CN114404436A - Metformin empagliflozin composition and preparation method thereof - Google Patents
Metformin empagliflozin composition and preparation method thereof Download PDFInfo
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- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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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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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
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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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/282—Organic compounds, e.g. fats
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- 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 discloses a metformin empagliflozin tablet and a preparation method thereof. The tablet is prepared from the following raw materials in parts by mass: 500 parts of metformin hydrochloride, 5 parts of engelet, 30.13 parts of corn starch, 47.2 parts of povidone, 2.95 parts of colloidal silicon dioxide, 4.72 parts of magnesium stearate and 29.5 parts of film coating premix. The preparation method comprises the following steps: pulverizing the engelizin and sieving the engelizin by a 80-mesh sieve, respectively sieving the metformin hydrochloride and the corn starch by a 40-mesh sieve, and sieving the colloidal silicon dioxide by a 80-mesh sieve for treatment; mixing metformin hydrochloride and corn starch; fluid bed granulation: a. dissolving copovidone in purified water, and adding the empagliflozin to obtain a drug-containing granulating liquid; b. granulating; after drying, the particles are granulated by a screen with the diameter of 1.0mm to 1.5 mm; adding the prescribed amount of colloidal silicon dioxide and magnesium stearate, and mixing; tabletting, and controlling the pressure to be 3.0 KN-6.0 KN; coating: the weight gain of the coating is controlled to be 2.0-5.0%.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a metformin empagliflozin composition and a preparation method thereof.
Background
The incidence of type II diabetes is increasing, and its complications (such as diabetic foot, blindness, renal failure, etc.) not only affect the quality of life of the patient, but also may lead to a shortened lifespan. Empagliflozin (empagliflozin) is an oral inhibitor of sodium-glucose cotransporter-2 (SGLT-2). SGLT-2 is the transporter responsible for the reabsorption of glucose from glomerular filtrate into the systemic circulation, and by inhibiting SGLT-2, engagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, thereby increasing urinary glucose excretion. Metformin hydrochloride is a classic hypoglycemic drug, and can reduce fasting hyperglycemia and postprandial hyperglycemia of type II diabetes patients.
The metformin empagliflozin tablet is a compound preparation of empagliflozin and metformin hydrochloride. The oral glucose tolerance experiment research of rats shows that the oral administration and the simultaneous administration of the engagliflozin hydrochloride and the metformin hydrochloride can reduce the blood glucose level, and the blood glucose reducing effect (reduced by 63%) of the simultaneous administration is obviously higher than that of the group which separately administers the engagliflozin hydrochloride (reduced by 37%) or the metformin hydrochloride (reduced by 39%), and the metformin engagliflozin hydrochloride tablet has better blood glucose reducing effect.
Metformin engeletin tablets are a compound preparation developed by the company brigling invarghan for the treatment of diabetes. On 5 months 2015, the european union approved the marketing application for metformin empagliflozin tablets. On 8 months 2015, metformin empagliflozin was FDA approved for marketing. The medicine is imported to China at present, and has the specification: 850mg/5mg, 850mg/12.5mg, 1000mg/5mg, 1000mg/12.5 mg. The 500mg/5mg standard product manufactured by Hangzhou Zhonghuadong pharmaceutical Co Ltd is approved to be on the market at 6 month 1 in 2021.
The engelizin is white to yellowish powder as a raw material: very slightly soluble in water (very slightly soluble in pHl.0, pH4.0, pH7.47 media), slightly soluble in ethanol, 50% methanol, soluble in 50% acetonitrile, slightly soluble in methanol, and hardly soluble in toluene. The metformin hydrochloride raw material is white crystalline powder: no bad smell. Is easily soluble in water, soluble in methanol, slightly soluble in ethanol, and insoluble in chloroform or diethyl ether.
At present, the preparation process of the metformin empagliflozin tablet in China has patents, such as: "pharmaceutical composition, pharmaceutical dosage form, process for its preparation, method of treatment and use thereof" (application No. 201510227017.5) filed by the international limited company berringer engheim discloses solid formulations of SGLT-2 inhibitor and metformin, and also discloses the formulation, and proposes granulation by premixing metformin hydrochloride, SGLT-2 inhibitor and cornstarch and spraying into a "granulation liquid" consisting of copovidone and purified water. Because the metformin hydrochloride bulk drug is easy to lose water and has poor compressibility, the tablet prepared by the process has small hardness, so that the friability of the tablet is unqualified, the subsequent coating process is not facilitated to be smoothly carried out, the dissolution RSD among the tablets is large finally, and the dissolution RSD in 15min exceeds 10%, which can cause great variation of blood concentration of a patient after the patient takes the medicine, and cause blood sugar fluctuation. The ratio of the empagliflozin in the product is small, is only 0.85%, is not easy to mix uniformly, further increases the RSD value dissolved out in 15min, and increases the risk of blood sugar fluctuation.
Thus. From the perspective of improving the quality of medicines, a proper production process is needed, so that the engagliflozin can be uniformly dispersed in a preparation product, the mixing uniformity of the engagliflozin is improved, the compressibility of the material is improved, the hardness of the tablet can be controlled by adjusting the pressure of a tablet press, the tablet with uniform content and hardness is obtained, and the 15-min dissolution RSD value between different tablets is reduced.
