Pharmaceutical composition containing dapagliflozin and preparation method thereof

Abstract

The invention discloses a dapagliflozin-containing pharmaceutical composition and a preparation method thereof.According to the preparation composition, amorphous bulk drugs are adopted, prescription design is conducted, a freeze-dried orally disintegrating tablet which is stable and controllable in quality is obtained, the oral bioavailability is high, the effect is rapid, the oral compliance of a patient is improved, preparation is convenient and fast, and industrialization is easy.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition containing dapagliflozin and a preparation method thereof, and in particular to a pharmaceutical composition containing dapagliflozin with stable quality and a preparation method thereof. Background Art

[0002] Dapagliflozin ((1S)-1,5-anhydride-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol) is a SGLT2-specific inhibitor with stable biological activity. It can inhibit the SGLT2 receptors in the renal tubules, prevent glucose in the primary urine from being reabsorbed by the kidneys and returned to the blood, and promote the excretion of glucose in the urine. It is a first-line or second-line treatment for type 2 diabetes. Dapagliflozin can also be used for adult patients with heart failure to reduce the risk of cardiovascular death, hospitalization for heart failure, or emergency visits for heart failure in adult patients with symptomatic chronic heart failure.

[0003]

[0004] CN105555258 discloses a preparation of amorphous dapagliflozin. Since amorphous dapagliflozin has a low glass transition temperature and is very hygroscopic, pure amorphous dapagliflozin changes from powder to semisolid at room temperature due to moisture absorption, which will have an adverse effect on preparation processing. Although the patent adopts solid dispersion technology to improve the uniformity and stability of the preparation, since the preparation dosage form is an ordinary solid oral tablet, there are still problems of slow onset and poor oral compliance; at the same time, during the preparation process, dapagliflozin undergoes a crystal transformation due to moisture absorption, and the content is abnormal due to inaccurate weighing of the raw material. Summary of the invention

[0005] Purpose of the invention: The present invention aims to provide a freeze-dried oral fast-dissolving tablet preparation composition of amorphous dapagliflozin with stable quality and a preparation method thereof.

[0006] Technical solution: The pharmaceutical composition containing dapagliflozin described in the present invention comprises, by weight, 10 to 30 parts of dapagliflozin, 50 to 60 parts of skeleton materials, 10 to 15 parts of adhesives, 0 to 2 parts of suspending agents and 10 to 15 parts of lyoprotectants; wherein dapagliflozin is in an amorphous state.

[0007] The present invention utilizes the advantages of the solubility of the amorphous state and overcomes the defects of the stability of the amorphous state, and designs a dapagliflozin freeze-dried orally disintegrating tablet preparation composition with rapid onset, high bioavailability and good treatment compliance.

[0008] Preferably, the pharmaceutical composition containing dapagliflozin comprises, by weight, 14 to 26 parts of dapagliflozin, 51 to 59 parts of skeleton materials, 12 to 15 parts of binders, 0.2 to 0.3 parts of suspending agents and 10 to 12 parts of lyoprotectants.

[0009] Preferably, the pharmaceutical composition containing dapagliflozin comprises, by weight percentage, 14.7% to 25.6% of dapagliflozin, 12.8% to 14.7% of binder, 0.26% to 0.3% of suspending agent, 10.2% to 11.7% of lyoprotectant and the remainder of skeleton material.

[0010] Preferably, the skeleton material is selected from one or more of mannitol, lactose and polyvinyl alcohol.

[0011] More preferably, the skeleton material is selected from one of mannitol, lactose and polyvinyl alcohol.

[0012] Preferably, the adhesive is selected from one or more of gelatin, gum arabic and carrageenan.

[0013] More preferably, the binder is selected from gelatin.

[0014] Preferably, the suspending agent is selected from one or more of xanthan gum, sodium alginate and povidone.

[0015] More preferably, the suspending agent is selected from xanthan gum.

[0016] Preferably, the lyoprotectant is selected from one or more of sugars, alcohols, amino acids and salts.

