A sustained-release formulation of saxagliptin and metformin and a preparation method thereof

Abstract

The application provides a slow-release preparation of saxagliptin and metformin and a preparation method thereof. The slow-release preparation of saxagliptin and metformin has the characteristics of slow release, can maintain sustained release within 24 hours, thereby maintaining a relatively stable blood drug concentration and a longer action time, reducing the frequency of taking medicine, improving the compliance of patients, and having good stability, simple process, high production efficiency and suitability for industrial mass production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical preparations, and particularly relates to a sustained-release formulation of saxagliptin metformin and a preparation method thereof. BACKGROUND

[0002] Saxagliptin (trade name Onglyza) is a competitive inhibitor of dipeptidyl peptidase 4 (DPP4), a drug for treating adult type II diabetes developed by American Bristol-Myers Squibb Pharmaceutical Company, which was approved for listing by the US FDA in March 2010, and was approved by the SFDA to enter the Chinese market in May 2011, and has advantages such as outstanding curative effect and long-lasting effect. Saxagliptin is a white to light yellow or light brown powder. It is slightly soluble in 95% ethanol and slightly soluble in water. Its chemical name is (1S, 3S, 5S)-2-[(2S)-2-amino-2-(3-hydroxy-l-adamantyl)-l-carbonyl ethyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile, monohydrate, and the structural formula is as shown below:

[0003]

[0004] Metformin Hydrochloride is a biguanide oral hypoglycemic drug, which is mainly used in the treatment of type II diabetes patients who are not satisfied with simple diet control, especially obese and high insulinemia patients. Metformin Hydrochloride is a white crystalline powder; odorless. The product is easily soluble in water, soluble in methanol, slightly soluble in ethanol, and insoluble in chloroform or diethyl ether. Its chemical name is 1, 1-dimethylbiguanide hydrochloride, and the structural formula is as shown below:

[0005]

[0006] The compound preparation of saxagliptin and metformin hydrochloride, in combination with diet and exercise treatment, is suitable for adult patients with type 2 diabetes treated with saxagliptin and metformin, so as to improve the blood glucose control of such patients. Saxagliptin metformin sustained-release tablets are first developed by AstraZeneca Pharmaceutical Company, and the main dosage form on the market is mainly double-layer tablet coating. The original preparation of saxagliptin layer adopts the preparation process of upper medicine coating, and the metformin hydrochloride layer selects the preparation process of wet granulation. After the prepared biguanide sustained-release granules are compressed into tablets, the saxagliptin layer is coated. The process flow time is long in scale-up production, and the coating process is complex. Since the specification of saxagliptin is small, the upper medicine coating method needs to be used, and the industrialized production is difficult, and the reproducibility is poor.

[0007] Patent CN102266325A discloses a preparation method of metformin crystal and a pharmaceutical composition of metformin and saxagliptin. The preparation method of the tablet needs to prepare metformin hydrochloride crystal first, then mix with other excipients, and then prepare the tablet together with the mixture of saxagliptin and excipients. The preparation process of metformin hydrochloride crystal is as follows: ① first prepare a metformin solution, and drop chloroform into the solution until it becomes turbid; ② ultrasonic and heat the above solution until the solution becomes clear; ③ let the product precipitate by standing the above solution, and vacuum dry to obtain metformin crystal. The process flow is complicated, and metformin crystal needs to be prepared separately. Chloroform needs to be used in the preparation process, which has certain toxicity. The temperature needs to be controlled during the standing process, and it takes 2-3 days, which leads to the extension of production time and the increase of overall production cost.

[0008] Compared with the prior art, metformin hydrochloride and saxagliptin are granulated respectively to prepare micro-tablets with different release speeds, and are filled respectively according to the dose, so that the process is simpler, the production efficiency is higher, the risk is smaller, and it is suitable for industrial mass production. SUMMARY

[0009] In view of the deficiencies of the prior art, the purpose of the present application is to provide a sustained-release preparation containing saxagliptin and metformin hydrochloride and a preparation method and application thereof.