Disclosure of Invention
The invention discloses a metformin empagliflozin composition and a preparation method thereof. The preparation method adopts a process of dispersing the engagliflozin in a granulating liquid and then carrying out fluidized bed granulation, and mainly solves the problems of poor content uniformity, small hardness of the tablet, unqualified friability and large 15min dissolved RSD value of the metformin engagliflozin tablet prepared by the traditional process by controlling the fluidized bed granulation parameters and particle moisture.
The metformin empagliflozin tablet provided by the invention is prepared from the following raw and auxiliary materials in parts by mass:
the metformin engelet tablet is a coated tablet, and other raw and auxiliary materials except the film coating premix are raw and auxiliary materials of a tablet core.
The invention also provides a preparation method of the metformin empagliflozin tablet.
The preparation method of the metformin empagliflozin tablet provided by the invention comprises the following steps:
(1) auxiliary material pretreatment: pulverizing the raw material medicines of the empagliflozin, sieving by a 80-mesh sieve, respectively sieving metformin hydrochloride and corn starch by a 40-mesh sieve, and sieving colloidal silicon dioxide by a 80-mesh sieve for treatment;
(2) premixing auxiliary materials: mixing metformin hydrochloride and corn starch; the adding sequence is that 50% of metformin hydrochloride is added firstly, then corn starch is added, and then the rest of metformin hydrochloride is added;
(3) fluid bed granulation:
a. preparing a granulating liquid: dissolving copovidone in purified water to obtain copovidone solution with the concentration of 21.2 percent (w/w), slowly adding the raw material medicine of the empagliflozin, and uniformly stirring and dispersing to obtain medicine-containing granulating liquid for later use;
b. and (3) granulating: placing the mixed metformin hydrochloride and corn starch in a fluidized bed, setting air inlet temperature to be 70-80 ℃, setting frequency of an induced draft fan to be 20Hz, starting preheating materials, spraying a drug-containing granulating liquid for granulation when the temperature of the materials is increased to be more than 45 ℃, setting the rotating speed of a liquid supply pump to be 50rpm, setting the sector pressure and the atomizing pressure to be 3bar/2bar respectively, controlling the temperature of the materials to be 40-50 ℃, closing heating after the granulating liquid is sprayed, and continuously spraying a proper amount of purified water, wherein the water content of the granules is controlled to be 1.5-2.5%;
(4) straightening: after drying, the particles are granulated by a screen with the diameter of 1.0mm to 1.5 mm;
(5) total mixing: adding the colloidal silicon dioxide and the magnesium stearate according to the formula amount according to the total yield after mixing, and mixing;
(6) tabletting: tabletting by adopting a rotary tablet press, and controlling the pressure to be 3.0 KN-6.0 KN;
(7) coating: purified water and a film coating premix are taken to prepare a coating solution with the solid content of 13 percent, and the weight gain of the coating is controlled to be 2.0 to 5.0 percent.
In the step (2), the mixing is carried out in a column hopper mixer at a rotating speed of 8r/min for 10 min.
In the step (5), the mixing time is 10 min. The required dosage of the colloidal silicon dioxide and the magnesium stearate can be converted according to the total yield after mixing, so that the material feeding amount of each material is consistent with the design proportion.
Compared with the prior art, the invention has the following advantages:
1. the particle size of each auxiliary material is controlled in the pretreatment stage of the raw and auxiliary materials, wherein metformin hydrochloride and corn starch are sieved by a 40-mesh sieve, the empagliflozin is crushed and sieved by a 80-mesh sieve, and the colloidal silicon dioxide is sieved by the 80-mesh sieve, so that the materials can be fully and uniformly mixed in the preparation process;
2. the invention adopts the method that the engelet is dispersed in the copovidone water solution to obtain the granulation liquid containing the engelet raw material medicine. Granulating by adopting a fluidized bed, and spraying granulating liquid to uniformly disperse the empagliflozin bulk drug in the material, so that the content uniformity is improved, and the 15min dissolution RSD value among different tablets is reduced;
3. the invention adopts a strategy of controlling granulation parameters in the fluidized bed granulation stage; the air inlet temperature is controlled to be 70-80 ℃, the actual temperature of the material is controlled to be 40-50 ℃, and the moisture of the particles is controlled to be 1.5-2.5%, so that the compressibility of the material can be improved;
4. the invention controls the mesh number of the screen in the dry granulation process to be 1.0-1.5 mm, and obtains the particles with uniform particle size, good fluidity and good compressibility.
5. The invention controls the pressure of the tablet press in the tabletting process to be 3.0 KN-6.0 KN, so as to obtain the tablet with higher hardness, qualified friability and higher dissolution speed.
Drawings
FIG. 1 is a graph comparing the dissolution profiles of metformin in example 1, example 2, comparative example 6 and commercially available metformin engrel tablets;
FIG. 2 is a graph comparing the dissolution profiles of empagliflozin in example 1, example 2, comparative example 6, and on-market metformin empagliflozin tablets;
figure 3 comparative graphs of the dissolution profiles of engelet in example 1, example 2, comparative example 1, comparative example 6 and on the market in the metformin engelet tablet.
