An empagliflozin pharmaceutical composition and preparation method thereof

Abstract

The present invention provides an empagliflozin pharmaceutical composition and a preparation method thereof, which comprises empagliflozin and pharmaceutically acceptable excipients. By screening specific excipients, especially the ratio of microcrystalline cellulose to mannitol, the prepared pharmaceutical composition can achieve higher dissolution and has better stability.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and specifically relates to an empagliflozin pharmaceutical composition and a preparation method thereof. Background Art

[0002] Diabetes is a chronic disease characterized by high blood sugar, caused by absolute or relative insulin deficiency and utilization disorder. The disease is mainly divided into three types: type 1, type 2 and gestational diabetes. The cause is mainly attributed to the endocrine and metabolic syndrome of sugar, protein, fat, water and electrolyte metabolism disorders in the body caused by the combined effects of genetic and environmental factors, which lead to reduced insulin secretion or defective insulin action. According to statistics, there are currently about 438 million people suffering from diabetes worldwide, and the incidence and prevalence of diabetes are on the rise worldwide.

[0003] Empagliflozin is an oral sodium-glucose co-transporter-2 (SGLT-2) inhibitor. SGLT2 is mainly expressed in the anterior SI segment of the renal proximal tubule, and more than 90% of glucose reabsorption is responsible for SGLT2 there. Therefore, inhibiting SGLT2 can inhibit sugar reabsorption, thereby allowing sugar to be excreted through urine and reducing the concentration of sugar in the blood.

[0004] Empagliflozin has low solubility and belongs to Class III drugs in the biopharmaceutics classification system. It may have problems affecting drug absorption due to its slow dissolution rate. In addition, due to the unique chemical structure and properties of the drug, it has poor chemical stability, which will affect the quality of the drug and may cause safety issues. Therefore, improving the solubility and stability of empagliflozin is a problem to be solved in the formulation process.

[0005] Patent CN104586803A discloses a method for preparing an empagliflozin microcrystalline cellulose composition using hot melt granulation technology. The high-temperature melting conditions can easily change the crystal state of the raw material, thereby changing the physical and chemical properties of empagliflozin and affecting the drug stability and efficacy.

[0006] Patent CN106692069A discloses that empagliflozin and povidone are dissolved in an organic solvent and a solid dispersion is prepared by solvent evaporation or spray drying. This method requires strict control of the residual organic solvent and is prone to explosion during high-temperature drying. The volatilization of the organic solution will bring certain toxic hazards to the health of the operators. This method not only poses a production safety hazard, but also does not conform to the trend of environmental friendliness.

[0007] Patent CN107281145A discloses an inclusion compound tablet of empagliflozin, which needs to be specially prepared into a corresponding inclusion compound with cyclodextrin in a solution state. The process conditions are harsh, and β-cyclodextrin is unstable and easily converted into glucose in the body, so it is not suitable for diabetic patients.

[0008] Chinese patent CN105147662A discloses a preparation of empagliflozin tablets. The preparation disclosed in the patent has a certain particle size range, and the particle size range D90 is controlled to be less than 200 μm. The particle size control range in the claims is too wide, which is not conducive to production quality control. When the particle size range is below 63 μm, the productivity during tableting will be affected due to adhesion or film formation, and the continuity and stability during production cannot be guaranteed.

[0009] Therefore, it is still necessary to provide a preparation process which is simple to operate, has a fast dissolution rate, good stability, and is suitable for large-scale production. Summary of the invention

[0010] In view of the deficiencies of the prior art, the present invention provides an empagliflozin pharmaceutical composition and a preparation method thereof. The empagliflozin pharmaceutical composition provided by the present invention has excellent performance, good particle fluidity, stable properties, rapid dissolution, complete dissolution, simple preparation process, and is easy for industrial production.

[0011] To achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0012] A pharmaceutical composition comprising empagliflozin, sodium lauryl sulfate, a filler, a disintegrant and a binder, wherein the weight ratio of each component is as follows:

[0013] .

[0014] Wherein, the disintegrants are sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose.

[0015] In a preferred embodiment of the present invention, the weight percentages of the components of the pharmaceutical composition are as follows:

[0016] .

[0017] In a preferred embodiment of the present invention, the weight percentages of the components of the pharmaceutical composition are as follows:

[0018] .

