Preparation method of tacrolimus solid dispersion

Abstract

The invention provides a preparation method of a tacrolimus solid dispersion. The preparation method of the tacrolimus solid dispersion comprises the following steps: S1, by taking persulfate as an initiator, carrying out graft polymerization on N-vinyl pyrrolidone and beta-cyclodextrin to generate polyvinylpyrrolidone grafted beta-cyclodextrin (PVP-g-beta-CD); s2, sequentially dissolving the tacrolimus, the PVP-g-beta-CD, the polyglycerol, the disintegrating agent and the excipient in the solvent step by step, and uniformly stirring; and S3, drying the solution obtained in S2, and crushing and sieving the product to obtain the tacrolimus solid dispersion. The preparation method is simple and low in raw material cost; pVP-g-beta-CD is used as a solid dispersion carrier, so that the solubility and the dissolution rate of tacrolimus are remarkably improved, zero-order release of the medicine is realized, the solubilizing effect and the controlled release performance are excellent, the blood concentration is more stable, and the treatment effect is improved.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly relates to a method for preparing a solid dispersion of tacrolimus, and more particularly to a method for preparing a solid dispersion using polyvinylpyrrolidone grafted β-cyclodextrin (PVP-g-β-CD) generated by N-vinylpyrrolidone and β-cyclodextrin in the presence of a persulfate initiator as a carrier. Background Art

[0002] Tacrolimus is a macrolide immunosuppressant that is widely used in anti-rejection treatment after organ transplantation and the treatment of autoimmune diseases. However, tacrolimus has extremely low water solubility (about 4-12 μg / mL) and belongs to class II drugs in the biopharmaceutics classification system (BCS), that is, low solubility. Its low dissolution rate results in low oral bioavailability, severely limiting its clinical application effect; Studies have shown that the low dissolution rate of tacrolimus is mainly attributed to its hydrophobic molecular structure and high crystallinity, which makes its dissolution rate in the gastrointestinal tract slow. In order to improve the dissolution rate and bioavailability of tacrolimus, various methods have been tried in the prior art, including micronization, cyclodextrin inclusion, solid dispersion technology, etc. Among them, solid dispersion technology is considered to be an effective means. By dispersing the drug in a hydrophilic carrier, the dissolution rate and solubility of the drug can be significantly improved; However, the existing methods for preparing solid dispersions still have the following problems: 1. Uneven drug dispersion: Traditional carriers (such as polyvinylpyrrolidone, polyethylene glycol, etc.) have limited dispersion effects on drugs and are prone to drug aggregation, affecting the dissolution effect. 2. Difficult to achieve controlled release: It is difficult to achieve zero-order release (i.e., constant-rate release) of drugs in the prior art, resulting in large fluctuations in blood drug concentration and affecting the treatment effect; Therefore, it is of great significance to develop a method for preparing a solid dispersion that can significantly improve the dissolution rate of tacrolimus, achieve zero-order release, and has a simple process and low cost. In recent years, the research on cyclodextrin and its derivatives as drug carriers has attracted much attention. Cyclodextrin has a unique hydrophobic cavity structure and can form inclusion complexes with hydrophobic drugs, thereby improving the solubility and stability of the drugs. And polyvinylpyrrolidone (PVP), as a hydrophilic polymer, has good dispersibility and film-forming properties and is commonly used in the preparation of solid dispersions. By chemically grafting PVP with β-cyclodextrin, the advantages of both can be combined to form a new type of carrier, further improving the solubilization effect and controlled release performance of the drug; Polymerized glycerol is a polyol compound, usually presented as a colorless viscous liquid or semi-solid state, soluble in water and ethanol. Its hygroscopic property is slightly lower than that of glycerol monomer, but it shows excellent chemical stability in aqueous solution. From the molecular structure, polymerized glycerol is formed by the polymerization of glycerol units, and the molecular chain shows a characteristic structure with alternating ether bonds and hydroxyl groups. This unique structure enables it to form a hydrogen bond network with water molecules through the oxygen atoms in the hydroxyl groups, thus showing significant hydrophilicity. It is worth noting that as the number of hydrophilic hydroxyl groups in the molecular chain increases, the solubility of polymerized glycerol in water will increase accordingly. Summary of the Invention