[0017] Further preferably, the carbohydrate freeze-drying protective agent is selected from dextran, fructose, lactose, trehalose, fructan, maltodextrin, and maltopolysaccharide; the alcohol freeze-drying protective agent is selected from mannitol, sorbitol, ethanol, glycerol, and xylitol; the amino acid freeze-drying protective agent is selected from glycine, cysteine, and sodium glutamate; and the salt freeze-drying protective agent is selected from sodium sulfate, calcium lactate, potassium chloride, sodium chloride, ammonium acetate, and ammonium chloride.

[0018] More preferably, the lyoprotectant is selected from one or more of dextran, lactose, trehalose and sorbitol.

[0019] Still more preferably, the lyoprotectant is selected from dextran.

[0020] Preferably, the pharmaceutical composition containing dapagliflozin comprises, by weight, 10 to 30 parts of dapagliflozin, 50 to 60 parts of any one of mannitol, lactose, and polyvinyl alcohol, 10 to 15 parts of gelatin, 0 to 2 parts of xanthan gum, and 10 to 15 parts of dextran.

[0021] Preferably, the pharmaceutical composition containing dapagliflozin comprises, by weight percentage, 14.7% to 25.6% dapagliflozin, 12.8% to 14.7% gelatin, 0.26% to 0.3% xanthan gum, 10.2% to 11.7% dextran, and the remainder is any one of mannitol, lactose, and polyvinyl alcohol.

[0022] Preferably, the pharmaceutical composition containing dapagliflozin is selected from any one of the following compositions:

[0023] (1) Dapagliflozin amorphous form: 5 weight units, skeleton material: 20 weight units, binder: 5 weight units, suspending agent: 0.1 weight unit and lyoprotectant: 4 weight units;

[0024] (2) dapagliflozin amorphous form: 10 weight units, skeleton material: 20 weight units, binder: 5 weight units, suspending agent: 0.1 weight unit and lyoprotectant: 4 weight units;

[0025] Wherein, each component has the same weight unit.

[0026] More preferably, the pharmaceutical composition containing dapagliflozin is selected from any one of the following compositions:

[0027] (1) dapagliflozin amorphous form: 5 weight units, any one of mannitol, lactose, and polyvinyl alcohol: 20 weight units, gelatin: 5 weight units, xanthan gum: 0.1 weight unit, and dextran: 4 weight units;

[0028] (2) dapagliflozin amorphous form: 10 weight units, any one of mannitol, lactose, polyvinyl alcohol: 20 weight units, gelatin: 5 weight units, xanthan gum: 0.1 weight unit and dextran: 4 weight units;

[0029] Wherein, each component has the same weight unit.

[0030] More preferably, the pharmaceutical composition containing dapagliflozin is selected from any one of the following compositions:

[0031] (1) dapagliflozin amorphous form: 5 or 10 weight units, mannitol: 20 weight units, gelatin: 5 weight units, xanthan gum: 0.1 weight unit and dextran: 4 weight units;

[0032] (2) dapagliflozin amorphous form: 5 or 10 weight units, lactose: 20 weight units, gelatin: 5 weight units, xanthan gum: 0.1 weight unit and dextran: 4 weight units;

[0033] (3) dapagliflozin amorphous form: 5 or 10 weight units, polyvinyl alcohol: 20 weight units, gelatin: 5 weight units, xanthan gum: 0.1 weight unit and dextran: 4 weight units;

[0034] Wherein, each component has the same weight unit.

