A solid dispersion of tolvaptan and a method for preparing the same

Abstract

The application discloses a solid dispersion of tolvaptan, and the raw material composition of the solid dispersion comprises tolvaptan, a hydrophilic carrier material, a hydrogen carbonate, and can further comprise a plasticizer and / or an organic acid. The solid dispersion is prepared by a hot melt extrusion process, the solubility of tolvaptan raw material can be obviously increased, and the oral preparation prepared from the solid dispersion can meet the sink condition of dissolution detection, and the accuracy of the detection result is ensured.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a solid dispersion of tolvaptan and a method for preparing the solid dispersion. Background Technology

[0002] Tolvaptan is a selective angiotensin V2 receptor antagonist that was approved by the FDA in 2009 for the treatment of clinically significant hypervolemia and hyponatremia with normal blood volume, including heart failure, cirrhosis, and antidiuretic hormone secretion syndrome.

[0003] The chemical name of tolvaptan is N-[4-[(5R)-7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1-benzozazepine-1-formyl]-3-methylphenyl]-2-methylbenzamide, and its structural formula is as follows:

[0004]

[0005] In the biopharmaceutics classification system, tolvaptan belongs to BCS class IV, which is classified as a low-solubility, low-permeability drug. Its extremely low water solubility leads to poor gastrointestinal absorption, which in turn affects bioavailability. Therefore, improving the solubility of tolvaptan has always been a key issue to be addressed in its formulation preparation.

[0006] Existing technologies employ various methods to address the low solubility of tolvaptan, but they still have various shortcomings, such as:

[0007] Patent CN102114001A discloses an oral solid dosage form containing tolvaptan. This patent involves micronizing the tolvaptan active pharmaceutical ingredient, reducing the particle size of over 90% of the raw material particles to less than 75 micrometers, thereby improving the solubility and dissolution rate of tolvaptan. However, due to the poor solubility of the tolvaptan raw material's crystal form, the method of increasing the specific surface area with the solvent through micronization has limited effectiveness in improving dissolution and is not ideal.

[0008] Patent CN101919864A discloses a tolvaptan pharmaceutical composition and its preparation method. The composition consists of tolvaptan, hydroxypropyl betacyclodextrin, microcrystalline cellulose pH102, cross-linked polyvinylpyrrolidone, pregelatinized starch, lactose, and magnesium stearate. The preparation process requires the raw materials to be processed by air jet milling, which is a complex process that is not conducive to industrialization.

[0009] Patent CN101686941A discloses a solid pharmaceutical preparation containing benzozazepine and its manufacturing method. The solid preparation comprises tolvaptan and / or its salt, hydroxypropyl cellulose containing 50% by weight or more of hydroxypropoxylated components, and at least one component selected from carboxymethyl cellulose, sodium carboxymethyl starch, crospovidone, and low-substituted hydroxypropyl cellulose having an average particle size of 30-70 μm and a 90% cumulative particle size of 100-200 μm. In the preparation of this solid preparation, tolvaptan and hydroxypropyl cellulose are dissolved in a mixed solvent of dichloromethane and lower alcohols and spray-dried to form an amorphous composition to improve its solubility.

[0010] Patent CN102406622A discloses a solid dosage form of tolvaptan, which includes tolvaptan or its pharmaceutically acceptable salt and a carrier. In preparation, tolvaptan or its pharmaceutically acceptable salt and the carrier need to be dissolved together in an organic solvent, and then the solvent is removed by drying the solution.

[0011] Patent CN102470178A discloses a tolvaptan solid dispersion and its preparation method, wherein the solid dispersion comprises tolvaptan and cross-linked polyvinylpyrrolidone. In the preparation process of this solid dispersion, tolvaptan needs to be dissolved in an organic solvent, cross-linked polyvinylpyrrolidone needs to be dissolved or dispersed in an organic solvent, and finally, the organic solvent needs to be removed.

[0012] The preparation of these tolvaptan solid dosage forms all require the use of large amounts of organic solvents. On the one hand, this places high demands on the production workshop and equipment, such as requiring explosion-proof measures, resulting in high production costs. On the other hand, it is not conducive to environmental protection and is difficult to adapt to the current trend of green production.