[0003] To solve the problems of low dissolution rate of tacrolimus in the prior art and the lack of controlled-release dosage forms in the market, the present invention provides a method for preparing a solid dispersion of tacrolimus. This method uses polyvinylpyrrolidone grafted β-cyclodextrin (PVP-g-β-CD) generated by N-vinylpyrrolidone and β-cyclodextrin in the presence of a persulfate initiator as a carrier, significantly improving the solubility and dissolution rate of tacrolimus, achieving zero-order release of the drug, and having excellent solubilization effect and controlled-release performance; this method has a simple process and low raw material cost, and can make the drug disperse more uniformly and dissolve rapidly.

[0004] To achieve the above object, the present invention adopts the following technical solutions: The present invention provides a method for preparing a solid dispersion of tacrolimus, which is characterized in that, by mass, it contains 1 part of tacrolimus, 5 - 15 parts of polyvinylpyrrolidone grafted β-cyclodextrin (PVP-g-β-CD), 1 - 10 parts of polymerized glycerol, 1 - 3 parts of disintegrant, and 5 - 15 parts of excipient; the method for preparing the solid dispersion of tacrolimus includes the following steps: S1. Dissolve β-cyclodextrin in an appropriate amount of water, add N-vinylpyrrolidone monomer, and stir evenly. The mass ratio of β-cyclodextrin to N-vinylpyrrolidone monomer is 1:(1 - 6); add ammonium persulfate initiator, with a mass of 1% of the N-vinylpyrrolidone monomer, react at 60 - 80 °C under nitrogen protection for 6 - 8 hours, and dry the reaction product to obtain PVP-g-β-CD; S2. Dissolve tacrolimus and PVP-g-β-CD in anhydrous ethanol to obtain a clear solution, dissolve polymerized glycerol in an appropriate amount of water, and the mass ratio of anhydrous ethanol to water is (1 - 5):1. Mix the above two solutions, add the disintegrant and excipient, and stir evenly to make them fully infiltrated; S3. Dry the soft material obtained in S2, crush it, and pass through a 100-mesh sieve to obtain the solid dispersion of tacrolimus.

[0005] Further, the polymerized glycerol is penta - to pentadeca - glycerol, preferably deca - glycerol.

[0006] Furthermore, the excipient is one of lactose monohydrate and mannitol, preferably lactose monohydrate.

[0007] Furthermore, the disintegrant is one of sodium carboxymethylcellulose and sodium carboxymethyl starch, preferably sodium carboxymethyl starch.

[0008] Furthermore, the mass ratio of β-cyclodextrin to N-vinylpyrrolidone in S1 is 1:2.

[0009] Furthermore, the mass ratio of tacrolimus to absolute ethanol in S2 is 1:(20 - 60).

[0010] Furthermore, an application of a tacrolimus solid dispersion prepared by the preparation method of the tacrolimus solid dispersion, using the tacrolimus solid dispersion as an intermediate to prepare a capsule or a tablet.

[0011] Compared with the prior art, the beneficial effects of the present invention are mainly reflected in: (1) The present invention uses PVP-g-β-CD as a carrier, and through its unique graft structure, significantly improves the solubility and dissolution rate of tacrolimus.

[0012] (2) Through the controlled release effect of PVP-g-β-CD, the present invention realizes the zero-order release (constant rate release) of the drug, makes the blood drug concentration more stable, and reduces the influence of blood drug concentration fluctuation on the therapeutic effect.

[0013] (3) The raw materials of the present invention are low in cost and easy to obtain, and the preparation method is simple, which is suitable for industrial production. Description of the Drawings Figure 1 It is the cumulative dissolution curve graph of Examples 1 - 3, Comparative Examples 1 - 4 and Blank Example 1; Figure 2 It is the cumulative dissolution curve graph of Examples 4 - 5, Comparative Examples 1 - 4 and Blank Example 1. Detailed Embodiments

[0015] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto: Example 1

[0016] Preparation of PVP-g-β-CD: Dissolve 5 g of β-cyclodextrin in 250 mL of water, add 10 g of N-vinylpyrrolidone monomer, and stir evenly; add 0.1 g of ammonium persulfate, stir evenly, react at 70°C under nitrogen protection for 7 hours, and vacuum dry the reaction product at 50°C to constant weight to obtain 15.5 g of PVP-g-β-CD.