[0035] Specifically, the unit dosage form is selected from any one of the following:

[0036] Element content Dapagliflozin 5mg Mannitol 20mg gelatin 5mg Xanthan gum 0.1mg Dextran 4mg Purified water 265.9mg

[0037] or

[0038] Element content Dapagliflozin 5mg lactose 20mg gelatin 5mg Xanthan gum 0.1mg Dextran 4mg Purified water 265.9mg

[0039] or

[0040]

[0041]

[0042] or

[0043] Element content Dapagliflozin 10mg Mannitol 20mg gelatin 5mg Xanthan gum 0.1mg Dextran 4mg Purified water 260.9mg

[0044] or

[0045] Element content Dapagliflozin 10mg lactose 20mg gelatin 5mg Xanthan gum 0.1mg Dextran 4mg Purified water 260.9mg

[0046] or

[0047] Element content Dapagliflozin 10mg Polyvinyl alcohol 20mg gelatin 5mg Xanthan gum 0.1mg Dextran 4mg Purified water 260.9mg .

[0048] The method for preparing the pharmaceutical composition containing dapagliflozin of the present invention comprises the following steps:

[0049] (1) Preparation of drug solution

[0050] Dissolving or swelling the suspending agent in a pharmaceutically acceptable solvent, dissolving the binder and the skeleton material in a pharmaceutically acceptable solvent, adding the prepared suspending solution, and stirring evenly to obtain a first solution;

[0051] Dissolving dapagliflozin and a lyophilization protective agent in a pharmaceutically acceptable solvent, mixing the mixture evenly with the first solution, adding water to a prescribed amount, and stirring the mixture evenly to obtain the drug solution;

[0052] (2) Pre-freezing

[0053] Add the drug solution to the pharmaceutical packaging material in a quantitative manner and pre-freeze at -40 to -80°C for 10 to 30 minutes;

[0054] (3) Freeze-drying

[0055] Precooling: -40℃ precooling;

[0056] Primary drying: drying at -20℃ and 10-20pa for 1-2 hours;

[0057] Secondary drying: drying at 0℃ and 10-20pa for 2-3 hours;

[0058] Final drying: drying at 25° C. and 10-20 Pa for 1-2 hours to obtain the pharmaceutical composition containing dapagliflozin.

[0059] Preferably, the pharmaceutically acceptable solvent is selected from one or more of water and ethanol.

[0060] Preferably, the dissolution or swelling temperature of the suspending agent is 60°C.

[0061] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0062] The present invention adopts amorphous dapagliflozin and designs a freeze-dried orally disintegrating tablet with stable and controllable quality through prescription optimization. The preparation is directly packaged and formed after freeze-drying, avoiding quality problems such as moisture absorption causing crystal form and stability changes during the preparation process. At the same time, the patient's oral compliance is improved, and the preparation is convenient and easy to industrialize. For patients with heart failure, it takes effect quickly and can quickly achieve a therapeutic effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0063] Figure 1 This is the XRD spectrum of the crystal form detection of the amorphous dapagliflozin sample placed at room temperature;

[0064] Figure 2 This is the XRD spectrum of the crystal form detection of the amorphous dapagliflozin orally disintegrating tablets prepared in Example 1;

[0065] Figure 3 This is the XRD spectrum of the crystal form detection of dapagliflozin tablets prepared in Comparative Example 1. DETAILED DESCRIPTION

[0066] The technical solution of the present invention is further described below in conjunction with embodiments.

[0067] Example 1: 5 mg amorphous dapagliflozin freeze-dried orally disintegrating tablets and preparation method

[0068] 1. Prescription composition

[0069] Element content Dapagliflozin 5mg Mannitol 20mg gelatin 5mg Xanthan gum 0.1mg Dextran 4mg Purified water 265.9mg

[0070] 2. Preparation method

[0071] (1) Preparation of solutions or suspensions

[0072] ① Weigh the prescribed amount of xanthan gum and dissolve it in 50 mg of purified water. Dissolve or swell it in a 60°C water bath and stir it with a magnetic stirrer for later use.

[0073] ② Weigh the prescribed amount of gelatin and mannitol and dissolve them in 100 mg of purified water, then add the solution from step ① and stir evenly;

[0074] ③ Weigh the prescribed amount of dapagliflozin and dextran and dissolve them in 100 mg of purified water, stir well and set aside;

[0075] ④Mix ② and ③ evenly according to the prescribed amount, add purified water to the prescribed amount, and stir evenly;

[0076] ⑤ Pour the evenly mixed solution into the blister in a quantitative manner.

