A high-dose ritonavir solid dispersion with good dissolution performance and its preparation method

Abstract

The present invention discloses a high drug-loading ritonavir solid dispersion with good dissolution performance and a preparation method thereof. The solid dispersion is made of the following components in mass percentages: 35-55% of ritonavir, 11.2-33.75% of hypromellose E50, and the balance of povidone K30. The solid dispersion provided by the present invention can effectively inhibit the crystal nucleation and growth of the drug in the supersaturated solution and improve the stability of the active drug in the solid-liquid interfacial layer. The present invention breaks through the release consistency concentration limit of the original solid dispersion and provides a new idea for the preparation or process innovation of high drug-loading ritonavir tablets.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a high drug-loading ritonavir solid dispersion with solubilization performance and a preparation method thereof. The present invention can obtain a high drug-loading solid dispersion with excellent dissolution performance. Technical Background

[0002] Ritonavir, chemically named (2S,3S,5S)-5-(N-(N-(((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valyl)amino)-2-(N-(5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane, is a weakly basic drug first developed by Abbott Company in the United States. It has high hydrophobicity and high permeability, belongs to BCS class II drugs, and is an HIV-1 protease inhibitor. Clinically, it is used for the treatment of AIDS and can be taken alone or in combination with other reverse transcriptase inhibitors and protease inhibitors. Due to its low bioavailability caused by low solubility, the ability of ritonavir to treat HIV is limited. Therefore, improving its solubility and dissolution rate is the primary problem to be overcome in the research and development of its oral preparations. Its chemical structural formula is as follows:

[0003]

[0004] Strategies for improving the bioavailability of poorly soluble drugs, especially BCS class II drugs, mainly include preparing prodrugs, nanocrystals, cocrystals, coamorphous substances, salts, amorphous solid dispersions, etc. Preparing amorphous solid dispersions is the most commonly used improvement strategy. The mechanism by which this strategy increases drug solubility is: (1) improving the wettability of the active drug; (2) compared with the crystalline form, the amorphous solid dispersion destroys the crystal lattice, and the system has higher free energy, making the drug have higher solubility and dissolution rate. However, at the same time, the amorphous active drug is prone to transform into a more stable crystal form during storage or dissolution, losing its original advantages. Therefore, the key to improving the stability of the amorphous solid dispersion and maintaining the excellent dissolution performance of the drug is to select a suitable carrier material.

[0005] Generally, a hydrophilic polymer is selected as the carrier for solid dispersions to increase the overall hydrophilicity of poorly soluble active drugs. The solubilization ability of the carrier, its crystal inhibition ability, the miscibility between the drug and the carrier, and their mass ratio all have a great impact on the solubilization performance of the solid dispersion. It is generally believed that with the increase of the drug loading, the gradually decreasing carrier material will make its solubilization effect weaker and weaker until the dissolution performance of the solid dispersion is the same as that of the raw drug. Too little carrier will also significantly reduce its crystal inhibition effect, resulting in the formation of crystals by the drug during storage and reducing its solubilization performance. In addition, during the dissolution process, too little carrier cannot effectively inhibit the crystallization process of the supersaturated drug solution, so that crystals of the drug precipitate on the surface of the solid dispersion, thus losing the solubilization advantage of the amorphous solid dispersion. Therefore, a large amount of carrier material is often required in the preparation of solid dispersions, resulting in a low drug loading of the solid dispersion. For some drugs with large doses, due to the too low drug loading, the final dosage form has a large volume and cannot be used, which has become the main obstacle affecting the wide use of solid dispersions. The clinically common dose of ritonavir is 600 mg, and it is of great significance to increase the drug loading of its solid dispersion. Although there are numerous literature reports on ritonavir solid dispersions, the drug loading of ritonavir in these articles is all below 30%. Therefore, based on the analysis of the solubilization and crystal inhibition effects of each carrier material, the present invention uses a co-formulated carrier system of solubilization and crystal inhibition to prepare a solid dispersion, so as to obtain a preparation method of a solid dispersion with good dissolution performance and high drug loading. Summary of the Invention

[0006] The main object of the present invention is to provide a high-drug-loading ritonavir solid dispersion with solubilization performance and its preparation method, breaking through the limitation of the low drug loading of the current ritonavir solid dispersion, and preparing a solid dispersion in which ritonavir can be rapidly dissolved at a high drug loading.