[0017] Preparation of solid dispersion: Accurately weigh 1 g of tacrolimus and 7 g of PVP-g-β-CD, dissolve them in 50 g of absolute ethanol, and stir evenly; dissolve 3 g of decaglycerol in 20 g of water, mix the above two solutions, add 1.5 g of sodium carboxymethyl starch and 10 g of lactose monohydrate, stir evenly to fully wet them, and remove the solvent by vacuum drying at 50 °C until constant weight, then pulverize and pass through a 100-mesh sieve to obtain the tacrolimus solid dispersion.

[0018] Examples 2 - 5 The preparation methods of the tacrolimus solid dispersions in Examples 2 - 5 are the same as that in Example 1, except for the specific dosages of the ingredients.

[0019] Comparative Example 1 (1) Preparation of PVP: Dissolve 10 g of N-vinylpyrrolidone in 100 mL of water and stir evenly, add 0.1 g of ammonium persulfate, react at 70 °C under nitrogen protection for 7 hours, and vacuum dry the reaction product at 50 °C until constant weight to obtain 10.3 g of PVP.

[0020] (2) Preparation method of tacrolimus solid dispersion: Refer to Example 1, replace PVP-g-β-CD with PVP, and the specific dosages of the other ingredients and the preparation process are the same as those in Example 1.

[0021] Comparative Example 2 Preparation method of tacrolimus solid dispersion: Refer to Example 1, replace PVP-g-β-CD with β-cyclodextrin, and the specific dosages of the other ingredients and the preparation process are the same as those in Example 1.

[0022] Comparative Example 3 (1) Preparation of PVP: Dissolve 10 g of N-vinylpyrrolidone in 100 mL of water and stir evenly, add 0.1 g of ammonium persulfate, react at 70 °C under nitrogen protection for 7 hours, and vacuum dry the reaction product at 50 °C until constant weight to obtain 10.3 g of PVP.

[0023] (2) Preparation method of tacrolimus solid dispersion: Refer to Example 1, replace PVP-g-β-CD with a mixture of β-cyclodextrin and PVP (mass ratio 1:2), and the specific dosages of the other ingredients and the preparation process are the same as those in Example 1.

[0024] Comparative Example 4 (1) Preparation of PVP-g-β-CD: The same as in Example 1.

[0025] (2)Preparation method of tacrolimus solid dispersion: Accurately weigh 1 g of tacrolimus and 7 g of PVP-g-β-CD, dissolve them in 50 g of absolute ethanol, stir evenly, add 20 g of water and mix well, then add 1.5 g of sodium carboxymethyl starch and 10 g of lactose monohydrate, stir evenly to make them fully infiltrated, and remove the solvent by vacuum drying at 50 °C until constant weight. Crush and pass through a 100-mesh sieve to obtain the tacrolimus solid dispersion.

[0026] Blank Example 1 Blank Example 1: Mix 1 g of tacrolimus, 1.5 g of sodium carboxymethyl starch, 10 g of lactose monohydrate, 50 g of absolute ethanol, and 20 g of water evenly to make them fully infiltrated, remove the solvent by vacuum drying at 50 °C until constant weight, crush and pass through a 100-mesh sieve.

[0027] The formulation compositions (except water and absolute ethanol) of the examples and comparative examples are shown in Table 1: Table 1. Formulation compositions of examples (except water and absolute ethanol)

[0028] Determination of in vitro dissolution rate

[0029] According to the second paddle method in the dissolution and release determination method of General Principles of Chinese Pharmacopoeia (2020 Edition), Volume IV, 0931, the dissolution rate was determined. The dissolution medium was an aqueous solution containing 0.10% sodium dodecyl sulfate and 0.005% hydroxypropyl cellulose, and the pH was adjusted to 4.5 with an aqueous phosphate solution and made up to 900 ml with pure water. Adjust the rotation speed to 75 r / min and the temperature to 37 °C. Accurately weigh the tacrolimus solid dispersion sample (equivalent to 5.0 mg of tacrolimus) and put it into the dissolution cup, and start timing. Sampling and detection were carried out at 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, and 240 minutes. Each time 5 mL of sample was taken and an equal volume of isothermal medium was added. The results are as shown in Figure 1 and 2 shown.