[0013] Patent CN102793706A discloses a method for preparing a tolvaptan solid dispersion. This method employs a hot-melt extrusion process, where tolvaptan, a carrier, and a plasticizer are mixed, heated and melted in a hot-melt extruder, and then extruded and cooled to obtain a solid dispersion, used to improve the solubility of tolvaptan. While this solid dispersion improves the dissolution rate of the formulation, it does not meet the leakage conditions of the dissolution medium. Leakage conditions refer to the concentration of the drug in the release medium being much lower than its saturation concentration. Physiologically, this means the drug is rapidly absorbed in the body. In vitro assays, including release rate measurements, need to mimic in vivo physiological conditions to satisfy the drug dissolution-absorption process. Leakage conditions play a corrective role; generally, the volume of the release medium is 3 to 5 times the volume of the medium required for a saturated drug solution. The "Technical Guidelines for Dissolution Testing of Common Oral Solid Dosage Forms" issued by the Center for Drug Evaluation of the National Medical Products Administration states that the volume of the dissolution medium is generally 500, 900, or 1000 mL, and ideally, the volume of the dissolution medium should meet the leakage conditions. However, the solid dispersion in this patent is limited by its solubilizing effect on poorly soluble raw materials. It is necessary to add surfactants to the dissolution medium to measure the dissolution behavior of the formulation. However, doing so may "mask" some properties of the formulation. It is not a dissolution medium with discriminative power. It is very likely that there will be similar in vitro dissolution curves but inequivalence in vivo, which will affect the accuracy of the test results. Summary of the Invention

[0014] The purpose of this invention is to provide a tolvaptan solid dispersion that can significantly increase the solubility of tolvaptan raw material.

[0015] To achieve the above objectives, the inventors have provided the following technical solutions.

[0016] A tolvaptan solid dispersion, wherein the raw material composition of the solid dispersion includes: tolvaptan, a hydrophilic carrier material, and a bicarbonate.

[0017] If necessary, plasticizers and / or organic acids may also be added to the raw material composition of the above solid dispersion.

[0018] The above-mentioned tolvaptan solid dispersion, by weight percentage, comprises: 5%-30% tolvaptan, 5%-60% hydrophilic carrier material, 2%-20% bicarbonate, 0%-15% plasticizer, and 0%-20% organic acid.

[0019] In the composition of the above-mentioned tolvaptan solid dispersion, the weight ratio of tolvaptan to hydrophilic carrier material is 1:0.5-10, the weight ratio of bicarbonate to hydrophilic carrier material is 1:1-5, and the weight ratio of bicarbonate to organic acid is 1:1-5.

[0020] In the composition of the above solid dispersion, the weight ratio of tolvaptan to the hydrophilic carrier material is preferably 1:2, the weight ratio of bicarbonate to the hydrophilic carrier material is preferably 1:3, and the weight ratio of bicarbonate to organic acid is preferably 1:3.

[0021] In the above-mentioned solid dispersion, the hydrophilic carrier material is selected from any one or more of polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, polyvinylpyrrolidone, copovidone, and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), preferably a mixture of polyethylene glycol 6000 and polyvinyl alcohol, with a weight ratio of polyethylene glycol 6000 to polyvinyl alcohol of 1:1-5, preferably 1:2; the bicarbonate is selected from any one or more of sodium bicarbonate, potassium bicarbonate, and ammonium bicarbonate; the plasticizer is selected from any one or more of polyethylene glycol, glycerol, propylene glycol, triacetin, triethyl citrate, polyoxyethylene hydrogenated castor oil, and dibutyl phthalate; the organic acid is selected from any one or more of citric acid, malic acid, tartaric acid, ascorbic acid, and fumaric acid, preferably citric acid.

[0022] This invention also provides a method for preparing the above-mentioned tolvaptan solid dispersion, the operation steps of which include:

[0023] a. Mix all the raw materials in the solid dispersion to obtain a physical mixture before hot melt extrusion;

[0024] b. Use a hot melt extruder to extrude the physical mixture obtained in step a before hot melt extrusion, cool, crush, and sieve to obtain tolvaptan solid dispersion.

[0025] In the above preparation method, the hot melt extruder in step b is a twin-screw extruder, the preset extrusion temperature of the hot melt extruder is 100℃-180℃, the preset extrusion speed of the hot melt extruder is 100r / min-300r / min, and the sieve is a 16-40 mesh sieve.

[0026] In the above-mentioned method for preparing tolvaptan solid dispersion, the preset extrusion temperature of the hot melt extruder in step b is preferably 120℃-150℃, more preferably 130℃; the preset extrusion speed of the hot melt extruder is preferably 150r / min-250r / min, more preferably 200r / min; and the sieve is preferably a 20-mesh sieve.

[0027] The tolvaptan solid dispersion provided by this invention can be prepared into an oral solid dosage form by adding pharmaceutically acceptable excipients as needed. Oral solid dosage forms include tablets, capsules, granules, etc.

