow release granules, engletin is prepared into quick release granules, a bilayer tablet press is adopted for tabletting, and finally film coating is carried out. The process flow is complex, and the requirements on the flowability and the compressibility of the granules are relatively high due to the fact that a double-layer tablet press is required for tabletting. The tablet core is a double-layer tablet, so that the joint of the double-layer tablet is cracked in the coating process, slow coating is needed, the setting requirements on the coating process and parameters are 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 empagliflozin hydrochloride and metformin hydrochloride, and a preparation method and application thereof.
The invention is realized by the following technical scheme.
The Engelliflozin slow release preparation of the invention is characterized in that the pill core of the Engelliflozin pellet is a quick release part, the pill core of the metformin hydrochloride pellet is a slow release part, the pill cores of the two parts are respectively coated by an isolation layer, and then the two parts of drug-loaded pellets are mixed and filled into a capsule.
The weight percentage of the empagliflozin in the core of the quick-release empagliflozin pellet is 1-20%, the weight percentage of the diluent is 30-90%, and the weight percentage of the adhesive is 1-30%.
The weight percentage of the metformin hydrochloride in the metformin hydrochloride sustained-release pellet core is 30-60%, the weight percentage of the diluent is 1-30%, the weight percentage of the adhesive is 1-30%, and the weight percentage of the sustained-release material is 10-50%.
The sustained-release pellet core and the quick-release pellet core of the empagliflozin metformin sustained-release preparation are both formed by extruding and rounding by an extruding and rounding machine, and the diameter of the pellet core is 0.5-3.0 mm, preferably 1.5-2.5 mm.
According to the Engelliflozin metformin sustained-release preparation, a sustained-release pellet core and a quick-release pellet core are mixed according to a certain proportion and filled into a capsule, and the ratio of metformin hydrochloride to Engelliflozin in two drug-containing pellets is 50-200.
The sustained-release formulation of the empagliflozin and the metformin is characterized in that the diluent is selected from any one or the combination of at least two of microcrystalline cellulose, lactose, mannitol or pregelatinized starch; the dosage proportion of the diluent in the engelizin quick-release pill core is 30-90%, and the dosage proportion in the metformin sustained-release pill core is 1-30%.
The sustained release preparation of the empagliflozin and metformin disclosed by the invention is characterized in that the adhesive is selected from any one of povidone, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose or hydroxypropyl cellulose, and preferably the sodium carboxymethyl cellulose; the dosage proportion of the adhesive in the engeletzin quick-release pill core is 1-30%, and the dosage proportion of the adhesive in the metformin sustained-release pill core is 1-30%.
The sustained-release material is selected from any one or the combination of at least two of polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium alginate, ethyl cellulose or carbomer, and the dosage proportion of the sustained-release agent in the metformin sustained-release pill core is 10-50%.
The Engelliflozin metformin sustained release preparation is characterized in that the coating material of the isolation layer is a gastric-soluble coating material, preferably premixed 'Opadry' series gastric-soluble coating powder or 'easy-release' series gastric-soluble coating powder.
The weight of the isolating layer is 3-15% of the weight of the pill core, and the isolating coating material is selected from Opadry.
The invention discloses an empagliflozin metformin sustained release preparation, which comprises the following steps: firstly, preparing a metformin hydrochloride sustained-release pill core by an extrusion rounding process; secondly, preparing an Engelliflozin quick-release pill core by an extrusion rounding process; thirdly, coating the two drug-loaded pill cores with an isolating layer respectively; and fourthly, filling the two drug-loaded pellets into capsules according to a certain proportion. The sustained-release preparation of the empagliflozin metformin provided by the invention has the following characteristics:
(1) the appearance is beautiful and the fluidity is good. The pellets do not need glidants when being filled into capsules, have small weight difference compared with the powder filled capsules, and are usually used for preparing compound preparations.
(2) Can be used for preparing sustained and controlled release preparations, mixing a plurality of pellets with different drug release rates, obtaining different drug release rates, and having easy preparation, reliable quality and good batch-to-batch reproducibility.
(3) The medicine carrying range is wide.
(4) Improve the stability of the medicine, avoid incompatibility among various medicines and slow down the degradation speed of the medicine.
(5) The micro-pill is less influenced by gastric emptying factors after being taken orally, and the medicine absorption speed is uniform.
(6) Is beneficial to the absorption of the medicine and has high bioavailability.
(7) Reduce the irritation of the medicine to the digestive tract, cover the uncomfortable taste of some medicines, and the like. The contact area of the micro-pill with body fluid after reaching the body is larger than that of tablets and other preparations, the micro-pill is widely distributed in the gastrointestinal tract, and adverse reaction and local irritation caused by overlarge local drug concentration can be avoided.