[0007] The technical solution of the present invention is as follows:

[0008] A high-drug-loading ritonavir solid dispersion with solubilization performance is made of the following components in mass percentage:

[0009] Ritonavir 35 - 55%

[0010] Crystal inhibitor hydroxypropyl methylcellulose E50 11.2 - 33.75%

[0011] Polyvinylpyrrolidone K30, the balance of the high molecular weight carrier material.

[0012] Preferably, the solid dispersion of the present invention is made of the following components in mass percentage:

[0013] Ritonavir 55%

[0014] Hydroxypropyl Methylcellulose E50 22.5%

[0015] Povidone K30 22.5%.

[0016] The solid dispersion of the present invention can be prepared by the solvent evaporation method, and the specific preparation method is as follows:

[0017] Add ritonavir, povidone K30, and hydroxypropyl methylcellulose into a mixed solvent of absolute ethanol and dichloromethane. After ultrasonic dissolution, evaporate the solvent under reduced pressure at 50 °C, then dry in a vacuum drying oven at 50 °C, and finally grind and crush, and pass through a 120-mesh sieve to obtain the solid dispersion;

[0018] Preferably, in the mixed solvent of absolute ethanol and dichloromethane, the volume ratio of absolute ethanol to dichloromethane is 3:1.

[0019] Under the condition of pH 6.8, the drug concentration maintained by the solid dispersion of the present invention can reach more than 10 times that of the physical mixture of the raw drug and the drug carrier.

[0020] The beneficial effects of the present invention are reflected in:

[0021] The solid dispersion provided by the present invention can effectively inhibit the crystal nucleation and growth of the drug in the supersaturated solution and improve the stability of the active drug in the solid-liquid interface layer. The present invention breaks through the release consistency concentration limit of the original solid dispersion and provides a new idea for the preparation or process innovation of high-dose ritonavir tablets. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 : Dissolution curves of the solid dispersions of Example 1 and Example 2 in a medium with pH = 1.4.

[0023] Figure 2 : Dissolution curves of the solid dispersions of Example 3 and Example 4 in a medium with pH = 6.8.

[0024] Figure 3 : Dissolution curves of the solid dispersions of Example 5 - Example 7 in a medium with pH = 1.4.

[0025] Figure 4 : Dissolution curves of the solid dispersions of Example 5 - Example 9 in a medium with pH = 6.8.

[0026] Figure 5 : Differential scanning calorimetry thermograms of the raw drug and the solid dispersion of Example 7.

[0027] Figure 6 : X-ray diffraction patterns of the raw drug and the solid dispersion of Example 7.

[0028] Figure 7: Dissolution curves of the solid dispersions of Example 5 and Example 7 in the gastric simulation environment of the artificial gastric-duodenal dissolution model.

[0029] Figure 8 : Dissolution curves of the solid dispersions of Example 5 and Example 7 in the duodenal simulation environment of the artificial gastric-duodenal dissolution model.

[0030] Figure 9 : Scanning electron micrographs of the tablet surface before the solid dispersion of Example 7 contacts the medium (A), at 0 s after contact (B), at 30 min after contact (C, D), and before the solid dispersion of RTV / PVP K30 / HPMC E50 = 55:22.5:22.5 contacts the medium (E), at 0 s after contact (F), at 30 min after contact (G, H). Among them, the magnification of A-C, E, G is 2000 times, and the scale bar is 10 μm; the magnification of F, D is 20000 times, and the scale bar is 1 μm; the magnification of H is 15000 times, and the scale bar is 1.5 μm.