[0077] (2) Pre-freezing

[0078] Place the blister containing the drug solution in a -40°C to -80°C environment and pre-freeze for 10 to 30 minutes to freeze the drug solution into a solid state.

[0079] (3) Freeze-drying

[0080] Freeze drying curve

[0081] stage Shelf precooling One-time drying Secondary drying Drying end point Set temperature -40℃ -20℃ 0℃ 25℃ Duration N / A 1-2 hours 2-3 hours 1-2 hours Vacuum degree N / A 10~20pa 10~20pa 10~20pa

[0082] (4) Packaging

[0083] Cover the freeze-dried blisters with aluminum paper composite film, cut them, and print the batch number.

[0084] Example 2: 10 mg amorphous dapagliflozin freeze-dried orally disintegrating tablets and preparation method

[0085] 1. Prescription composition

[0086] Element content Dapagliflozin 10mg Mannitol 20mg gelatin 5mg Xanthan gum 0.1mg Dextran 4mg Purified water 260.9mg

[0087] 2. Preparation method

[0088] (1) Preparation of solutions or suspensions

[0089] ① Weigh the prescribed amount of xanthan gum and dissolve it in 50 mg of purified water. Dissolve or swell it in a 60°C water bath and stir it with a magnetic stirrer for later use.

[0090] ② Weigh the prescribed amount of gelatin and mannitol and dissolve them in 100 mg of purified water, then add the solution from step ① and stir evenly;

[0091] ③ Weigh the prescribed amount of dapagliflozin and dextran and dissolve them in 100 mg of purified water, stir well and set aside;

[0092] ④Mix ② and ③ evenly according to the prescribed amount, add purified water to the prescribed amount, and stir evenly;

[0093] ⑤ Pour the evenly mixed solution into the blister in a quantitative manner.

[0094] (2) Pre-freezing

[0095] Place the blister containing the drug solution in a -40°C to -80°C environment and pre-freeze for 10 to 30 minutes to freeze the drug solution into a solid state.

[0096] (3) Freeze-drying

[0097] Freeze drying curve

[0098] stage Shelf precooling One-time drying Secondary drying Drying end point Set temperature -40℃ -20℃ 0℃ 25℃ Duration N / A 1-2 hours 2-3 hours 1-2 hours Vacuum degree N / A 10~20pa 10~20pa 10~20pa

[0099] (4) Packaging

[0100] Cover the freeze-dried blisters with aluminum paper composite film, cut them, and print the batch number.

[0101] Example 3: 5 mg amorphous dapagliflozin freeze-dried orally disintegrating tablets and preparation method

[0102] 1. Prescription composition

[0103] Element content Dapagliflozin 5mg lactose 20mg gelatin 5mg Xanthan gum 0.1mg Dextran 4mg Purified water 265.9mg

[0104] 2. Preparation method

[0105] (1) Preparation of solutions or suspensions

[0106] ① Weigh the prescribed amount of xanthan gum and dissolve it in 50 mg of purified water. Dissolve or swell it in a 60°C water bath and stir it with a magnetic stirrer for later use.

[0107] ② Weigh the prescribed amount of gelatin and lactose and dissolve them in 100 mg of purified water, then add the solution from step ① and stir evenly;

[0108] ③ Weigh the prescribed amount of dapagliflozin and dextran and dissolve them in 100 mg of purified water, stir well and set aside;

[0109] ④Mix ② and ③ evenly according to the prescribed amount, add purified water to the prescribed amount, and stir evenly;

[0110] ⑤ Pour the evenly mixed solution into the blister in a quantitative manner.

[0111] (2) Pre-freezing

[0112] Place the blister containing the drug solution in a -40°C to -80°C environment and pre-freeze for 10 to 30 minutes to freeze the drug solution into a solid state.