The Engelliflozin metformin sustained release preparation has the characteristic of slow release, can be sustained to release medicine within 24 hours, thereby maintaining relatively stable blood concentration and longer action time, reducing the medicine taking times, improving the compliance of patients, having good stability of preparation process, simple process and high production efficiency, and being suitable for industrialized mass production.
Drawings
FIG. 1 is an empagliflozin and commercially available empagliflozin metformin sustained release tablet of different types of fillers and filler compositions of the invention (trade name: Synjardy:)
) Comparative dissolution curves of (a).
FIG. 2 shows different types of binders and amounts of Empagliflozin and commercially available Empagliflozin metformin sustained release tablets (trade name: Synjardy) according to the invention
) Comparative dissolution curves of (a).
FIG. 3 shows different types of binders and amounts of metformin in accordance with the present invention in combination with commercially available Empagliflozin metformin sustained release tablets (trade name: Synjardy)
) The release curves of (c) are compared.
FIG. 4 shows different types of sustained release materials and amounts of metformin and commercially available Empagliflozin metformin sustained release tablets (trade name: Synjardy) according to the present invention
) 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, sodium carboxymethylcellulose 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. engelizin quick-release pellet: the microcrystalline cellulose and the lactose are uniformly mixed, and the adhesive containing the empagliflozin (sodium carboxymethylcellulose aqueous solution is prepared as the adhesive, and the empagliflozin is uniformly dispersed in the adhesive solution) is uniformly sprayed 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;
c. isolation layer: dispersing the Opadry coating powder in purified water, uniformly mixing to obtain coating liquid, and respectively coating the metformin sustained-release pellet core and the Engelliflozin quick-release pellet core to increase the weight by 10% of the weight of the sustained-release pellet core;
d. filling the metformin sustained-release pill core and the engelizin quick-release pill core into capsules according to the dosage of the prescription respectively.
Example 2
The filler of the Engelliflozin fast-release pill core adopts microcrystalline cellulose and pregelatinized starch, and the other prescription compositions and the preparation process are the same as those of the example 1.
Example 3
The filler of the Engelliflozin fast-release pill core adopts microcrystalline cellulose, and the other prescription compositions and the preparation process are the same as the example 1.
Example 4
The adhesive of the Engelliflozin fast-release pill core adopts povidone K30, and the other prescription compositions and the preparation process are the same as the example 1.
Example 5
The adhesive of the Engelliflozin fast-release pill core adopts sodium carboxymethyl cellulose, the dosage is adjusted to 20 mg/tablet, and the other prescription components and the preparation process are the same as the example 1.
Example 6
The adhesive of the metformin sustained-release pellet core adopts hydroxypropyl methylcellulose, and the other prescription compositions and the preparation process are the same as the embodiment 1.
Example 7
The adhesive of the metformin sustained-release pellet core adopts povidone K30, and the other prescription components and the preparation process are the same as those in the example 1.
Example 8
The adhesive of the metformin sustained-release pill core adopts sodium carboxymethylcellulose, the dosage is adjusted to 50 mg/tablet, and the other prescription components and the preparation process are the same as those in the embodiment 1.
Example 9
The slow release material of the metformin slow release pellet core adopts carbomer, and the other formula components and the preparation process are the same as the example 1.
Example 10
The slow release material of the metformin slow release pellet core adopts ethyl cellulose, and the other prescription compositions and the preparation process are the same as the embodiment 1.
Example 11
The slow release material of the metformin slow release pellet core adopts polyethylene oxide, and the other formula components and the preparation process are the same as the example 1.
Example 12
The sustained-release material of the metformin sustained-release pellet core adopts hypromellose, the dosage is adjusted to 200 mg/tablet, and the other prescription components and the preparation process are the same as those in the embodiment 1.
Example 13
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.
Comparative example 1
The preparation process comprises the following steps:
a. metformin hydrochloride sustained-release layer: adding metformin hydrochloride, microcrystalline cellulose, sodium carboxymethylcellulose and hydroxypropyl methylcellulose into a wet granulation pot, starting a stirring knife and a cutting knife, and mixing for 5 min; starting a spray gun, spraying the aqueous solution into the mixed powder, finishing spraying within 3min, adjusting the rotating speed of a stirring knife and a cutting knife, and granulating for 3 min; wet granulating the granulated wet granules by using a 20-mesh sieve of a swing granulator, and drying the granules in a fluidized bed until the moisture content is less than 3%; drying and granulating the dried granules by using a 20-mesh sieve of a swing granulator; converting the consumption of magnesium stearate according to the yield, and mixing for 5 min;
b. the quick-release layer of the empagliflozin: adding engletin, microcrystalline cellulose, lactose and sodium carboxymethylcellulose into a wet granulation pot, starting a stirring knife and a cutting knife, and mixing for 5 min; starting a spray gun, spraying the aqueous solution into the mixed powder, finishing spraying within 3min, adjusting the rotating speed of a stirring knife and a cutting knife, and granulating for 3 min; wet granulating the granulated wet granules by using a 20-mesh sieve of a swing granulator, and drying the granules in a fluidized bed until the moisture content is less than 3%; drying and granulating the dried granules by using a 20-mesh sieve of a swing granulator; converting the consumption of magnesium stearate according to the yield, and mixing for 5 min;
c. double-layer tablets: pressing the double-layer tablet according to the prescription dosage, and controlling the hardness to be 6-10 kg;
d. isolation layer: dispersing the Opadry coating powder in purified water, uniformly mixing to obtain a coating solution, and coating the metformin empagliflozin sustained-release tablet, wherein the weight gain is 3% of the weight of the sustained-release tablet core.