[0030] From the results shown in Figure 1 and 2 , it can be seen that the tacrolimus solid dispersion described in this patent exhibits excellent drug release characteristics: within 160 minutes, the dissolution rates of Examples 1-3 reached over 90% in sequence, and the highest could reach 95.7%; when the dissolution time was further extended to 240 minutes, the cumulative dissolution rates of Examples 4-5 could still be stably maintained at over 80% level. Compared with the untreated raw drug, the cumulative dissolution rates of each example were significantly improved, and all examples showed typical zero-order release characteristics, and the release rate remained constant throughout the process.

[0031] Compared with this patent, under the same conditions, the dissolution rates of Comparative Examples 1-4 prepared by traditional preparation processes were only 38.1%, 30.4%, 34.2% and 48.6% respectively at 240 minutes. There was an obvious lag in the dissolution rate compared with this patent. More critically, the comparative example group failed to achieve the zero-order release characteristics of the drug, and its release curve showed an obvious initial burst release phenomenon, indicating that the prior art could not achieve the sustained and stable release effect reached by this patent.

[0032] In summary, the tacrolimus solid dispersion prepared by the present invention uses PVP-g-β-CD as a carrier, significantly improving the dissolution rate and release performance of tacrolimus and achieving zero-order release of the drug. Moreover, for the preparation method of the tacrolimus solid dispersion described in the present invention, the raw materials used are low in cost and easy to obtain, and the preparation method is simple, which is suitable for industrial production.

Claims

1. A method for preparing a solid dispersion of tacrolimus, characterized in that, By mass fraction, it contains 1 part of tacrolimus, 5 - 15 parts of polyvinylpyrrolidone grafted β - cyclodextrin (PVP - g - β - CD), 1 - 10 parts of polyglycerol, 1 - 3 parts of disintegrant and 5 - 15 parts of excipient; The preparation method of the solid dispersion of tacrolimus includes the following steps: S1. Dissolve β - cyclodextrin in an appropriate amount of water, add N - vinylpyrrolidone monomer, and stir evenly. The mass ratio of β - cyclodextrin to N - vinylpyrrolidone monomer is 1:(1 - 6); add ammonium persulfate initiator, with a mass of 1% of the N - vinylpyrrolidone monomer; react at 60 - 80 °C under nitrogen protection for 6 - 8 hours, and dry the reaction product to obtain PVP - g - β - CD; S2. Dissolve tacrolimus and PVP - g - β - CD in absolute ethanol to obtain a clear solution, dissolve polyglycerol in an appropriate amount of water, and the mass ratio of absolute ethanol to water is (1 - 5):

1. Mix the above two solutions, add disintegrant and excipient, and stir evenly to make them fully infiltrated; S3. Dry, crush and pass through a 100 - mesh sieve the soft material obtained in S2 to obtain the solid dispersion of tacrolimus.

2. The preparation method of the solid dispersion of tacrolimus according to claim 1, characterized in that, The polyglycerol is pentaglycerol to pentadeca - glycerol.

3. The preparation method of the solid dispersion of tacrolimus according to claim 1, wherein, The excipient is one of lactose monohydrate and mannitol.

4. The preparation method of the solid dispersion of tacrolimus according to claim 1, characterized in that, The disintegrant is one of sodium carboxymethylcellulose and sodium carboxymethyl starch.

5. The preparation method of the tacrolimus solid dispersion according to claim 1, characterized in that, In S1, the mass ratio of β - cyclodextrin to N - vinylpyrrolidone is 1:

2.

6. The preparation method of the tacrolimus solid dispersion according to claim 1, wherein In S2, the mass ratio of tacrolimus to absolute ethanol is 1:(20 - 60).

7. The preparation method of the tacrolimus solid dispersion according to claim 1, characterized in that, The solid dispersion of tacrolimus is used as an intermediate to prepare capsules or tablets.

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