Detailed Description
The present invention will be further illustrated with reference to the following specific examples, but the present invention is not limited to the following examples. The method is a conventional method unless otherwise specified. The starting materials are commercially available from the open literature unless otherwise specified.
Example 1, preparation of metformin engletin tablet (500/5 mg):
prescription composition of metformin empagliflozin tablet
The preparation method of the metformin empagliflozin tablet comprises the following steps:
(1) auxiliary material pretreatment: crushing and sieving the raw material medicines of the engelizin by a universal crusher to 80 meshes, respectively sieving metformin hydrochloride and corn starch by 40 meshes, and sieving colloidal silicon dioxide by 80 meshes;
(2) premixing auxiliary materials: putting metformin hydrochloride and corn starch into a column type hopper mixer to be mixed, wherein the rotating speed is 8r/min, the mixing is carried out for 10min, and the adding sequence comprises adding 50% metformin hydrochloride, adding corn starch and adding the rest metformin hydrochloride;
(3) fluid bed granulation:
a. preparing a granulating liquid: dissolving copovidone in purified water to obtain copovidone solution with the concentration of 21.2 percent (w/w), slowly adding the raw material medicine of the empagliflozin, and uniformly stirring and dispersing to obtain medicine-containing granulating liquid for later use;
b. and (3) granulating: placing the mixed metformin hydrochloride and corn starch in a fluidized bed, setting air inlet temperature to be 70-80 ℃, setting frequency of an induced draft fan to be 20Hz, starting preheating materials, spraying a drug-containing granulating liquid for granulation when the temperature of the materials is increased to be more than 45 ℃, setting the rotating speed of a liquid supply pump to be 50rpm, setting the sector pressure and the atomizing pressure to be 3bar/2bar respectively, controlling the temperature of the materials to be 40-50 ℃, closing heating after the granulating liquid is sprayed, and continuously spraying a proper amount of purified water, wherein the water content of the granules is controlled to be 1.5-2.5%;
(4) straightening: after drying, the particles are granulated by a 1.0mm screen;
(5) total mixing: adding the colloidal silicon dioxide and magnesium stearate according to the formula amount according to the yield, and mixing for 10 min;
(6) tabletting: tabletting by adopting a rotary tablet press, and controlling the pressure to be 3.0 KN-6.0 KN;
(7) coating: coating liquid with solid content of 13% (w/w) is prepared, and the weight gain of the coating is controlled to be 2.0-5.0%. Example 2, preparation of metformin engletin tablet (500/5 mg): (Dry granulation Using 1.5mm mesh)
Prescription composition of metformin empagliflozin tablet
The preparation method of the metformin empagliflozin tablet comprises the following steps:
(1) auxiliary material pretreatment: crushing and sieving the raw material medicines of the engelizin by a universal crusher to 80 meshes, respectively sieving metformin hydrochloride and corn starch by 40 meshes, and sieving colloidal silicon dioxide by 80 meshes;
(2) premixing auxiliary materials: putting metformin hydrochloride and corn starch into a column type hopper mixer to be mixed, wherein the rotating speed is 8r/min, the mixing is carried out for 10min, and the adding sequence comprises adding 50% metformin hydrochloride, adding corn starch and adding the rest metformin hydrochloride;
(3) fluid bed granulation:
a. preparing a granulating liquid: dissolving copovidone in purified water to obtain copovidone solution with the concentration of 21.2 percent (w/w), slowly adding the raw material medicine of the empagliflozin, and uniformly stirring and dispersing to obtain medicine-containing granulating liquid for later use;
b. and (3) granulating: placing the mixed metformin hydrochloride and corn starch in a fluidized bed, setting air inlet temperature to be 70-80 ℃, setting frequency of an induced draft fan to be 20Hz, starting preheating materials, spraying a drug-containing granulating liquid for granulation when the temperature of the materials is increased to be more than 45 ℃, setting the rotating speed of a liquid supply pump to be 50rpm, setting the sector pressure and the atomizing pressure to be 3bar/2bar respectively, controlling the temperature of the materials to be 40-50 ℃, closing heating after the granulating liquid is sprayed, and continuously spraying a proper amount of purified water, wherein the water content of the granules is controlled to be 1.5-2.5%;
(4) straightening: after drying, the particles are granulated by a 1.5mm screen;
(5) total mixing: adding the colloidal silicon dioxide and magnesium stearate according to the formula amount according to the yield, and mixing for 10 min;
(6) tabletting: tabletting by adopting a rotary tablet press, and controlling the pressure to be 3.0 KN-6.0 KN;
(7) coating: preparing coating liquid with solid content of 13% (w/w), controlling the weight gain of the coating to be 2.0-5.0%
Comparative example 1, preparation of metformin engletin tablet (500/5 mg): (mixing Engelliflozin hydrochloride, metformin hydrochloride and corn starch, spraying copovidone solution for granulating)
Prescription composition of metformin empagliflozin tablet
The preparation method of the metformin empagliflozin tablet comprises the following steps:
(1) auxiliary material pretreatment: crushing and sieving the raw material medicines of the engelizin by a universal crusher to 80 meshes, respectively sieving metformin hydrochloride and corn starch by 40 meshes, and sieving colloidal silicon dioxide by 80 meshes;
(2) premixing auxiliary materials: putting metformin hydrochloride, engeletin and corn starch into a column type hopper mixer for mixing at the rotating speed of 8r/min for 10min, and adding the metformin hydrochloride with the amount of 50 percent, then adding the corn starch and the engeletin and then adding the rest of the metformin hydrochloride;
(3) fluid bed granulation:
a. preparing a granulating liquid: dissolving copovidone in purified water to obtain copovidone solution with the concentration of 21.2 percent (w/w) for later use;