[0010] The present application provides a sustained-release preparation containing saxagliptin and metformin hydrochloride, which is composed of metformin hydrochloride sustained-release micro-tablets and saxagliptin immediate-release micro-tablets, wherein the metformin hydrochloride sustained-release micro-tablets are composed of 40-70% metformin hydrochloride, 1-20% diluent, 1-10% binder, 10-50% sustained-release material and 0-10% glidant by weight percentage; and the saxagliptin immediate-release micro-tablets are composed of 3-15% saxagliptin, 70-90% filler, 1-20% disintegrant and 1-10% lubricant by weight percentage.

[0011] In some embodiments, the metformin hydrochloride sustained-release micro-tablets are composed of 53.2% metformin hydrochloride, 10.6% diluent, 2.1% binder, 31.9% sustained-release material and 2.2% glidant by weight percentage; and the saxagliptin immediate-release micro-tablets are composed of 8.3% saxagliptin, 83.4% filler, 5% disintegrant and 3.3% lubricant by weight percentage.

[0012] In some embodiments, the diluent in the metformin hydrochloride sustained-release micro-tablets is selected from any one or a combination of at least two of mannitol, lactose, microcrystalline cellulose or pregelatinized starch, and is preferably microcrystalline cellulose.

[0013] In some embodiments, the binder in the metformin hydrochloride sustained release microtablet is selected from one or more of povidone K30, hypromellose or dextrin; preferably povidone K30.

[0014] In some embodiments, the sustained release material in the metformin hydrochloride sustained release microtablet is selected from one or more of polyox, hypromellose K100M, methylcellulose or carbomer; preferably polyox, hypromellose K100M or methylcellulose.

[0015] In some embodiments, the glidant in the metformin hydrochloride sustained release microtablet is selected from one or more of talc, magnesium stearate or colloidal silicon dioxide; preferably a combination of magnesium stearate and colloidal silicon dioxide.

[0016] In some embodiments, the filler in the saxagliptin immediate release microtablet is selected from one or more of mannitol, lactose, microcrystalline cellulose or pregelatinized starch; preferably a combination of lactose and microcrystalline cellulose.

[0017] In some embodiments, the disintegrant in the saxagliptin immediate release microtablet is selected from one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, croscarmellose sodium or cross-linked polyvinyl pyrrolidone; preferably sodium carboxymethyl starch.

[0018] In some embodiments, the lubricant in the saxagliptin immediate release microtablet is selected from magnesium stearate.

[0019] In some typical embodiments, the saxagliptin metformin hydrochloride sustained release formulation consists of the following ingredients:

[0020] The saxagliptin immediate release microtablet consists of the following ingredients:

[0021]

[0022] The metformin hydrochloride sustained release microtablet consists of the following ingredients:

[0023]

[0024] In another aspect, the present application provides a method for preparing the saxagliptin metformin hydrochloride sustained release formulation, comprising the following steps: ① the raw material drug and excipients are pretreated;

[0025] ② the metformin hydrochloride sustained release microtablet is prepared by dry granulation process;

[0026] ③ the saxagliptin immediate release microtablet is prepared by full powder direct compression process;

[0027] ④ the prepared saxagliptin immediate release microtablet and metformin hydrochloride sustained release microtablet can be packaged separately for independent use, or the microtablet formulations are packed into capsules to prepare oral preparations in the form of capsules.

[0028] The saglitin metformin sustained release preparation of the present application has the diameter of 1-5 mm, preferably 2-4 mm.

[0029] The saglitin metformin sustained release preparation of the present application can be used independently as a new type of preparation (adopting double aluminum small bags for direct packaging) different from the common tablets, and the microtablet preparation can also be packed into capsules to prepare oral preparations in the form of capsules. The microtablet of the present application is preferably used independently as a new type of preparation.

[0030] The saglitin metformin sustained release preparation of the present application has the following advantages:

[0031] (1) The production process of the microtablet is simple and has good reproducibility, and can be prepared by using common preparation process and equipment.

[0032] (2) When the microtablet is used, the dosage of the drug needs to be adjusted, and the individualized medication scheme can be formulated according to the needs of the patient, and the microtablet is counted and taken, so that the dosage is more accurate.

[0033] (3) After the patient orally takes the microtablet, the microtablet is uniformly dispersed in the gastrointestinal tract, and the gastrointestinal transport and absorption of the drug is less affected by the gastric emptying rate, so that the individual difference is small.