[0028] The pharmaceutically acceptable excipients described in this invention include fillers, disintegrants, binders, flavoring agents, and lubricants. Fillers include, but are not limited to, lactose, mannitol, starch, pregelatinized starch, and microcrystalline cellulose; disintegrants include, but are not limited to, croscarmellose sodium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, croscarmellose, and calcium carboxymethyl cellulose; binders include, but are not limited to, hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, copovidone, polyvinyl alcohol, and starch; flavoring agents include, but are not limited to, sucralose, aspartame, sodium saccharin, and flavorings; and lubricants include, but are not limited to, magnesium stearate, sodium stearate fumarate, and talc.

[0029] The oral solid dosage form of the present invention can be prepared by powder direct compression process, wet granulation process, dry granulation process, etc.

[0030] The tolvaptan solid dispersion provided by this invention has an increased solubility of over 0.05 mg / mL. At the same time, solid formulations prepared using the solid dispersion provided by this invention can meet the trough conditions recommended by the Chinese Pharmacopoeia for a dissolution medium volume of 900 mL, ensuring the accuracy of the formulation dissolution test results. Attached Figure Description

[0031] Figure 1 This is the X-ray diffraction pattern of the tolvaptan raw material powder.

[0032] Figure 2 The image shows the X-ray diffraction pattern of the tolvaptan solid dispersion powder prepared in Example 1.

[0033] Figure 3 Scanning electron microscope images of tolvaptan raw material, the tolvaptan solid dispersion prepared in Example 1, and the solid dispersion prepared in Comparative Example 1.

[0034] Figure 4 Dissolution curves of tolvaptan tablets prepared in Examples 5-8 and Comparative Examples 4-7 are shown. Detailed Implementation

[0035] The present invention will be further described in detail below with reference to specific embodiments.

[0036] Preparation of Tolvaptan Solid Dispersions in Examples 1-4

[0037] The inventors prepared tolvaptan solid dispersion according to the method described in this invention, and conducted comparative experiments, as shown in Table 1.

[0038] Table 1

[0039]

[0040]

[0041] Table 1 shows the raw material composition and process parameters for the preparation of tolvaptan solid dispersions in Examples 1-4, along with comparative examples.

[0042] The inventors tested the tolvaptan solid dispersions prepared according to Examples 1-4 and Comparative Examples 1-3. (Appendix) Figure 2 The X-ray diffraction pattern of the tolvaptan solid dispersion powder prepared in Example 1 is shown below, along with the X-ray diffraction pattern of the tolvaptan raw material powder (attached). Figure 1 Compared to the two, the characteristic peaks of the two are not significantly different, indicating that the solid dispersion was successfully prepared in Example 1.

[0043] Table 2 shows the solubility and total impurities of the solid dispersions prepared in Examples 1-4 and Comparative Examples 1-3.

[0044] Table 2

[0045] experimental group Solubility (mg / mL) Total impurities (%) Example 1 0.0523 0.21 Example 2 0.0607 0.23 Example 3 0.0558 0.19 Example 4 0.0541 0.20 Raw materials (D90 < 10 μm) 0.0025 0.18 Comparative Example 1 0.0202 0.19 Comparative Example 2 0.0211 0.22 Comparative Example 3 0.0197 0.24

[0046] As shown in Table 2, the dissolution rate of the tolvaptan solid dispersions prepared in Examples 1-4 was significantly higher than that of Comparative Examples 1-3, and also significantly higher than that of the micronized tolvaptan raw material (D90 < 10 μm), without a significant increase in total impurities. This indicates that the tolvaptan solid dispersions provided by this invention exhibit superior solubility.

[0047] Appendix Figure 3 Electron micrographs of tolvaptan raw material, the solid dispersion prepared in Example 1, and the solid dispersion prepared in Comparative Example 1 show that the solid dispersion prepared in Example 1 has more pores, which means that the solid dispersion prepared in Example 1 has a larger specific surface area. It is precisely because of the increase in specific surface area that the solubility of the poorly soluble drug tolvaptan is effectively improved.

[0048] Based on the standard dosage of tolvaptan (15 mg), the solid dispersions prepared in Examples 1-4 can all meet the leakage conditions within the recommended dissolution medium volume (900 mL) in the Chinese Pharmacopoeia. That is, the volume of the release medium is 3 to 5 times the volume of the medium required for the saturated drug solution. However, in the comparative examples, more than 2 L of dissolution medium is required to meet the leakage conditions, indicating that the solubility does not meet the experimental detection conditions and it is difficult to ensure the accuracy of the detection.