b. and (3) granulating: putting the premixed metformin hydrochloride, the empagliflozin and the corn starch into a fluidized bed, setting the air inlet temperature to be 70-80 ℃, setting the frequency of an induced draft fan to be 20Hz, starting to preheat the materials, spraying the copovidone solution for granulation when the temperature of the materials is increased to be more than 45 ℃, setting the rotating speed of a liquid supply pump to be 50rpm, setting the sector pressure and the atomizing pressure to be 3bar/2bar respectively, controlling the temperature of the materials to be 40-50 ℃, closing heating and continuously spraying a proper amount of purified water after the granulating liquid is sprayed, and controlling the water content of the granules to be 1.5% -2.5%;
(4) straightening: after drying, the particles are granulated by a 1.0mm screen;
(5) total mixing: adding the colloidal silicon dioxide and magnesium stearate according to the formula amount according to the yield, and mixing for 10 min;
(6) tabletting: tabletting by adopting a rotary tablet press, and controlling the pressure to be 3.0 KN-6.0 KN;
(7) coating: preparing coating liquid with solid content of 13% (w/w), controlling the weight gain of the coating to be 2.0-5.0%
Comparative example 2, preparation of metformin engletin tablet (500/5 mg): (the temperature of the inlet air is increased to 80-90 ℃ and the temperature of the material is 50-60 ℃)
Prescription composition of metformin empagliflozin tablet
The preparation method of the metformin empagliflozin tablet comprises the following steps:
(1) auxiliary material pretreatment: crushing and sieving the raw material medicines of the engelizin by a universal crusher to 80 meshes, respectively sieving metformin hydrochloride and corn starch by 40 meshes, and sieving colloidal silicon dioxide by 80 meshes;
(2) premixing auxiliary materials: putting metformin hydrochloride and corn starch into a column type hopper mixer to be mixed, wherein the rotating speed is 8r/min, the mixing is carried out for 10min, and the adding sequence comprises adding 50% metformin hydrochloride, adding corn starch and adding the rest metformin hydrochloride;
(3) fluid bed granulation:
a. preparing a granulating liquid: dissolving copovidone in purified water to obtain copovidone solution with the concentration of 21.2 percent (w/w), slowly adding the raw material medicine of the empagliflozin, and uniformly stirring and dispersing to obtain medicine-containing granulating liquid for later use;
b. and (3) granulating: placing the mixed metformin hydrochloride and corn starch in a fluidized bed, setting the air inlet temperature to be 80-90 ℃, setting the frequency of an induced draft fan to be 20Hz, starting preheating materials, spraying a drug-containing granulating liquid for granulation when the temperature of the materials is increased to be more than 45 ℃, setting the rotating speed of a liquid supply pump to be 50rpm, setting the sector pressure and the atomizing pressure to be 3bar/2bar respectively, controlling the temperature of the materials to be 50-60 ℃, closing heating after the granulating liquid is sprayed, and continuously spraying a proper amount of purified water, wherein the water content of the granules is controlled to be 1.5-2.5%;
(4) straightening: after drying, the particles are granulated by a 1.0mm screen;
(5) total mixing: adding the colloidal silicon dioxide and magnesium stearate according to the formula amount according to the yield, and mixing for 10 min;
(6) tabletting: tabletting by adopting a rotary tablet press, and controlling the pressure to be 3.0 KN-6.0 KN;
(7) coating: coating liquid with solid content of 13% (w/w) is prepared, and the weight gain of the coating is controlled to be 2.0-5.0%.
Comparative example 3, preparation of metformin engletin tablet (500/5 mg): (reducing the inlet air temperature to 60-70 ℃ and the material temperature to 30-40 ℃)
Prescription composition of metformin empagliflozin tablet
The preparation method of the metformin empagliflozin tablet comprises the following steps:
(1) auxiliary material pretreatment: crushing and sieving the raw material medicines of the engelizin by a universal crusher to 80 meshes, respectively sieving metformin hydrochloride and corn starch by 40 meshes, and sieving colloidal silicon dioxide by 80 meshes;
(2) premixing auxiliary materials: putting metformin hydrochloride and corn starch into a column type hopper mixer to be mixed, wherein the rotating speed is 8r/min, the mixing is carried out for 10min, and the adding sequence comprises adding 50% metformin hydrochloride, adding corn starch and adding the rest metformin hydrochloride;
(3) fluid bed granulation:
a. preparing a granulating liquid: dissolving copovidone in purified water to obtain copovidone solution with the concentration of 21.2 percent (w/w), slowly adding the raw material medicine of the empagliflozin, and uniformly stirring and dispersing to obtain medicine-containing granulating liquid for later use;
b. and (3) granulating: placing the mixed metformin hydrochloride and corn starch in a fluidized bed, setting the air inlet temperature to be 60-70 ℃, setting the frequency of an induced draft fan to be 20Hz, starting preheating materials, spraying a drug-containing granulating liquid for granulation when the temperature of the materials is increased to be more than 45 ℃, setting the rotating speed of a liquid supply pump to be 50rpm, setting the sector pressure and the atomizing pressure to be 3bar/2bar respectively, controlling the temperature of the materials to be 30-40 ℃, closing heating after the granulating liquid is sprayed, and continuously spraying a proper amount of purified water, wherein the water content of the granules is controlled to be 1.5-2.5%;
(4) straightening: after drying, the particles are granulated by a 1.0mm screen;
(5) total mixing: adding the colloidal silicon dioxide and magnesium stearate according to the formula amount according to the yield, and mixing for 10 min;
(6) tabletting: tabletting by adopting a rotary tablet press, and controlling the pressure to be 3.0 KN-6.0 KN;
(7) coating: coating liquid with solid content of 13% (w/w) is prepared, and the weight gain of the coating is controlled to be 2.0-5.0%.