[0031] Figure 10 : Powder X-ray diffraction pattern of the stability study experiment of the solid dispersion of Example 7.

[0032] Figure 11 : Dissolution curve of the stability study experiment of the solid dispersion of Example 7. Detailed implementation manners

[0033] The preparation process and implementation effects of the preparation of the present invention are further described through the following examples. It should be noted that the following description is only for explaining the present invention and does not limit its content. Unless otherwise specified, the content of each component used below is the weight percentage content.

[0034] Example 1:

[0035] Weigh 2.10 g of ritonavir and 3.90 g of polyvinylpyrrolidone K30, mix them evenly, and add them to 40 mL of a mixed solution of anhydrous ethanol and dichloromethane (mixed in a volume ratio of 3:1). After ultrasonic dissolution, use a rotary evaporator to evaporate the solvent under reduced pressure at 50 °C. After 3 hours, remove it and transfer the solid product to a watch glass, and dry it overnight in a vacuum drying oven at 50 °C. Finally, grind and crush it, and pass through a 120-mesh sieve to obtain the solid dispersion.

[0036] Weigh three portions of 0.143 g of the solid dispersion and separately add them to 500 mL of hydrochloric acid solution with pH = 1.4. Conduct the dissolution test according to the paddle method in the Dissolution Test Method of the Chinese Pharmacopoeia (2020 Edition). The rotation speed is 50 rpm. Sampling is carried out at 5, 10, 15, 20, 30, 45, and 60 min respectively. After rapid filtration, the drug concentration is determined by ultraviolet-visible spectrophotometry, and the cumulative dissolution percentage at each time point is calculated. Separately weigh three portions of 50 mg of ritonavir raw material and operate in the same way to determine the cumulative dissolution percentage at each time point. The results are shown in Figure 1 . It can be seen from Figure 1 that the dissolution of the ritonavir-povidone solid dispersion with a drug loading of 35% is significantly increased, and the dissolution within 60 min exceeds 70%, while the dissolution of the raw material within 60 min is less than 40%.

[0037] Example 2:

[0038] Weigh 2.1 g of ritonavir, 1.95 g of povidone K30, and 1.95 g of hypromellose E50, mix them evenly, and add them to 40 mL of a mixed solution of anhydrous ethanol and dichloromethane (mixed in a volume ratio of 3:1). After ultrasonic dissolution, use a rotary evaporator to remove the solvent under reduced pressure at 50 °C. After 3 hours, remove it and transfer the solid product to a watch glass, and dry it overnight in a vacuum drying oven at 50 °C. Finally, grind and crush it, and pass it through a 120-mesh sieve to obtain the solid dispersion.

[0039] Weigh three portions of 0.143 g of the solid dispersion and separately add them to 500 mL of hydrochloric acid solution with pH = 1.4, and conduct the powder dissolution experiment according to the method of Example 1. The results are shown in Figure 1 . It can be seen from Figure 1 that under a drug loading of 35%, the solid dispersion prepared with a binary carrier of povidone and hypromellose has a higher dissolution. The dissolution of ritonavir reaches 90% at 20 min, which is much higher than that of the raw material and the solid dispersion with povidone alone as the carrier.

[0040] Example 3:

[0041] Weigh 2.70 g of ritonavir and 3.30 g of povidone K30, mix them evenly, and add them to 40 mL of a mixed solution of anhydrous ethanol and dichloromethane (mixed in a volume ratio of 3:1). After ultrasonic dissolution, use a rotary evaporator to remove the solvent under reduced pressure at 50 °C. After 3 hours, remove it and transfer the solid product to a watch glass, and dry it overnight in a vacuum drying oven at 50 °C. Finally, grind and crush it, and pass it through a 120-mesh sieve to obtain the solid dispersion.