Test example 1: comparison of examples 1 to 3
The results show (table 1) that the use of different types and combinations of fillers in the engelet pellet cores, respectively, had no significant effect on the pellet properties and no significant difference in the release profiles in phosphate buffer at ph 6.8.
Table 1 dissolution profiles of engelizin for different types of bulking agents and bulking agent compositions in phosphate buffer ph6.8 (n ═ 6)
Test example 2: comparison of examples 1, 4 and 5
The results show (table 2) that the use of different types and amounts of binder in the core of the engelizin pellet, respectively, had no significant effect on the pellet properties, with a tendency to slow down the dissolution profile in phosphate buffer at ph6.8 with increasing binder amount.
Table 2 dissolution profiles of different types of binders and amounts of engelizin in phosphate buffer ph6.8 (n ═ 6)
Test example 3: comparison of examples 1, 6, 7 and 8
The results show (table 3) that the cores of metformin hydrochloride pellet pellets of examples 1, 6 and 7 respectively using different types of materials as binders have no significant influence on the moldability of the pellets, and the release profiles in phosphate buffer at ph6.8 have no significant difference; the cores of the metformin hydrochloride pellet pills in examples 1 and 8 adopt the same binding agent, but the formulation dosage ratio is different, so that the moldability of the granules is not obviously influenced, and the release curve tends to be slowed down in a phosphate buffer solution with pH 6.8.
Table 3 release profile of different types of binders and amounts of metformin in ph6.8 phosphate buffer (n ═ 6)
Test example 4: comparison of examples 1, 9, 10, 11 and 12
The results show (table 4), that the metformin hydrochloride pellet cores in examples 1, 9, 10 and 11 respectively adopt different types of sustained-release materials, the release curves in phosphate buffer solution with pH6.8 are significantly 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 significantly different; the cores of the metformin hydrochloride pellet pills in examples 1 and 12 adopt the same sustained-release material, but the moldability of the granules is not obviously influenced by different dosage proportions of the prescription, and the release curve tends to slow down in phosphate buffer solution with pH value of 6.8.
Table 4 release profile of metformin in ph6.8 phosphate buffer (n ═ 6) for different types and amounts of sustained release material
Test example 5: comparison of comparative example 1 and example 1
The results show (table 5), the sustained release tablet prepared in comparative example 1 has complex process in the preparation process, needs more equipment, and has higher requirements on the flowability and compressibility of the granules due to the need of double-layer tabletting; example 5 the sustained release pellet prepared has a simple process and excellent detection indexes in the preparation process. The comparative example 1 and the example 5 adopt different preparation processes, and the results show that the release curve of the sustained-release preparation prepared in the example 5 in the phosphate buffer solution with the pH value of 6.8 can effectively control the sustained and slow release of the drug within 24h to achieve the sustained-release effect.
Table 5 release profile of metformin in ph6.8 phosphate buffer (n ═ 6) versus sustained release formulations of different preparation processes
Test example 6: 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 6 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 | 0.653 | 0.728 | 0.15 | 36.7 | 68 |
| 1.0mm | 0.623 | 0.711 | 0.15 | 37.8 | 150 |
| 1.5mm | 0.590 | 0.678 | 0.17 | 35.9 | 187 |
| 2.0mm | 0.573 | 0.662 | 0.18 | 36.3 | 289 |
| 2.5mm | 0.549 | 0.654 | 0.18 | 37.0 | 343 |
Test example 7: accelerated test of product stability
The reference formulation and experimental example 1 were subjected to a stability acceleration test at 40 c and 75% relative humidity after double aluminum packaging (4 pellets/plate), and the color of the product, the total impurity content of engeletin and metformin hydrochloride after 0 month, 1 month, 3 months and 6 months were examined, and the final results are shown in table 7.
The results show (table 7): after accelerated 6 months of stability, no significant change in appearance was seen for the reference formulation and example 1; the total impurity content is comparable to the comparison of the reference formulation.