Comparative example 4, preparation of metformin engletin tablet (500/5 mg): (controlling the moisture content of the granules to be less than 1.5%)
Prescription composition of metformin empagliflozin tablet
The preparation method of the metformin empagliflozin tablet comprises the following steps:
(1) auxiliary material pretreatment: crushing and sieving the raw material medicines of the engelizin by a universal crusher to 80 meshes, respectively sieving metformin hydrochloride and corn starch by 40 meshes, and sieving colloidal silicon dioxide by 80 meshes;
(2) premixing auxiliary materials: putting metformin hydrochloride and corn starch into a column type hopper mixer to be mixed, wherein the rotating speed is 8r/min, the mixing is carried out for 10min, and the adding sequence comprises adding 50% metformin hydrochloride, adding corn starch and adding the rest metformin hydrochloride;
(3) fluid bed granulation:
a. preparing a granulating liquid: dissolving copovidone in purified water to obtain copovidone solution with the concentration of 21.2 percent (w/w), slowly adding the raw material medicine of the empagliflozin, and uniformly stirring and dispersing to obtain medicine-containing granulating liquid for later use;
b. and (3) granulating: placing the mixed metformin hydrochloride and corn starch in a fluidized bed, setting air inlet temperature to be 70-80 ℃, setting frequency of an induced draft fan to be 20Hz, starting preheating materials, spraying a drug-containing granulating liquid for granulation when the temperature of the materials is increased to be more than 45 ℃, setting the rotating speed of a liquid supply pump to be 50rpm, setting the sector pressure and the atomizing pressure to be 3bar/2bar respectively, controlling the temperature of the materials to be 40-50 ℃, closing heating after the granulating liquid is sprayed, and continuously spraying a proper amount of purified water, wherein the water content of the granules is controlled to be less than 1.5%;
(4) straightening: after drying, the particles are granulated by a 1.0mm screen;
(5) total mixing: adding the colloidal silicon dioxide and magnesium stearate according to the formula amount according to the yield, and mixing for 10 min;
(6) tabletting: tabletting by adopting a rotary tablet press, and controlling the pressure to be 3.0 KN-6.0 KN;
(7) coating: coating liquid with solid content of 13% (w/w) is prepared, and the weight gain of the coating is controlled to be 2.0-5.0%.
Comparative example 5, preparation of metformin engletin tablet (500/5 mg): (controlling the moisture of the granules to be 2.5-3.0%)
Prescription composition of metformin empagliflozin tablet
The preparation method of the metformin empagliflozin tablet comprises the following steps:
(1) auxiliary material pretreatment: crushing and sieving the raw material medicines of the engelizin by a universal crusher to 80 meshes, respectively sieving metformin hydrochloride and corn starch by 40 meshes, and sieving colloidal silicon dioxide by 80 meshes;
(2) premixing auxiliary materials: putting metformin hydrochloride and corn starch into a column type hopper mixer to be mixed, wherein the rotating speed is 8r/min, the mixing is carried out for 10min, and the adding sequence comprises adding 50% metformin hydrochloride, adding corn starch and adding the rest metformin hydrochloride;
(3) fluid bed granulation:
a. preparing a granulating liquid: dissolving copovidone in purified water to obtain copovidone solution with the concentration of 21.2 percent (w/w), slowly adding the raw material medicine of the empagliflozin, and uniformly stirring and dispersing to obtain medicine-containing granulating liquid for later use;
b. and (3) granulating: placing the mixed metformin hydrochloride and corn starch in a fluidized bed, setting air inlet temperature to be 70-80 ℃, setting frequency of an induced draft fan to be 20Hz, starting preheating materials, spraying a drug-containing granulating liquid for granulation when the temperature of the materials is increased to be more than 45 ℃, setting the rotating speed of a liquid supply pump to be 50rpm, setting the sector pressure and the atomizing pressure to be 3bar/2bar respectively, controlling the temperature of the materials to be 40-50 ℃, closing heating after the granulating liquid is sprayed, and continuously spraying a proper amount of purified water, wherein the water content of the granules is controlled to be 2.5-3.0%;
(4) straightening: after drying, the particles are granulated by a 1.0mm screen;
(5) total mixing: adding the colloidal silicon dioxide and magnesium stearate according to the formula amount according to the yield, and mixing for 10 min;
(6) tabletting: tabletting by adopting a rotary tablet press, and controlling the pressure to be 3.0 KN-6.0 KN;
(7) coating: coating liquid with solid content of 13% (w/w) is prepared, and the weight gain of the coating is controlled to be 2.0-5.0%.