[0042] Weigh three portions of 0.111 g of the solid dispersion and separately add them to 900 mL of phosphate buffer solution with a pH of 6.8. Perform the dissolution test according to the paddle method in the dissolution determination method of the Chinese Pharmacopoeia (2020 Edition). The rotation speed is 50 rpm. Sampling is carried out at 5, 10, 15, 20, 30, 45, and 60 min respectively. After rapid filtration, the drug concentration is determined by ultraviolet-visible spectrophotometry. The results are shown in Figure 2 . It can be seen from Figure 2 that the obtained solid dispersion dissolves very slowly in the phosphate buffer solution, and the drug concentration increases slowly. The drug concentration at 60 min is only 4.93 μg / mL.

[0043] Example 4:

[0044] Weigh 2.70 g of ritonavir, 1.65 g of povidone K30, and 1.65 g of hypromellose E50, mix them evenly, and add them to 40 mL of a mixed solution of anhydrous ethanol and dichloromethane (mixed in a volume ratio of 3:1). After ultrasonic dissolution, use a rotary evaporator to remove the solvent under reduced pressure at 50 °C. After 3 hours, remove it and transfer the solid product to a watch glass, and dry it overnight in a vacuum drying oven at 50 °C. Finally, grind and crush it, and pass it through a 120-mesh sieve to obtain the solid dispersion.

[0045] Weigh three portions of 0.111 g of the solid dispersion and separately add them to 900 mL of phosphate buffer solution with a pH of 6.8. Perform the powder dissolution experiment according to the method of Example 3. The results are shown in Figure 2 . It can be seen from Figure 2 that at a drug loading of 45%, compared with the solid dispersion using povidone alone as the carrier, the solid dispersion prepared with povidone and hypromellose E50 as the mixed carrier can significantly improve the dissolution rate of ritonavir. Even in the phosphate buffer solution with a pH of 6.8, the concentration can reach 20 μg / mL at 10 min and can be maintained above this level.

[0046] Example 5:

[0047] Weigh 3.30 g of ritonavir and 2.7 g of povidone K30, mix them evenly, and add them to 40 mL of a mixed solution of anhydrous ethanol and dichloromethane (mixed in a volume ratio of 3:1). After ultrasonic dissolution, use a rotary evaporator to remove the solvent under reduced pressure at 50 °C. After 3 hours, remove it and transfer the solid product to a watch glass, and dry it overnight in a vacuum drying oven at 50 °C. Finally, grind and crush it, and pass it through a 120-mesh sieve to obtain the solid dispersion.

[0048] Weigh three portions of 0.091 g of the solid dispersion and separately add them to 500 mL of hydrochloric acid solution with pH = 1.4, and conduct the powder dissolution experiment according to the method of Example 1. It was found that the dissolution rate of the obtained solid dispersion with a drug loading of 55% was much higher than that of the raw drug, and the drug concentration at 60 min could reach 67.05 μg / mL (see Figure 3 ). Separately weigh three portions of the same amount of the solid dispersion and add them to 900 mL of phosphate buffer solution with pH = 6.8, and conduct the powder dissolution experiment under non-sink conditions according to the method of Example 3. It was found that under this pH condition, the dissolution of the obtained solid dispersion was very poor, and the concentration at 60 min was only 3.66 μg / mL (see Figure 4 ).

[0049] Example 6:

[0050] Weigh 3.30 g of ritonavir, 2.02 g of polyvinylpyrrolidone K30, and 0.68 g of hypromellose E50, mix them evenly, and add them to 40 mL of a mixed solution of anhydrous ethanol and dichloromethane (mixed in a volume ratio of 3:1). After ultrasonic dissolution, use a rotary evaporator to evaporate the solvent under reduced pressure at 50 °C. After 3 hours, remove it and transfer the solid product to a watch glass, and dry it overnight in a vacuum drying oven at 50 °C. Finally, grind and crush it, and pass it through a 120-mesh sieve to obtain the solid dispersion.