[0113] (3) Freeze-drying

[0114] Freeze drying curve

[0115] stage Shelf precooling One-time drying Secondary drying Drying end point Set temperature -40℃ -20℃ 0℃ 25℃ Duration N / A 1-2 hours 2-3 hours 1-2 hours Vacuum degree N / A 10~20pa 10~20pa 10~20pa

[0116] (4) Packaging

[0117] Cover the freeze-dried blisters with aluminum paper composite film, cut them, and print the batch number.

[0118] Example 4: 10 mg dapagliflozin freeze-dried orally disintegrating tablets and preparation method

[0119] 1. Prescription composition

[0120] Element content Dapagliflozin 10mg lactose 20mg gelatin 5mg Xanthan gum 0.1mg Dextran 4mg Purified water 260.9mg

[0121] 2. Preparation method

[0122] (1) Preparation of solutions or suspensions

[0123] ① Weigh the prescribed amount of xanthocollagen and dissolve it in 50 mg of purified water. Dissolve or swell it in a 60℃ water bath and stir it with a magnetic stirrer for later use.

[0124] ② Weigh the prescribed amount of gelatin and lactose and dissolve them in 100 mg of purified water, then add the solution from step ① and stir evenly;

[0125] ③ Weigh the prescribed amount of dapagliflozin and dextran and dissolve them in 100 mg of purified water, stir well and set aside;

[0126] ④Mix ② and ③ evenly according to the prescribed amount, add purified water to the prescribed amount, and stir evenly;

[0127] ⑤ Pour the evenly mixed solution into the blister in a quantitative manner.

[0128] (2) Pre-freezing

[0129] Place the blister containing the drug solution in a -40°C to -80°C environment and pre-freeze for 10 to 30 minutes to freeze the drug solution into a solid state.

[0130] (3) Freeze-drying

[0131] Freeze drying curve

[0132] stage Shelf precooling One-time drying Secondary drying Drying end point Set temperature -40℃ -20℃ 0℃ 25℃ Duration N / A 1-2 hours 2-3 hours 1-2 hours Vacuum degree N / A 10~20pa 10~20pa 10~20pa

[0133] (4) Packaging

[0134] Cover the freeze-dried blisters with aluminum paper composite film, cut them, and print the batch number.

[0135] Example 5: 5 mg amorphous dapagliflozin freeze-dried orally disintegrating tablets and preparation method

[0136] 1. Prescription composition

[0137]

[0138]

[0139] 2. Preparation method

[0140] (1) Preparation of solutions or suspensions

[0141] ① Weigh the prescribed amount of xanthan gum and dissolve it in 50 mg of purified water. Dissolve or swell it in a 60°C water bath and stir it with a magnetic stirrer for later use.

[0142] ② Weigh the prescribed amount of gelatin and polyvinyl alcohol and dissolve them in 100 mg of purified water, then add the solution from step ① and stir evenly;

[0143] ③ Weigh the prescribed amount of dapagliflozin and dextran and dissolve them in 100 mg of purified water, stir well and set aside;

[0144] ④Mix ② and ③ evenly according to the prescribed amount, add purified water to the prescribed amount, and stir evenly;

[0145] ⑤ Pour the evenly mixed solution into the blister in a quantitative manner.

[0146] (2) Pre-freezing

[0147] Place the blister containing the drug solution in a -40°C to -80°C environment and pre-freeze for 10 to 30 minutes to freeze the drug solution into a solid state.

[0148] (3) Freeze-drying

[0149] Freeze drying curve

[0150] stage Shelf precooling One-time drying Secondary drying Drying end point Set temperature -40℃ -20℃ 0℃ 25℃ Duration N / A 1-2 hours 2-3 hours 1-2 hours Vacuum degree N / A 10~20pa 10~20pa 10~20pa

[0151] (4) Packaging

[0152] Cover the freeze-dried blisters with aluminum paper composite film, cut them, and print the batch number.

