CN113318076B - A kind of ritonavir solid dispersion with both solubilization and crystallization inhibition effects and preparation method thereof - Google Patents

Abstract

The invention discloses a ritonavir solid dispersion with solubilization and crystal inhibition effects, which is prepared from the following components in percentage by weight: 10-30% of ritonavir, 50-90% of a high-molecular carrier material and 0-33.3% of a surfactant. The solid dispersion is formed by the medicament and the carrier material, so that the medicament can be kept in a high-dispersion state, and ritonavir bulk drugs exist in a microcrystalline state, an amorphous state, a colloid dispersion state or a molecular dispersion state, so that the dispersion degree is high, the dissolution speed of the medicament is accelerated, the absorption of the medicament can be promoted, and the bioavailability is improved.

Description

A kind of ritonavir solid dispersion with both solubilization and crystallization inhibition effects and preparation thereof method

technical field

The invention belongs to the technical field of medicine, and in particular relates to a ritonavir solid dispersion with both solubilizing and crystal-inhibiting effects and a preparation method thereof.

Background technique

Ritonavir (RTV) is a human immunodeficiency virus (HIV) protease inhibitor for the treatment of AIDS, its chemical name is N-[(2S,3S,5R)-3-hydroxy-5-[ [(2S)-3-methyl-2-[[methyl-[(2-isopropyl-1,3-thiazol-4-yl)methyl]carbamoyl]amino]butyryl]amino]- 1,6-Diphenyl-hex-2-yl]carbamic acid 5-thiazolyl methyl ester, the chemical structure is as follows:

The appearance of this product is white powder, the molecular formula is C ₃₇ H ₄₈ N ₆ O ₅ S ₂ , the relative molecular mass is 720.95, and the melting point is 120-122°C. It is easily soluble in organic solvents such as ethanol, methanol, and acetone, but almost insoluble in water. , strong lipophilicity.

Aspartic protease is a key enzyme in the maturation of human immunodeficiency virus (HIV) particles, and ritonavir inhibits the activity of this protease to block the replication of the HIV virus, thereby preventing the spread of the HIV virus in the body. Since ritonavir is an effective inhibitor of CYP3A liver drug enzyme and can inhibit CYP3A-mediated biotransformation, it can be used alone or in combination with other antiretroviral protease inhibitors for the treatment of AIDS patients. . Ritonavir was first marketed in liquid preparations and capsule preparations, and was later withdrawn from the market because the capsule preparations were prone to precipitation of drug crystals during storage, which affected the efficacy of the drug ^[1] . Later, tablets prepared by hot melt extrusion technology were marketed, which can be placed at room temperature without refrigeration, and have higher bioavailability than capsules. Due to drug resistance and toxicity issues, ritonavir is often used in combination with other antiviral drugs, known as "cocktail therapy". Whether it is first-line or second-line treatment, ritonavir plays an important role ^[2] .

Solid dispersion generally refers to a dispersion system in solid form in which the drug is uniformly dispersed in the carrier in an amorphous or molecular state ^[3] . The technology of dispersing the drug uniformly in the carrier is called solid dispersion technology. Solid dispersion technology is often used to improve the dissolution of poorly soluble drugs and improve bioavailability. According to drug release properties, solid dispersions can be divided into immediate-release, sustained-controlled-release, and enteric-coated ^[4] . According to the dispersion state of the drug, solid dispersions can be divided into eutectic mixtures, solid solutions, glass solutions, and coprecipitates. The concept of solid dispersion was first proposed by Sekiguchi and Obi in 1961 ^[5] . At that time, insoluble drugs and water-soluble materials (urea) were prepared into sulfathiazole solid dispersions by melting method, which improved the dissolution of sulfathiazole, and the absorption rate of the drug was significantly faster than that of pure sulfathiazole. Urea and sugar are the earliest crystalline carrier materials used, and the dispersion prepared from crystalline carrier is the first generation of solid dispersion ^[6] . After decades of development, five generations of products have appeared, and the properties of each generation of solid dispersions are different.