[0051] Weigh three portions of 0.091 g of the solid dispersion and separately add them to 500 mL of hydrochloric acid solution with pH = 1.4, and conduct the powder dissolution experiment according to the method of Example 1. It was found that compared with the binary solid dispersion with polyvinylpyrrolidone as the carrier alone, after adding 11.2% of hypromellose, the dissolution rate of the ritonavir ternary solid dispersion in hydrochloric acid showed a phenomenon of first decreasing and then increasing, and the drug concentration at 60 min could reach 71 μg / mL (see Figure 3 ). Separately weigh three portions of the same amount of the solid dispersion and add them to 900 mL of phosphate buffer solution with pH = 6.8, and conduct the powder dissolution experiment under non-sink conditions according to the method of Example 3. It was found that under this pH condition, the dissolution rate of the solid dispersion containing hypromellose was much higher than that of the solid dispersion with polyvinylpyrrolidone as the carrier alone, and the drug concentration at 60 min could reach 10.87 μg / mL (see Figure 4 ).

[0052] Example 7:

[0053] Weigh 3.30 g of ritonavir, 1.35 g of polyvinylpyrrolidone K30, and 1.35 g of hypromellose E50. Mix them evenly and add to 40 mL of a mixed solution of absolute ethanol and dichloromethane (mixed in a volume ratio of 3:1). After ultrasonic dissolution, use a rotary evaporator to remove the solvent under reduced pressure at 50 °C. After 3 hours, remove it and transfer the solid product to a watch glass, and dry it overnight in a vacuum drying oven at 50 °C. Finally, grind and crush it, and pass through a 120-mesh sieve to obtain the solid dispersion.

[0054] Weigh three portions of 0.091 g of the solid dispersion and separately add them to 500 mL of hydrochloric acid solution with pH = 1.4, and conduct the powder dissolution experiment according to the method of Example 1. The results show that compared with the binary solid dispersion with polyvinylpyrrolidone as the carrier alone, after adding 22.5% of hypromellose, the dissolution rate of the ternary solid dispersion of ritonavir in hydrochloric acid increases significantly, and the drug concentration at 45 min can reach 80 μg / mL (see Figure 3 ). Take another three portions of the same amount of the solid dispersion and add them to 900 mL of phosphate buffer solution with pH = 6.8, and conduct the powder dissolution experiment under non-sink conditions according to the method of Example 3. The results show that under this pH condition, the dissolution rate of the ternary solid dispersion containing 22.5% of hypromellose is much higher than that of the binary solid dispersion with polyvinylpyrrolidone as the carrier alone. The drug concentration at 10 min reaches 19.40 μg / mL and can maintain above this level (see Figure 4 ).

[0055] Example 8:

[0056] Weigh 3.30 g of ritonavir, 0.68 g of polyvinylpyrrolidone K30, and 2.02 g of hypromellose E50. Mix them evenly and add to 40 mL of a mixed solution of absolute ethanol and dichloromethane (mixed in a volume ratio of 3:1). After ultrasonic dissolution, use a rotary evaporator to remove the solvent under reduced pressure at 50 °C. After 3 hours, remove it and transfer the solid product to a watch glass, and dry it overnight in a vacuum drying oven at 50 °C. Finally, grind and crush it, and pass through a 120-mesh sieve to obtain the solid dispersion.

[0057] Weigh three portions of 0.091 g of the solid dispersion and add them to 900 mL of phosphate buffer solution with pH = 6.8, and conduct the powder dissolution experiment under non-sink conditions according to the method of Example 3. The results show that under this pH condition, the dissolution rate of the solid dispersion containing 33.75% of hypromellose is much higher than that of the solid dispersion with polyvinylpyrrolidone as the carrier alone. The drug concentration at 10 min reaches 15.09 μg / mL, and the drug concentration at 60 min is 21.19 μg / mL (see Figure 4 ).