[0153] Example 6: 10 mg amorphous dapagliflozin freeze-dried orally disintegrating tablets and preparation method

[0154] 1. Prescription composition

[0155] Element content Dapagliflozin 10mg Polyvinyl alcohol 20mg gelatin 5mg Xanthan gum 0.1mg Dextran 4mg Purified water 260.9mg

[0156] 2. Preparation method

[0157] (1) Preparation of solutions or suspensions

[0158] ① Weigh the prescribed amount of xanthan gum and dissolve it in 50 mg of purified water. Dissolve or swell it in a 60°C water bath and stir it with a magnetic stirrer for later use.

[0159] ② Weigh the prescribed amount of gelatin and polyvinyl alcohol and dissolve them in 100 mg of purified water, then add the solution from step ① and stir evenly;

[0160] ③ Weigh the prescribed amount of dapagliflozin and dextran and dissolve them in 100 mg of purified water, stir well and set aside;

[0161] ④Mix ② and ③ evenly according to the prescribed amount, add purified water to the prescribed amount, and stir evenly;

[0162] ⑤ Pour the evenly mixed solution into the blister in a quantitative manner.

[0163] (2) Pre-freezing

[0164] Place the blister containing the drug solution in a -40°C to -80°C environment and pre-freeze for 10 to 30 minutes to freeze the drug solution into a solid state.

[0165] (3) Freeze-drying

[0166] Freeze drying curve

[0167] stage Shelf precooling One-time drying Secondary drying Drying end point Set temperature -40℃ -20℃ 0℃ 25℃ Duration N / A 1-2 hours 2-3 hours 1-2 hours Vacuum degree N / A 10~20pa 10~20pa 10~20pa

[0168] (4) Packaging

[0169] Cover the freeze-dried blisters with aluminum paper composite film, cut them, and print the batch number.

[0170] Comparative Example 1: Preparation of 10 mg dapagliflozin tablets according to the method of CN105555258

[0171] 1. Preparation of adsorption composition

[0172] Element content Dapagliflozin 10mg Microcrystalline Cellulose PH101 266mg

[0173] 5 g of amorphous dapagliflozin was dissolved in a mixture of 200 ml of tert-butyl methyl ether, 400 ml of chloroform, and 400 ml of hexane. 532 g of microcrystalline cellulose PH101 (Avicel PH 101) was added to the solution and stirred. The solvent was slowly removed under reduced pressure over 1 hour, and the solvent was further removed at 50° C. and 10 mbar.

[0174] 2. Preparation of tablet composition

[0175] Element content Dapagliflozin adsorbent 138mg Microcrystalline Cellulose 50mg Croscarmellose Sodium 10mg Magnesium Stearate 2mg

[0176] The prescribed amount of dapagliflozin adsorbate, microcrystalline cellulose, and cross-linked carboxymethyl cellulose sodium are mixed and sieved, and then the prescribed amount of magnesium stearate is added and mixed, and then the prepared final mixture is compressed into tablets.

[0177] Comparative Example 2: Preparation of 5 mg dapagliflozin tablets according to the method of CN105555258

[0178] 1. Preparation of adsorption composition

[0179] Element content Dapagliflozin 5mg Microcrystalline Cellulose PH101 133mg

[0180] 5 g of amorphous dapagliflozin was dissolved in a mixture of 200 ml of tert-butyl methyl ether, 400 ml of chloroform, and 400 ml of hexane. 532 g of microcrystalline cellulose PH101 (Avicel PH 101) was added to the solution and stirred. The solvent was slowly removed under reduced pressure over 1 hour, and the solvent was further removed at 50° C. and 10 mbar.

[0181] 2. Tablet composition

[0182] Element content Dapagliflozin adsorbent 138mg Microcrystalline Cellulose 50mg Croscarmellose Sodium 10mg Magnesium Stearate 2mg

[0183] The prescribed amount of dapagliflozin adsorbate, microcrystalline cellulose, and cross-linked carboxymethyl cellulose sodium are mixed and sieved, and then the prescribed amount of magnesium stearate is added and mixed, and then the prepared final mixture is compressed into tablets.