[0019] In a preferred embodiment of the present invention, the weight ratio of sodium lauryl sulfate is 0.5-1.5%, preferably 0.5%, 1% or 1.5%, and more preferably 1%.

[0020] In a preferred embodiment of the present invention, the disintegrant is selected from one or more of cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl starch, preferably sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose. The weight ratio of sodium carboxymethyl starch to low-substituted hydroxypropyl cellulose is 1-5:5-1, preferably 1-4:1, more preferably 2-3:1, and further preferably 3:1.

[0021] In a preferred embodiment of the present invention, the filler is selected from one or more of lactose, microcrystalline cellulose, sorbitol, mannitol or pregelatinized starch; preferably one or more of microcrystalline cellulose, lactose or mannitol, more preferably a mixture of microcrystalline cellulose and mannitol, wherein the ratio of microcrystalline cellulose to mannitol is 1-4:1, preferably 2-3:1, more preferably or 5:3 or 3:1.

[0022] In a preferred embodiment of the present invention, the binder is selected from one or more of povidone, copovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose or hydroxyethyl methyl cellulose, preferably one or more of povidone or hydroxypropyl cellulose; more preferably povidone.

[0023] In a preferred embodiment of the present invention, a lubricant is further included, and the lubricant is selected from one or more of talc, stearic acid, sodium stearyl fumarate, glyceryl behenate or magnesium stearate, preferably magnesium stearate.

[0024] In a preferred embodiment of the present invention, a glidant is further included, and the glidant is selected from one of talc and colloidal silicon dioxide or a mixture thereof, preferably colloidal silicon dioxide.

[0025] In a preferred embodiment of the present invention, when containing 10 mg of empagliflozin, the raw materials and auxiliary materials are included in the following weight percentages:

[0026] .

[0027] In a preferred embodiment of the present invention, the following raw materials are included in weight percentage:

[0028] .

[0029] In a preferred embodiment of the present invention, the following raw materials are included in weight percentage:

[0030] .

[0031] In a preferred embodiment of the present invention, the weight percentage of sodium lauryl sulfate is 1%.

[0032] The pharmaceutical composition of the present invention is intended for oral administration, wherein the dosage form is selected from powders, sachets, stick packs, capsules, mini-tablets or tablets, preferably capsules and tablets, more preferably tablets, more preferably ordinary tablets.

[0033] On the other hand, the present invention provides a method for preparing an empagliflozin pharmaceutical composition, the preparation method adopts wet granulation, dry granulation or mixed direct compression, preferably wet granulation.

[0034] The above technical solution has the following technical effects:

[0035] 1. It has a relatively stable process, a smooth production process, good reproducibility, good fluidity of intermediate particles, and good content uniformity and mixing uniformity;

[0036] 2. High solubility. The cumulative dissolution of the prescription tablets is ≥85% at 15 minutes. It can dissolve quickly and completely, and can achieve high solubility without the need for special preparations;

[0037] 3. The product has high quality, good reproducibility and good stability. Under the conditions of 40℃±2℃ / RH75%±5% accelerated test and 30℃±2℃ / RH65%±5% long-term test, the quality indicators of the samples did not change significantly, the maximum unknown single impurity was <0.1%, and the total impurity level was <0.2%. DETAILED DESCRIPTION

[0038] In order to better illustrate the present invention, the present invention will be further described below in conjunction with specific embodiments, but the protection content of the present invention is not limited to the embodiments.

[0039] Example 1: Screening of fillers for the empagliflozin pharmaceutical composition. The specific example prescription is shown in Table 1.

[0040] Table 1

[0041]

[0042] The preparation of the empagliflozin pharmaceutical composition comprises the following steps: empagliflozin, microcrystalline cellulose, lactose, mannitol, sodium carboxymethyl starch, and povidone are weighed according to the prescription amount and mixed evenly, 65 mg of purified water is added as a wetting agent to prepare a soft material, and after drying, dry granulation is performed, and after granulation, magnesium stearate and colloidal silicon dioxide are added to mix, and after mixing evenly, tableting or capsule filling is performed.