[0058] Example 9:

[0059] Weigh 3.30 g of ritonavir and 2.7 g of hypromellose E50, mix them evenly, and add them to a mixed solution of 40 mL of anhydrous ethanol and dichloromethane (mixed in a volume ratio of 3:1). After ultrasonic dissolution, use a rotary evaporator to remove the solvent under reduced pressure at 50 °C. After 3 hours, remove it and transfer the solid product to a watch glass, and dry it overnight in a vacuum drying oven at 50 °C. Finally, grind and crush it, and pass it through a 120-mesh sieve to obtain a solid dispersion.

[0060] Weigh 0.091 g of the solid dispersion and put it into 900 mL of phosphate buffer solution with pH = 6.8, and conduct the powder dissolution experiment under non-sink conditions according to the method of Example 3. The results show that under this pH condition, the dissolution rate of the ritonavir solid dispersion with hypromellose as the carrier and a drug loading of 55% is much higher than that of the solid dispersion with povidone as the carrier. The drug concentration at 60 min is 9.73 μg / mL (see Figure 4 ).

[0061] Example 10:

[0062] Weigh about 5 mg of the solid dispersion prepared in Example 7 in an aluminum pot, and use a differential scanning calorimeter to detect the thermal behavior of the sample. The nitrogen flow rate is 50 mL / min, the heating rate is 10 °C / min, and the scanning range is 30 °C to 200 °C. Another 5 mg of ritonavir raw material is operated in the same way, and the obtained spectrum is shown in Figure 5 . It can be seen from the figure that the ritonavir raw material has a strong endothermic peak at 125 °C, which is its melting point. However, the solid dispersion has no such endothermic peak, indicating that the obtained product is an amorphous solid dispersion.

[0063] Take appropriate amounts of ritonavir raw material and the solid dispersion product of Example 7, and use powder X-ray diffraction to measure their diffraction patterns. The results are shown in Figure 6 . From Figure 6 , it can be seen that within the scanning range, the strong sharp diffraction peak of the ritonavir raw material does not appear in the solid dispersion obtained in Example 7, indicating that the product obtained in Example 7 is an amorphous solid dispersion.

[0064] Example 11:

[0065] The products obtained in Example 5 and Example 7 were subjected to an in vitro artificial gastric-duodenal model simulation dissolution experiment to evaluate the dissolution effect of the solid dispersion under simulated in vivo dynamic changes. The specific operation steps are as follows: Two jacketed beakers were connected in series to simulate the gastric chamber and the duodenal chamber respectively. The gastric chamber consisted of 50 mL of pH 1 hydrochloric acid and 200 mL of water, and the duodenal chamber was 30 mL of pH 6.8 phosphate buffer solution. An infusion pump was used to pump pH 2 hydrochloric acid into the gastric chamber at a rate of 2 mL / min to simulate gastric juice secretion, and pH 6.8 phosphate buffer solution was pumped into the duodenum to simulate duodenal juice secretion. A programmed peristaltic pump was used to simulate the transfer process of the gastric chamber contents to the duodenal chamber at a first-order kinetic rate (t 1 / 2 = 15 min). The duodenal chamber and the waste liquid chamber were connected by a connecting tube to keep the liquid volume of 30 mL constant. The gastric chamber and the duodenal chamber were maintained at a temperature of 37 °C and were magnetically stirred respectively to maintain uniform dispersion. 0.091 g of the solid dispersions obtained in Example 5 and Example 7 were weighed and put into the gastric chamber for the dissolution experiment. The drug concentration was monitored in real time by an optical fiber probe, and the experiment was carried out in three parallel groups. The obtained dissolution curves are shown in Figure 7 (gastric chamber) and Figure 8 (duodenal chamber). It can be seen from the figure that the highest concentration of ritonavir in the gastric chamber of the ternary solid dispersion with a drug loading of 55% obtained in Example 7 can reach 100.17 μg / mL, and the highest concentration that the binary solid dispersion with a drug loading of 55% obtained in Example 5 can reach is 46.27 μg / mL. In the intestinal chamber, the highest drug concentration of the ternary solid dispersion in Example 7 is 82.32 μg / mL, and an obvious supersaturation phenomenon can occur. The highest drug concentration of the binary solid dispersion in Example 5 is 21.97 μg / mL. It is proved that the hydroxypropyl methylcellulose E50 added in Example 7 can effectively inhibit the crystallization behavior of ritonavir when transferring from an acidic environment to a neutral environment, increase the drug concentration in the solution, and improve the bioavailability of the drug.