Comparative example 6, preparation of metformin engletin tablet (500/5 mg): (increasing tablet press pressure to 7KN ~ 10KN)
Prescription composition of metformin empagliflozin tablet
The preparation method of the metformin empagliflozin tablet comprises the following steps:
(1) auxiliary material pretreatment: crushing and sieving the raw material medicines of the engelizin by a universal crusher to 80 meshes, respectively sieving metformin hydrochloride and corn starch by 40 meshes, and sieving colloidal silicon dioxide by 80 meshes;
(2) premixing auxiliary materials: putting metformin hydrochloride and corn starch into a column type hopper mixer to be mixed, wherein the rotating speed is 8r/min, the mixing is carried out for 10min, and the adding sequence comprises adding 50% metformin hydrochloride, adding corn starch and adding the rest metformin hydrochloride;
(3) fluid bed granulation:
a. preparing a granulating liquid: dissolving copovidone in purified water to obtain copovidone solution with the concentration of 21.2 percent (w/w), slowly adding the raw material medicine of the empagliflozin, and uniformly stirring and dispersing to obtain medicine-containing granulating liquid for later use;
b. and (3) granulating: placing the mixed metformin hydrochloride and corn starch in a fluidized bed, setting air inlet temperature to be 70-80 ℃, setting frequency of an induced draft fan to be 20Hz, starting preheating materials, spraying a drug-containing granulating liquid for granulation when the temperature of the materials is increased to be more than 45 ℃, setting the rotating speed of a liquid supply pump to be 50rpm, setting the sector pressure and the atomizing pressure to be 3bar/2bar respectively, controlling the temperature of the materials to be 40-50 ℃, closing heating after the granulating liquid is sprayed, and continuously spraying a proper amount of purified water, wherein the water content of the granules is controlled to be 1.5-2.5%;
(4) straightening: after drying, the particles are granulated by a 1.0mm screen;
(5) total mixing: adding the colloidal silicon dioxide and magnesium stearate according to the formula amount according to the yield, and mixing for 10 min;
(6) tabletting: tabletting by adopting a rotary tablet press, and controlling the pressure to be 7 KN-10 KN;
(7) coating: coating liquid with solid content of 13% (w/w) is prepared, and the weight gain of the coating is controlled to be 2.0-5.0%.
Comparative example 7, preparation of metformin engletin tablet (500/5 mg): (reducing the tablet press pressure to 1 KN-3 KN)
Prescription composition of metformin empagliflozin tablet
The preparation method of the metformin empagliflozin tablet comprises the following steps:
(1) auxiliary material pretreatment: crushing and sieving the raw material medicines of the engelizin by a universal crusher to 80 meshes, respectively sieving metformin hydrochloride and corn starch by 40 meshes, and sieving colloidal silicon dioxide by 80 meshes;
(2) premixing auxiliary materials: putting metformin hydrochloride and corn starch into a column type hopper mixer to be mixed, wherein the rotating speed is 8r/min, the mixing is carried out for 10min, and the adding sequence comprises adding 50% metformin hydrochloride, adding corn starch and adding the rest metformin hydrochloride;
(3) fluid bed granulation:
a. preparing a granulating liquid: dissolving copovidone in purified water to obtain copovidone solution with the concentration of 21.2 percent (w/w), slowly adding the raw material medicine of the empagliflozin, and uniformly stirring and dispersing to obtain medicine-containing granulating liquid for later use;
b. and (3) granulating: placing the mixed metformin hydrochloride and corn starch in a fluidized bed, setting air inlet temperature to be 70-80 ℃, setting frequency of an induced draft fan to be 20Hz, starting preheating materials, spraying a drug-containing granulating liquid for granulation when the temperature of the materials is increased to be more than 45 ℃, setting the rotating speed of a liquid supply pump to be 50rpm, setting the sector pressure and the atomizing pressure to be 3bar/2bar respectively, controlling the temperature of the materials to be 40-50 ℃, closing heating after the granulating liquid is sprayed, and continuously spraying a proper amount of purified water, wherein the water content of the granules is controlled to be 1.5-2.5%;
(4) straightening: after drying, the particles are granulated by a 1.0mm screen;
(5) total mixing: adding the colloidal silicon dioxide and magnesium stearate according to the formula amount according to the yield, and mixing for 10 min;
(6) tabletting: tabletting by adopting a rotary tablet press, and controlling the pressure to be 1.0 KN-3.0 KN;
(7) coating: coating liquid with solid content of 13% (w/w) is prepared, and the weight gain of the coating is controlled to be 2.0-5.0%.