[0184] Example 7: Quality evaluation of freeze-dried orally disintegrating tablets

[0185] Carry out relevant tests in accordance with existing test methods and the test methods recorded in the general technical requirements of the Chinese Pharmacopoeia.

[0186] 1. Initial quality evaluation

[0187] The orally disintegrating tablets after freeze-drying were tested for appearance, content, related substances and disintegration time. The results are as follows:

[0188] Sample source Appearance evaluation content(%) Total impurities (%) Disintegration time(s) Example 1 The flakes are full and bulge in the center 100.3 0.12 5 Example 2 The flakes are full and bulge in the center 102.9 0.10 5 Example 3 The flakes are full and bulge in the center 101.4 0.10 4 Example 4 The flakes are full and bulge in the center 102.3 0.13 5 Example 5 The flakes are full and bulge in the center 100.8 0.14 8 Example 6 The flakes are full and bulge in the center 101.9 0.15 6

[0189] 2. Stability evaluation

[0190] The freeze-dried orally disintegrating tablets were placed at 40°C and 75% RH. After 3 months, samples were taken to determine their appearance, content, related substances, and disintegration time. The results are as follows:

[0191] Sample source Appearance content(%) Total impurities (%) Disintegration time(s) Example 1 The flakes are full and bulge in the center 100.3 0.15 6 Example 2 The flakes are full and bulge in the center 102.9 0.16 6 Example 3 The flakes are full and bulge in the center 101.4 0.16 5 Example 4 The flakes are full and bulge in the center 102.3 0.18 5 Example 5 The flakes are full and bulge in the center 101.3 0.23 5 Example 6 The flakes are full and bulge in the center 100.9 0.25 7 Comparative Example 1 / 98.3 0.40 259s Comparative Example 2 / 99.6 0.52 310s

[0192] 3. Crystal form evaluation

[0193] Sample source Crystal form evaluation results Amorphous dapagliflozin sample placed at room temperature for 1 day The characteristic peaks of dapagliflozin hydrate crystal form exist Example 1 Stability Evaluation of Day 0 Sample No characteristic peaks of dapagliflozin hydrate crystal form Comparative Example 1 0-day sample for stability evaluation The characteristic peaks of dapagliflozin hydrate crystal form exist

[0194] Depend on Figure 1 to Figure 3 It can be seen that in the XRD detection patterns of the amorphous raw material and the preparation prepared in Comparative Example 1, hydrate characteristic peaks appeared at 7.6±0.2°~8.7±0.2° ( Figure 1 : 7.554°, 8.060°, 8.701°, Figure 2: 7.639°, 8.145°, 8.783°), indicating that the preparation composition designed by the present invention and the preparation method thereof are more conducive to maintaining the initial amorphous solid form of the raw material drug, thereby facilitating the rapid onset of the preparation in vivo.

[0195] In summary, the formulation formula and preparation process designed by the present invention can obtain amorphous dapagliflozin freeze-dried orally disintegrating tablets with complete dissolution, uniform content and controllable quality. Further in the stability study, its stability is better than that of amorphous ordinary tablets. In the crystal form evaluation, the crystal form of the freeze-dried orally disintegrating tablets prepared by the present invention did not change, while the ordinary tablets prepared in the comparative example underwent a crystal form transformation.

Claims

1. A pharmaceutical composition containing dapagliflozin, characterized in that: In parts by weight, it comprises 10 to 30 parts of dapagliflozin, 50 to 60 parts of skeleton materials, 10 to 15 parts of adhesives, 0 to 2 parts of suspending agents and 10 to 15 parts of lyophilization protectants; wherein dapagliflozin is in an amorphous state.

2. The pharmaceutical composition containing dapagliflozin according to claim 1, characterized in that In parts by weight, the composition comprises 14 to 26 parts of dapagliflozin, 51 to 59 parts of skeleton materials, 12 to 15 parts of adhesives, 0.2 to 0.3 parts of suspending agents and 10 to 12 parts of freeze-drying protective agents.