[0066] Example 12:

[0067] The microscopic morphological changes on the surface of the tablets during the dissolution process were observed by scanning electron microscopy. 100 mg of the solid dispersions obtained in Example 5 and Example 7 were weighed and pressed into tablets under a pressure of 172 MPa. The tablets were fixed in a mold and taken out after dissolving in 200 ml of pH = 6.8 phosphate buffer solution (37 °C) at a rotation speed of 240 rpm for 0 s and 30 min, and then vacuum dried overnight. The surface of the dried tablets was observed by a scanning electron microscope to obtain scanning electron microscope images ( Figure 9) The results showed that no obvious crystals appeared on the surface of the tablets after dissolution of the ternary solid dispersion obtained in Example 7 with hypromellose E50 added. However, obvious acicular crystals of ritonavir appeared on the surface of the binary solid dispersion obtained in Example 5 without hypromellose E50 added at 0 s of dissolution. When the dissolution time was extended to 30 min, the crystals grew into irregular polyhedra with larger volumes. This indicates that hypromellose E50 inhibited the crystallization behavior of ritonavir during the dissolution process, and the combined use with povidone K30 can obtain a high-loading ritonavir solid dispersion with excellent dissolution performance.

[0068] Example 13:

[0069] The solid dispersion obtained in Example 7 was placed in an environment with a temperature of 40 °C and a relative humidity of 75% for stability experiment investigation. It was taken out at 0, 1, 2, and 3 months respectively and the crystal form structure of the drug was characterized by powder X-ray diffraction method; another 0.091 g of the sample was weighed and put into 500 mL of hydrochloric acid solution with pH = 1.4 for powder dissolution experiment, and the experiment was carried out in three parallel groups. Figure 10 As the obtained powder X-ray diffraction pattern, it can be seen that no strong and sharp diffraction peaks appeared in the obtained solid dispersion within three months, proving that the amorphous form was maintained. Figure 11 As the obtained dissolution curves, no obvious differences appeared between the dissolution curves, and they all had excellent dissolution performance, proving the good stability of the solid dispersion obtained in Example 7.

Claims

1. A high drug loading ritonavir solid dispersion with solubilizing properties, characterized in that: Made of the following components in mass percentage: Ritonavir 35-55% Hydroxypropyl methylcellulose E50 11.2~33.75% Povidone K30 balance.

2. The solid dispersion according to claim 1, wherein Made of the following components in mass percentage: Ritonavir 55% Hydroxypropyl methylcellulose E50 22.5% Povidone K30 22.5%.

3. The method for preparing a solid dispersion according to claim 1, wherein The preparation method is as follows: Ritonavir, povidone K30, and hydroxypropyl methylcellulose were added to a mixed solvent of anhydrous ethanol and dichloromethane, and after ultrasonic dissolution, the solvent was evaporated under reduced pressure at 50°C, and then dried in a vacuum drying oven at 50°C. Finally, the mixture was ground and sieved through a 120-mesh sieve to obtain a solid dispersion.

4. The preparation method according to claim 3, wherein In the mixed solvent of anhydrous ethanol and dichloromethane, the volume ratio of anhydrous ethanol to dichloromethane is 3:1.

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