Evaluation of effects of the above examples and comparative examples:
1. improve the content uniformity
The metformin empagliflozin tablet prepared in the technical scheme of the invention adopts a fluidized bed granulation process, and as the empagliflozin in the tablet has a small specification, the empagliflozin raw material medicine is dispersed in an adhesive for granulation, so as to achieve the purpose of uniformly dispersing the raw material medicine.
The content uniformity of the empagliflozin of the metformin hydrochloride tablets in the embodiment 1, the embodiment 2, the comparative example 1 and the market sold metformin hydrochloride tablets is detected, and the specific detection method refers to a content uniformity inspection method of four 0941 parts in the China pharmacopoeia 2020 edition. The results are shown in Table-1.
TABLE-1 comparison of the content uniformity of Empagliflozin
The content uniformity detection result shows that: the content uniformity of the products of the examples 1 and 2 is obviously better than that of the comparative example 1 and the metformin empagliflozin sold in the market, which shows that the content uniformity of the products can be obviously improved by granulating the empagliflozin after dispersing in the adhesive, and the good content uniformity is beneficial to improving the effectiveness and the safety of the products.
2. Increase tablet hardness and reduce friability
The metformin empagliflozin tablet prepared in the technical scheme of the invention adopts a fluidized bed granulation process, the air inlet temperature and the material temperature are controlled, the moisture of the granules is ensured to be between 1.5 and 2.5 percent, the aim of improving the hardness of the tablet is achieved, and the friability is reduced.
The hardness and friability tests of example 1, example 2, comparative example 3, comparative example 4, comparative example 5, comparative example 6 and comparative example 7 of the invention are carried out, and the detailed test method refers to the friability test method of 0923 tablets in four parts of the year 2020 edition of Chinese pharmacopoeia. The results are shown in Table-3.
TABLE 2 hardness and friability comparison results
| / | Example 1 | Example 2 | Comparative example 2 | Comparative example 3 | Comparative example 4 | Comparative example 5 | Comparative example 6 | Comparative example 7 |
| Hardness (KG) | 12.3 | 13.6 | 6.3 | 8.6 | 3.6 | 11.2 | 16.7 | 5.4 |
| The friability is less than 1.0% | 0.42 | 0.38 | 1.53 | 1.21 | 1.94 | Drop cover | 0.31 | 1.51 |
The hardness test result shows that: the hardness of the tablets in the examples 1 and 2 can reach more than 10kg, the hardness is high, and the friability of the tablets is small. The hardness of the products of comparative example 2, comparative example 3, comparative example 4 and comparative example 7 is small, and the hardness is less than 10kg, the friability of the tablets is large, and the products exceed the pharmacopoeia limit requirements and do not meet the regulations. Comparative example 5 and comparative example 6 have hardness of more than 10kg, but comparative example 5 fails to cover when the friability is measured, indicating that the subsequent coating process cannot be performed.
3. Increase the dissolution speed of the product
The metformin engagliflozin tablet prepared in the technical scheme of the invention adopts a fluidized bed granulation process, the air inlet temperature and the material temperature are controlled, the moisture of the granules is ensured to be between 1.5 and 2.5 percent, the tabletting pressure is controlled to be between 3.0 and 6.0KN, and the purposes of higher tablet hardness and high dissolution speed are achieved.
The dissolution curve detection and comparison are carried out on the metformin engelet tablets sold in the market in example 1, example 2 and comparative example 6 of the invention, and the specific detection method refers to the dissolution and release determination method of the four 9031 parts in the 2020 edition of Chinese pharmacopoeia. The results are shown in Table-3.
TABLE-3 dissolution Curve test results
The dissolution curves are shown in fig. 1 and fig. 2. The test results show that: from example 1 and example 2, it can be seen that, by adopting fluidized bed granulation, the water content of the granules is controlled to be between 1.5% and 2.5%, the tabletting pressure is controlled to be between 3.0KN and 6.0KN, the dissolution rate of the product is high, the 15min cumulative dissolution rate reaches more than 85%, and the dissolution curve is consistent with that of the commercially available product. As can be seen from comparative example 6, when the tableting pressure was increased to 6.0KN or more, the dissolution rate of the product was decreased, and the 15min cumulative dissolution rate was not more than 85%, which is inconsistent with that of the commercially available product.
4. Improvement of dissolution rate experiment RSD value
The metformin empagliflozin tablet prepared in the technical scheme of the invention adopts a fluidized bed granulation process, and as the empagliflozin in the tablet has a smaller specification, the empagliflozin raw material medicine is dispersed in the adhesive for granulation so as to achieve the purpose of uniformly dispersing the raw material medicine, and meanwhile, the moisture of the granules is controlled to be between 1.5 and 2.5 percent, so that the hardness of the tablet after tabletting is ensured to be stable and controllable, and the RSD value of a dissolution experiment is reduced.
The dissolution curve detection and comparison are carried out on the metformin engelet tablets sold in the market, namely the embodiment 1, the embodiment 2, the comparative example 1 and the comparative example 7 of the invention, and the specific detection method refers to the dissolution and release determination method of the four 9031 parts in the year-old edition of Chinese pharmacopoeia 2020. The results are shown in Table-4.