[0034] (4) The microtablet also overcomes the problem of poor drug compliance, and for children and the elderly and other people who have difficulty in taking medicine, the microtablet can be taken with jam and bread.

[0035] (5) The prepared saglitin metformin sustained release microtablet can be used independently by using separate packaging, and the microtablet preparation can also be packed into capsules to prepare oral preparations in the form of capsules.

[0036] The saglitin metformin sustained release preparation of the present application has the characteristics of slow release, can maintain the sustained release within 24 h, thereby maintaining a relatively stable blood drug concentration and a longer action time, reducing the frequency of taking medicine, improving the patient compliance, and at the same time, the preparation process has good stability, the process is simple, the production efficiency is high, and it is suitable for industrial mass production. BRIEF DESCRIPTION OF DRAWINGS

[0037] Figure 1 The dissolution curve comparison chart of the preparations of Examples 1-3 and the commercially available saglitin metformin sustained release tablets (trade name: Anlig).

[0038] Figure 2 The release curve comparison chart of the preparations of Examples 1, 5, 6 and 7 and the commercially available saglitin metformin sustained release tablets (trade name: Anlig).

[0039] Figure 3 The release curve comparison chart of the preparations of Examples 1 and Comparative Example 1. DETAILED DESCRIPTION

[0040] In order for those skilled in the art to better understand the technical solutions of the present application, some non-limiting embodiments are further disclosed below to further illustrate the present application in detail.

[0041] The specific material proportions, process conditions and results described in the present application are only used to illustrate the present application, and should not and will not limit the present application described in detail in the claims.

[0042] Example 1

[0043]

[0044]

[0045] Preparation process:

[0046] a, Saxagliptin immediate-release tablet core: Saxagliptin and lactose are mixed uniformly by equal amount addition method, then microcrystalline cellulose and sodium carboxymethyl starch are mixed, and finally magnesium stearate is mixed uniformly, and tabletting is performed according to 10-30 mg / tablet.

[0047] b, Metformin hydrochloride sustained-release tablet core: Metformin hydrochloride is crushed, and the treated metformin hydrochloride, microcrystalline cellulose and povidone are mixed uniformly, and dry granulation is performed using a 1.2 mm screen. The metformin hydrochloride granules after dry granulation are mixed uniformly with additional excipients (polyethylene oxide, magnesium stearate and colloidal silicon dioxide), and tabletting is performed according to 10-30 mg / tablet.

[0048] c, according to the prescription amount, fill the saxagliptin immediate-release microtablet and metformin hydrochloride sustained-release microtablet into the capsule shell.

[0049] Example 2

[0050]

[0051] The filler of the saxagliptin immediate-release microtablet is microcrystalline cellulose, and the other prescription components and preparation process are the same as in Example 1.

[0052] Example 3

[0053]

[0054] The disintegrant of the saxagliptin immediate-release microtablet is cross-linked sodium carboxymethyl cellulose, and the preparation process is the same as in Example 1.

[0055] Example 4

[0056]

[0057] The binder of the metformin hydrochloride sustained-release microtablet is hydroxypropyl methyl cellulose E5, and the preparation process is the same as that of Example 1.

[0058] Example 5

[0059]

[0060] The sustained-release material of the metformin hydrochloride sustained-release microtablet is hydroxypropyl methyl cellulose K100M, and the preparation process is the same as that of Example 1.

[0061] Example 6

[0062]

[0063]

[0064] The sustained-release material of the metformin hydrochloride sustained-release microtablet is methyl cellulose, and the preparation process is the same as that of Example 1.

[0065] Example 7

[0066]

[0067] The sustained-release material of the metformin hydrochloride sustained-release microtablet is carbomer, and the preparation process is the same as that of Example 1.

[0068] Example 8

[0069]

[0070] Preparation process:

[0071] a. Saxagliptin immediate-release tablet core: Saxagliptin and lactose are uniformly mixed by equal amount addition method, then microcrystalline cellulose and sodium carboxymethyl starch are added and mixed, and finally magnesium stearate is added and mixed uniformly, and tabletting is performed according to 10-30 mg / tablet.