[0049] Tablets prepared from tolvaptan solid dispersions in Examples 5-8

[0050] The inventors prepared tablets by adding excipients to the tolvaptan solid dispersions obtained according to Examples 1-4 using conventional methods, and tested the dissolution rate of the tablets. Simultaneously, tablets were prepared by adding excipients to the tolvaptan solid dispersions obtained in Comparative Examples 1-3 using the same method, and their dissolution rates were tested, as detailed below.

[0051] Table 3 shows the prescribed dosage for the tablets.

[0052] Table 3

[0053]

[0054] Dissolution test:

[0055] The dissolution determination method II in Appendix II of the 2020 edition of the Chinese Pharmacopoeia was used. The dissolution medium was 900 mL of purified water, the stirring speed was 50 rpm, and the sampling times were 5 min, 15 min, 30 min, 45 min, 60 min, and 90 min. The dissolution results are shown in Table 4.

[0056] Table 4

[0057]

[0058] As shown in Table 4, the dissolution rate of the solid formulation prepared using the solid dispersion provided by this invention is significantly improved, indicating that the solid dispersion provided by this invention can significantly improve the drug release characteristics of tolvaptan. (Appendix) Figure 4 The dissolution curves of the tablets prepared in Examples 4-8 and Comparative Examples 4-7 are shown in the comparison diagram. It can be seen that in a dissolution medium with discriminative power (without added surfactant), compared with the solid dispersion prepared according to the prior art, the tablets prepared by the solid dispersion of the present invention have a significantly improved drug release rate and can reach the release endpoint (>85%).

Claims

1. A solid dispersion of tolvaptan, characterized in that, The raw material composition of the solid dispersion comprises: tolvaptan, a hydrophilic carrier material, and a bicarbonate; the hydrophilic carrier material is selected from any one or more of polyvinyl alcohol, hypromellose, polyethylene glycol, polyvinylpyrrolidone, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; the bicarbonate is selected from any one of sodium bicarbonate and potassium bicarbonate.

2. The solid dispersion of claim 1, wherein, The raw material composition of the solid dispersion further comprises a plasticizer and / or an organic acid.

3. The solid dispersion of claim 2, wherein, The raw material composition of the solid dispersion comprises, by weight percentage: tolvaptan 5%-30%, a hydrophilic carrier material 5%-60%, a bicarbonate 2%-20%, a plasticizer 0%-15%, and an organic acid 0%-20%.

4. The solid dispersion of claim 2, wherein, In the raw material composition of the solid dispersion, the weight ratio of tolvaptan to the hydrophilic carrier material is 1:0.5-10, the weight ratio of the bicarbonate to the hydrophilic carrier material is 1:1-5, and the weight ratio of the bicarbonate to the organic acid is 1:1-5.

5. The solid dispersion of claim 2, wherein, In the raw material composition of the solid dispersion, the weight ratio of tolvaptan to the hydrophilic carrier material is 1:2, the weight ratio of the bicarbonate to the hydrophilic carrier material is 1:3, and the weight ratio of the bicarbonate to the organic acid is 1:

3.

6. The solid dispersion according to any one of claims 2 to 5, wherein, The plasticizer is selected from any one or more of polyethylene glycol, glycerol, propylene glycol, glyceryl triacetate, triethyl citrate, polyoxyethylene hydrogenated castor oil, and dibutyl phthalate; and the organic acid is selected from any one or more of citric acid, malic acid, tartaric acid, ascorbic acid, and fumaric acid.

7. The method of preparing a solid dispersion of tolvaptan according to claim 1, wherein The operation steps comprise: a. mixing all the raw materials in the solid dispersion composition to obtain a physical mixture before hot melt extrusion; b. extruding the physical mixture before hot melt extrusion obtained in step a. using a hot melt extruder, cooling, crushing, and sieving to obtain a tolvaptan solid dispersion.

8. The process for preparing a solid dispersion of tolvaptan according to claim 7, wherein The hot melt extruder in step b. is a double-screw extruder, the preset extrusion temperature of the hot melt extruder is 100-180°C, the preset extrusion speed of the hot melt extruder is 100-300 r / min, and the sieve is a 16-40 mesh sieve.

9. The process for preparing a solid dispersion of tolvaptan according to claim 7, wherein The preset extrusion temperature of the hot melt extruder in step b. is 120-150°C, the preset extrusion speed of the hot melt extruder is 150-250 r / min, and the sieve is a 20 mesh sieve.

10. An oral solid preparation prepared from the tolvaptan solid dispersion of any one of claims 1-5.

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