TABLE-4 comparison of Empagliflozin dissolution
The content uniformity detection result shows that: the RSD values of the products in the examples 1 and 2 at all time points are small (less than 10%), the RSD values of the products in the comparative examples 1 and 7 and the RSD values of the products in the metformin empagliflozin tablet sold at all time points of 5min, 10min and 15min (5min RSD is more than 20%, 10min RSD is more than 10% and 15min RSD is more than 5%), and the results show that the content uniformity of the products can be obviously improved, the RSD values of the products at all time points in a dissolution test are reduced, and the effectiveness and the safety of the products are improved.
Claims (4)
1. The metformin empagliflozin tablet is prepared from the following raw and auxiliary materials in parts by mass:
the metformin engelet tablet is a coated tablet, and other raw and auxiliary materials except the film coating premix are raw and auxiliary materials of a tablet core.
2. A process for preparing metformin empagliflozin tablet as claimed in claim 1, comprising the steps of:
(1) auxiliary material pretreatment: pulverizing the raw material medicines of the empagliflozin, sieving by a 80-mesh sieve, respectively sieving metformin hydrochloride and corn starch by a 40-mesh sieve, and sieving colloidal silicon dioxide by a 80-mesh sieve for treatment;
(2) premixing auxiliary materials: mixing metformin hydrochloride and corn starch; the feeding sequence is that 50% of metformin hydrochloride is added, corn starch is added, and the rest of metformin hydrochloride is added;
(3) fluid bed granulation:
a. preparing a granulating liquid: dissolving copovidone in purified water to obtain copovidone solution with the concentration of 21.2 percent (w/w), slowly adding the raw material medicine of the empagliflozin, and uniformly stirring and dispersing to obtain medicine-containing granulating liquid for later use;
b. and (3) granulating: placing the mixed metformin hydrochloride and corn starch in a fluidized bed, setting air inlet temperature to be 70-80 ℃, setting frequency of an induced draft fan to be 20Hz, starting preheating materials, spraying a drug-containing granulating liquid for granulation when the temperature of the materials is increased to be more than 45 ℃, setting the rotating speed of a liquid supply pump to be 50rpm, setting the sector pressure and the atomizing pressure to be 3bar/2bar respectively, controlling the temperature of the materials to be 40-50 ℃, closing heating and continuing spraying purified water after the granulating liquid is sprayed, and controlling the water content of granules to be 1.5% -2.5%;
(4) straightening: after drying, the particles are granulated by a screen with the diameter of 1.0mm to 1.5 mm;
(5) total mixing: adding the prescribed amount of colloidal silicon dioxide and magnesium stearate, and mixing;
(6) tabletting: tabletting by adopting a rotary tablet press, and controlling the pressure to be 3.0 KN-6.0 KN;
(7) coating: purified water and a film coating premix are taken to prepare a coating solution with the solid content of 13 percent (w/w), and the weight increment of the coating is controlled to be 2.0 to 5.0 percent.
3. The method of claim 2, wherein: in the step (2), the mixing is carried out in a column type hopper mixer at the rotating speed of 8r/min for 10 min.
4. The method of claim 2, wherein: in the step (3), the mixing time is 10 min.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4285894A1 (en) * | 2022-05-31 | 2023-12-06 | Sanovel Ilac Sanayi Ve Ticaret A.S. | A formulation of empagliflozin and metformin hydrochloride |
| EP4285893A1 (en) * | 2022-05-31 | 2023-12-06 | Sanovel Ilac Sanayi Ve Ticaret A.S. | A combination comprising empagliflozin and metformin hydrochloride |
| WO2023234901A1 (en) * | 2022-05-31 | 2023-12-07 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | A formulation comprising empagliflozin and metformin hydrochloride |
| WO2023234900A1 (en) * | 2022-05-31 | 2023-12-07 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | A tablet comprising empagliflozin and metformin hydrochloride |
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| CN106924237A (en) * | 2017-03-03 | 2017-07-07 | 杭州华东医药集团新药研究院有限公司 | A kind of pharmaceutical composition of and Metformin hydrochloride net containing En Gelie |
| 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 |
| CN113616624A (en) * | 2021-09-16 | 2021-11-09 | 南京康川济医药科技有限公司 | Empagliflozin metformin sustained release preparation and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| CN106924237A (en) * | 2017-03-03 | 2017-07-07 | 杭州华东医药集团新药研究院有限公司 | A kind of pharmaceutical composition of and Metformin hydrochloride net containing En Gelie |
| CN113616624A (en) * | 2021-09-16 | 2021-11-09 | 南京康川济医药科技有限公司 | Empagliflozin metformin sustained release preparation and preparation method thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4285894A1 (en) * | 2022-05-31 | 2023-12-06 | Sanovel Ilac Sanayi Ve Ticaret A.S. | A formulation of empagliflozin and metformin hydrochloride |
| EP4285893A1 (en) * | 2022-05-31 | 2023-12-06 | Sanovel Ilac Sanayi Ve Ticaret A.S. | A combination comprising empagliflozin and metformin hydrochloride |
| WO2023234901A1 (en) * | 2022-05-31 | 2023-12-07 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | A formulation comprising empagliflozin and metformin hydrochloride |
| WO2023234900A1 (en) * | 2022-05-31 | 2023-12-07 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | A tablet comprising empagliflozin and metformin hydrochloride |
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