[0072] b. Metformin hydrochloride sustained-release tablet core: Metformin hydrochloride is pulverized, and the treated metformin hydrochloride, microcrystalline cellulose and povidone are uniformly mixed, and dry granulation is performed by using different screens (0.8 mm, 1.2 mm, 1.5 mm and 2.0 mm). The metformin hydrochloride granules after dry granulation are uniformly mixed with additional excipients (polyethylene oxide, magnesium stearate and colloidal silicon dioxide), and tabletting is performed according to 10-30 mg / tablet.

[0073] c. According to the prescription amount, saxagliptin immediate-release microtablet and metformin hydrochloride sustained-release microtablet are filled into the capsule shell.

[0074] Comparative Example 1

[0075]

[0076] Preparation process:

[0077] a. SGLT-1 granules: SGLT and lactose are mixed uniformly by equal incremental method, sprayed into purified water for wet granulation, dried, granulated, and mixed uniformly with lubricant to obtain SGLT-1 granules.

[0078] b. Metformin hydrochloride sustained-release granules: Metformin hydrochloride is crushed, and the crushed metformin hydrochloride and hydroxypropyl methyl cellulose are mixed uniformly, sprayed into purified water for wet granulation, dried, granulated, and mixed uniformly with lubricant to obtain metformin hydrochloride sustained-release granules.

[0079] c. The sustained-release mixed granules are used as the base material, and the immediate-release mixed granules are used as the additional material, and the double-layer tablet press is used to press the tablets to obtain SGLT-1 metformin hydrochloride double-layer tablets.

[0080] Test Example 1: Comparison of Examples 1-3

[0081] Test method for content uniformity:

[0082] Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Test 0512).

[0083] The test solution is prepared by taking an appropriate amount of the product in a conical flask, adding 50 ml of diluent (0.1 mol / L hydrochloric acid solution), ultrasonicating and shaking for 30 minutes to completely dissolve the SGLT tablet core, immediately taking an appropriate amount of the solution, centrifuging, filtering, and taking the filtrate as the test solution.

[0084] The control solution is prepared by taking an appropriate amount of SGLT control product, accurately weighing, dissolving and quantitatively diluting to prepare a solution containing about 0.1 mg per 1 ml.

[0085] Chromatographic conditions: octadecylsilane-bonded silica gel as the filler [chromatographic column: Waters C18 (250 mm x 3.9 mm, 3 μm) or a chromatographic column with equivalent performance]; methanol-water-trifluoroacetic acid (20:80:0.1) as the mobile phase; flow rate: 1.5 ml per minute; column temperature: 40℃; detection wavelength: 215 nm.

[0086] System suitability requirements: accurately measure the control solution, inject it into the liquid chromatograph, and record the chromatogram. The tailing factor of the SGLT peak should not be greater than 2.0.

[0087] Determination method: accurately measure 20 μl of the test solution and the control solution, respectively, inject them into the liquid chromatograph, and calculate by the external standard method with peak area.

[0088] The limit should meet the requirements (Chinese Pharmacopoeia 2020 Edition Part IV General Test 0941).

[0089] ​Dissolution test method in pH 6.8 phosphate buffer:

[0090] Determined according to the dissolution and release test method (Chinese Pharmacopoeia 2020 edition four general rules 0931 first method).

[0091] The dissolution conditions are as follows: 1000 ml of pH 6.8 phosphate buffer as the dissolution medium, rotation speed of 100 revolutions per minute, temperature of 37℃, and sampling at 5 minutes, 10 minutes, 15 minutes (for determination of saxagliptin), 1 hour, 3 hours, 5 hours, 7 hours, 10 hours and 12 hours (for determination of metformin hydrochloride) according to the law.

[0092] Reference solution

[0093] Take saxagliptin reference substance, accurately weigh, dissolve in dissolution medium and quantitatively dilute to prepare a solution containing about 2.5 μg per 1 ml.

[0094] Take metformin hydrochloride reference substance, accurately weigh, dissolve in dissolution medium and quantitatively dilute to prepare a solution containing about 1 mg per 1 ml.