TABLE 7 summary of stability test results for reference formulation and example 1
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 compound preparation containing engeletin and metformin hydrochloride is provided, wherein an engeletin pellet core is a quick-release part, a metformin hydrochloride pellet core is a slow-release part, the two pellet cores are respectively coated by an isolating layer, and then the two pellets are mixed and filled into a capsule.
2. The compound preparation of claim 1, wherein: the composition of the Engelliflozin pellet core comprises: 1-20% of engagliflozin, 30-90% of diluent and 1-30% of adhesive;
the metformin hydrochloride pellet core comprises the following components: 30-60% of metformin hydrochloride, 1-30% of diluent, 1-30% of adhesive and 10-50% of slow-release material.
3. The compound preparation of claim 1, wherein the two pellets are mixed and filled into a capsule, and the content ratio of metformin hydrochloride to engagliflozin in the two pellets is 1: 50-200.
4. The compound preparation according to claim 1, wherein the pellet core of the sustained-release part and the pellet core of the quick-release part are both formed by extrusion and rounding by an extrusion and rounding machine, and the diameter of the pellet core is 0.5-3.0 mm, preferably 1.5-2.5 mm.
5. The compound preparation of claim 2, wherein the diluent is selected from any one or a combination of at least two of microcrystalline cellulose, lactose, mannitol or pregelatinized starch; the dosage proportion of the diluent in the quick-release pill core of the empagliflozin is 30-90%, and the dosage proportion in the slow-release pill core of the metformin hydrochloride is 1-30%.
6. The compound preparation of claim 2, wherein the binder is selected from any one of povidone, sodium carboxymethyl cellulose, hypromellose or hydroxypropyl cellulose, preferably sodium carboxymethyl cellulose; the dosage proportion of the adhesive in the quick-release pill core of the empagliflozin is 1-30%, and the dosage proportion of the adhesive in the slow-release pill core of the metformin hydrochloride is 1-30%.
7. The compound preparation of claim 2, wherein the sustained-release material is selected from one or a combination of at least two of polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium alginate, ethyl cellulose and carbomer, and the dosage proportion of the metformin hydrochloride sustained-release pellet core is 10-50%.
8. The compound preparation as claimed in claim 1, wherein the coating material of the isolating layer is gastric soluble coating material, preferably premixed "Opadry" series gastric soluble coating powder or "easy-release" series gastric soluble coating powder.
9. The compound preparation as claimed in claim 1, wherein the weight of the isolating layer is 3-15% of the weight of the pellet core, and the isolating coating material is selected from Opadry.
10. A method of preparing a combination formulation as claimed in any one of claims 1 to 9, comprising the steps of: firstly, preparing a metformin hydrochloride sustained-release pill core by an extrusion rounding process; secondly, preparing an Engelliflozin quick-release pill core by an extrusion rounding process; thirdly, coating the two drug-loaded pill cores with an isolating layer respectively; and fourthly, filling the two drug-loaded pellets into capsules according to a certain proportion.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114404436A (en) * | 2022-02-24 | 2022-04-29 | 北京百奥药业有限责任公司 | Metformin empagliflozin composition and preparation method thereof |
| WO2023234901A1 (en) * | 2022-05-31 | 2023-12-07 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | A formulation comprising empagliflozin and metformin hydrochloride |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN103976997A (en) * | 2014-05-13 | 2014-08-13 | 中国药科大学 | Hypoglycemic compound sustained-release capsule and preparation method thereof |
| CN106727420A (en) * | 2017-01-02 | 2017-05-31 | 佛山市腾瑞医药科技有限公司 | A kind of net fast release micropill preparations of En Gelie, preparation method |
| CN107432869A (en) * | 2016-05-27 | 2017-12-05 | 天津药物研究院有限公司 | Include net double-layer tablets of Metformin hydrochloride and En Gelie and preparation method thereof |
-
2021
- 2021-09-16 CN CN202111087376.7A patent/CN113616624B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN103976997A (en) * | 2014-05-13 | 2014-08-13 | 中国药科大学 | Hypoglycemic compound sustained-release capsule and preparation method thereof |
| CN107432869A (en) * | 2016-05-27 | 2017-12-05 | 天津药物研究院有限公司 | Include net double-layer tablets of Metformin hydrochloride and En Gelie and preparation method thereof |
| CN106727420A (en) * | 2017-01-02 | 2017-05-31 | 佛山市腾瑞医药科技有限公司 | A kind of net fast release micropill preparations of En Gelie, preparation method |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114404436A (en) * | 2022-02-24 | 2022-04-29 | 北京百奥药业有限责任公司 | Metformin empagliflozin composition and preparation method thereof |
| WO2023234901A1 (en) * | 2022-05-31 | 2023-12-07 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | A formulation comprising empagliflozin and metformin hydrochloride |
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