3. The pharmaceutical composition containing dapagliflozin according to claim 1, characterized in that: Calculated by weight percentage, the composition comprises 14.7% to 25.6% of dapagliflozin, 12.8% to 14.7% of a binder, 0.26% to 0.3% of a suspending agent, 10.2% to 11.7% of a lyophilizing protectant and the remainder of a skeleton material.

4. The pharmaceutical composition containing dapagliflozin according to claim 1, characterized in that: The skeleton material is selected from one or more of mannitol, lactose and polyvinyl alcohol.

5. The pharmaceutical composition containing dapagliflozin according to claim 1, characterized in that: The adhesive is selected from one or more of gelatin, gum arabic and carrageenan.

6. The pharmaceutical composition containing dapagliflozin according to claim 1, characterized in that: The suspending agent is selected from one or more of xanthan gum, sodium alginate and povidone.

7. The pharmaceutical composition containing dapagliflozin according to claim 1, characterized in that: The freeze-drying protective agent is selected from one or more of dextran, lactose, trehalose and sorbitol.

8. The pharmaceutical composition containing dapagliflozin according to claim 1, characterized in that: Select any one of the following compositions: (1) Dapagliflozin amorphous form: 5 weight units, skeleton material: 20 weight units, binder: 5 weight units, suspending agent: 0.1 weight unit and lyoprotectant: 4 weight units; (2) Dapagliflozin amorphous form: 10 weight units, skeleton material: 20 weight units, binder: 5 weight units, suspending agent: 0.1 weight unit and lyophilization protective agent: 4 weight units.

9. The pharmaceutical composition containing dapagliflozin according to claim 8, characterized in that: Select any one of the following compositions: (1) dapagliflozin amorphous form: 5 weight units, any one of mannitol, lactose, and polyvinyl alcohol: 20 weight units, gelatin: 5 weight units, xanthan gum: 0.1 weight unit, and dextran: 4 weight units; (2) The amorphous form of dapagliflozin: 10 weight units, any one of mannitol, lactose and polyvinyl alcohol: 20 weight units, gelatin: 5 weight units, xanthan gum: 0.1 weight unit and dextran: 4 weight units.

10. The pharmaceutical composition containing dapagliflozin according to claim 9, characterized in that: Select any one of the following compositions: (1) dapagliflozin amorphous form: 5 or 10 weight units, mannitol: 20 weight units, gelatin: 5 weight units, xanthan gum: 0.1 weight unit and dextran: 4 weight units; (2) dapagliflozin amorphous form: 5 or 10 weight units, lactose: 20 weight units, gelatin: 5 weight units, xanthan gum: 0.1 weight unit and dextran: 4 weight units; (3) Dapagliflozin amorphous form: 5 or 10 weight units, polyvinyl alcohol: 20 weight units, gelatin: 5 weight units, xanthan gum: 0.1 weight unit and dextran: 4 weight units.

11. A method for preparing the pharmaceutical composition containing dapagliflozin according to claim 1, characterized in that: The following steps are involved: (1) Preparation of drug solution Dissolving or swelling the suspending agent in water, dissolving the binder and the skeleton material in water, adding the prepared suspending solution, and stirring evenly to obtain a first solution; Dissolve dapagliflozin and lyophilization protective agent in water, mix evenly with the first solution, add water to a predetermined amount to the prescribed amount, and stir evenly to obtain the drug solution; (2) Pre-freezing Add the drug solution to the pharmaceutical packaging material in a quantitative manner and pre-freeze at -40 to -80°C for 10 to 30 minutes; (3) Freeze-drying Precooling: -40℃ precooling; Primary drying: drying at -20℃ and 10-20pa for 1-2 hours; Secondary drying: drying at 0℃ and 10-20pa for 2-3 hours; Final drying: drying at 25° C. and 10-20 Pa for 1-2 hours to obtain the pharmaceutical composition containing dapagliflozin.

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