[0095] The chromatographic conditions are as follows: see the determination of saxagliptin content uniformity.

[0096] Determination method: accurately take 100 μl of test solution and reference solution, respectively, inject into liquid chromatograph, record chromatogram, calculate the dissolution amount of each saxagliptin tablet by external standard method with saxagliptin peak area, and calculate the dissolution amount of each metformin hydrochloride tablet by external standard method with metformin hydrochloride peak area.

[0097] The results show that different types of fillers and filler compositions have an impact on the uniformity of saxagliptin immediate-release microtablets (Table 1), among which the tablet core content uniformity of the filler composition of lactose and microcrystalline cellulose is the best; the dissolution curves in pH 6.8 phosphate buffer have no significant difference (Table 2).

[0098] Table 1 Saxagliptin microtablets prepared by different types of fillers and filler compositions

[0099]

[0100]

[0101] Table 2 Release curves of saxagliptin immediate-release microtablets prepared by different types of fillers and filler compositions in pH 6.8 phosphate buffer (n = 6)

[0102]

[0103] Test example 2: comparison of examples 1, 5, 6 and 7

[0104] The results show (Table 3) that the release curves of the metformin hydrochloride sustained-release microtablets of Examples 1, 5, 6 and 7, which use different types of sustained-release materials, are significantly different in the pH 6.8 phosphate buffer solution. The release curve of the sustained-release microtablets using methyl cellulose as the sustained-release material is the slowest, the release curve of the sustained-release microtablets using carbomer as the sustained-release material is the fastest, and the release curves of the sustained-release microtablets using other different types of sustained-release materials are not significantly different.

[0105] Table 3 Release curves of sustained-release preparations using different types of sustained-release materials in a pH 6.8 phosphate buffer solution (n = 6)

[0106]

[0107] Test Example 3: Comparison of Comparative Example 1 and Example 1

[0108] The results show (Table 4) that the preparation of the sustained-release tablets of Comparative Example 1 is complex and requires more equipment, and because double-layer compression is required, the flowability and compressibility of the granules are required to be higher. The preparation of the saxagliptin immediate-release microtablets and the metformin hydrochloride sustained-release microtablets of Example 1 is simple, and the test indexes are all better. Comparative Example 1 and Example 5 use different preparation processes, and the results show that the release curve of the sustained-release preparation prepared in Example 1 in the pH 6.8 phosphate buffer solution can effectively control the sustained and slow release of the drug within 24 h to achieve the effect of sustained release.

[0109] Table 4 Release curves of metformin in sustained-release preparations using different preparation processes in a pH 6.8 phosphate buffer solution (n = 6)

[0110]

[0111] Test Example 4: Comparison of the powder properties of metformin granules prepared by dry granulators with different screen mesh sizes and the content uniformity of the microtablets

[0112] The results show that the granules with good flowability can be obtained by controlling the screen mesh size to be between 0.8 mm and 2.0 mm, and the content uniformity of the microtablets and pellets meets the requirements. The screen mesh with a pore size of 1.2 mm to 1.5 mm is preferably selected for the preparation of metformin granules.

[0113] Table 5 Comparison of the powder properties of metformin hydrochloride pellet cores prepared by extrusion and spheronization using different screen mesh sizes

[0114] Screen opening Loose density / g / ml Tapped density / g / ml Rest angle / ° 0.8 mm 0.701 0.753 43.4 1.0 mm 0.645 0.676 40.1 1.5 mm 0.590 0.646 38.7 2.0 mm 0.575 0.637 39.4

[0115] Table 6 Comparison of the content uniformity of the pellets prepared by extrusion and spheronization using different screen mesh sizes

[0116]

Claims

1. A formulation containing saxagliptin and metformin hydrochloride, wherein the formulation has the following composition: Saxagliptin immediate-release tablets: Saxagliptin 5mg Mannitol 20mg Microcrystalline cellulose 30mg Sodium carboxymethyl starch 3mg Magnesium stearate 2mg; Metformin hydrochloride sustained-release microtablets: Metformin Hydrochloride 500mg Microcrystalline cellulose 100mg Povidone K30 20mg 300mg of methylcellulose Magnesium stearate 10mg 10mg of collagen-peptide silica.

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