[0043] Dissolution determination method: Refer to the "General Rules of Part IV of the 2020 Edition of the Chinese Pharmacopoeia 0931 Method 1" and the "Technical Guidelines for Dissolution Test of Ordinary Solid Preparations" for dissolution studies, and evaluate according to the following dissolution method: paddle method (with sinker), rotation speed 50 rpm, medium temperature: 37±0.5℃, target medium is pH 4.5 acetate buffer medium.

[0044] The results showed that when microcrystalline cellulose and mannitol were used as co-fillers, the dissolution was more complete.

[0045] Example 2: Screening of disintegrants for the empagliflozin pharmaceutical composition. The specific example prescription is shown in Table 2.

[0046] Table 2

[0047]

[0048] The preparation of the empagliflozin pharmaceutical composition is as in Example 1.

[0049] The dissolution determination method is shown in Example 1.

[0050] The results showed that when sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose were used as disintegrants, the dissolution of empagliflozin tablets was greater than 90% in 30 minutes, the dissolution rate was faster, and the dissolution was more complete.

[0051] Example 3: Screening of the dosage of sodium dodecyl sulfate in the empagliflozin pharmaceutical composition. The specific example prescription is shown in Table 3.

[0052] Table 3

[0053]

[0054] The preparation of the empagliflozin pharmaceutical composition is as in Example 1.

[0055] The dissolution determination method is shown in Example 1.

[0056] The results showed that after adding 0.5-1.5% sodium dodecyl sulfate to the empagliflozin drug composition, the dissolution rate was faster and the dissolution was more complete.

[0057] Example 4: The flowability, mixing uniformity and content uniformity of empagliflozin particles were measured. The results are shown in Table 4.

[0058] Table 4

[0059]

[0060] The results show that the particles have good fluidity, good mixing uniformity and good content uniformity as shown by the Carr index and Hausner ratio.

[0061] Example 5: Stability study of empagliflozin in compositions 11, 12 and 13.

[0062] Tablets prepared from compositions 11, 12 and 13 were subjected to stability studies under accelerated test (40°C / RH75%) and long-term test (30°C / RH65%) conditions, with content and related substance levels as evaluation indicators. The results are shown in Tables 5A-5B.

[0063] Table 5A Results of the study on the stability (40°C / RH75%) of empagliflozin for compositions 11, 12 and 13

[0064]

[0065] Table 5B Results of the study on the stability (30°C / RH65%) of Engliflozin for compositions 11, 12 and 13

[0066]

[0067] The results show that under the long-term accelerated test conditions, the pharmaceutical composition of the present invention has no significant changes in the relevant substances and contents compared with the results on day 0, has good stability, and meets the quality standards.

Claims

1. An empagliflozin pharmaceutical composition, characterized in that: The weight percentage of each component is as follows: Empagliflozin 2%-8% Sodium lauryl sulfate 0.5%-1.5% Microcrystalline cellulose 50%-70% Mannitol 12%-25% Sodium carboxymethyl starch 3%-10% Low substituted hydroxypropyl cellulose 1%-8% Povidone 2%-10% Magnesium stearate 0.5%-3% Colloidal silicon dioxide 0.3%-3%; The ratio of microcrystalline cellulose to mannitol is 2-3:1; The weight ratio of sodium carboxymethyl starch to low-substituted hydroxypropyl cellulose is 1-4:1; The pharmaceutical composition is a common tablet.

2. The pharmaceutical composition according to claim 1, characterized in that The weight percentage of each component is as follows: Empagliflozin 3%-6% Sodium dodecyl sulfate 0.5%-1% Microcrystalline cellulose 55%-65% Mannitol 18%-23% Sodium carboxymethyl starch 5%-10% Low substituted hydroxypropyl cellulose 1%-5% Povidone 2%-8% Magnesium stearate 1%-2% Colloidal silicon dioxide 0.3%-1%.

3. The pharmaceutical composition according to claim 1, characterized in that The weight ratio of sodium carboxymethyl starch to low-substituted hydroxypropyl cellulose is 2-3:

1.

4. The pharmaceutical composition according to claim 1, characterized in that The ratio of microcrystalline cellulose to mannitol is 3:

1.

5. A method for preparing the empagliflozin pharmaceutical composition according to claim 1, characterized in that: The preparation method adopts wet granulation, dry granulation or mixed direct compression.

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