Solid dispersions usually consist of two main components: API and carrier. When the API is constant, the type and quantity of the carrier have a crucial influence on the physical and chemical properties of the solid dispersion and the effect of the drug. The carriers of solid dispersions include water-soluble carriers, enteric carriers, and insoluble carriers ^[7] . Among them, water-soluble carriers are the most widely used, including polyvinylpyrrolidone (PVP) ^[8] , such as PVP K30, which is an amorphous polymer, which is easy to form hydrogen bonds with APIs, has high viscosity, and has strong anti-crystallizing properties. Polyvinylpyrrolidone-vinyl acetate copolymer (PVP VA) ^[9] , such as PVP VA64, the carrier has low hygroscopicity, which improves the stability of solid dispersion and can be used to replace PVP; polyethylene glycols (PEG) ^[10] , such as PEG 4000 and PEG 6000, have the advantages of low melting point and easy solubility in organic solvents; surfactants, such as Poloxamer 188 (Poloxamer188) ^[11] , Poloxamer 407 (Poloxamer407) ^{[ 12]} , sodium dodecyl sulfate (SDS) ^[13] , polysorbate 80 (Tween 80) ^[14] . Enteric carriers mainly include hydroxypropyl methylcellulose phthalate (HPMCP) ^[15] , hypromellose acetate succinate (HPMCAS) ^[16] and polyacrylic resins (Eudragit L and Eudragit S) ^{[ 17]} . HPMCAS is amphiphilic and pH-dependent, and has strong crystal-inhibiting ability, which can maintain drug supersaturation for a long time and prevent drug recrystallization. However, its drug solubilization ability is limited, which may affect the bioavailability of preparations. According to the content of succinyl and acetyl groups, HPMCAS can be divided into three types of H, M and L ^[18] . Insoluble carriers mainly include ethyl cellulose (EC) ^[19] and polyacrylic resins (Eudragit RL and Eudragit RS) ^[20] .

With the in-depth understanding of the solid dispersion stability and solubility enhancement mechanism, the binary solid dispersion of a single polymer encounters a bottleneck, and a third component (eg: surfactant) is added on the basis of the binary solid dispersion. The development of ternary solid dispersions to improve the performance of solid dispersions began. Ternary solid dispersion is a dispersion system formed by dispersing the drug in two excipients. The advantage of ternary solid dispersions is to improve the processability of materials, improve dissolution and bioavailability, and enhance the stability of drugs by combining excipients with different properties ^[21] .

RH 40/60)、维生素E聚乙二醇琥珀酸酯(TPGS)、柠檬酸三乙酯(TEC)等。值得注意的是，表面活性剂较好的增溶效果不一定转化为较高的渗透性和生物利用度，实际上，表面活性剂通过增加溶解度和降低晶体生长的表面张力，可能会导致药物重结晶，不利于维持过饱和度。总之，表面活性剂需要谨慎使用，不同的表面活性剂对固体分散体的性能具有不同的影响。One of the keys to the preparation of ternary solid dispersions is to select appropriate excipients. In addition to drugs and polymers, the third component added is often additives, such as surfactants and plasticizers. The use of surfactants and plasticizers can increase the solubility of the drug to improve the dissolution behavior of the drug or reduce the glass transition temperature of the system to make the solid dispersion easier to process ^[22] . Commonly used surfactants and plasticizers are sodium dodecyl sulfate (SDS), Tween 80 (Tween 80), Poloxamer, polyoxyethylene hydrogenated castor oil (

RH 40/60), vitamin E polyethylene glycol succinate (TPGS), triethyl citrate (TEC), etc. It is worth noting that the better solubilization effect of surfactants does not necessarily translate into higher permeability and bioavailability, in fact, surfactants may lead to drug reweight by increasing solubility and reducing surface tension for crystal growth. Crystallization is not conducive to maintaining supersaturation. In conclusion, surfactants need to be used carefully, and different surfactants have different effects on the performance of solid dispersions.

SUMMARY OF THE INVENTION

The main purpose of the present invention is to provide a ritonavir solid dispersion with both solubilization and crystallization inhibition effects and a preparation method thereof, thereby greatly improving the dissolution amount of ritonavir in a medium, thereby improving its bioavailability , in order to ensure the efficacy; at the same time inhibit the recrystallization phenomenon of ritonavir in vitro and in vivo, and improve the stability of the solid dispersion.

The invention provides a ritonavir solid dispersion with both solubilization and crystallization inhibition effects and a preparation method thereof. The solid dispersion is prepared from the following components in weight percentage: ritonavir 10-30 %, polymer carrier material 50%-90%, surfactant 0%-33.3%.

For the ritonavir solid dispersion, the ratio of ritonavir: polymer carrier material: surfactant is 1:4:1.

For the ritonavir solid dispersion, the preparation method of the solid dispersion can be a solvent method, comprising the following steps: respectively weighing the ritonavir bulk drug, the polymer carrier material and the surfactant in the recipe quantity, And mix evenly to obtain a physical mixture, add 15 mL of methanol, vortex, ultrasonically dissolve, place in a 60° C. blast drying oven for 6 hours, and scrape off to obtain the ritonavir solid dispersion.

Described ritonavir solid dispersion, the macromolecular carrier material is hypromellose acetate succinate HF type, hypromellose acetate succinate LF type, hypromellose acetate succinate MF Type, Povidone PVP K30, Hypromellose E5, Hypromellose E15.

The ritonavir solid dispersion is characterized in that, the preferred polymer carrier material is hypromellose succinate HF type.

The ritonavir solid dispersion is characterized in that the surfactant is one of Tween 80, Span 20 and sodium lauryl sulfate.

The ritonavir solid dispersion is characterized in that the preferred surfactant is sodium lauryl sulfate.

The ritonavir solid dispersion is characterized in that the crystallization inhibition effect of the polymer can last for at least 2 hours; and under the condition of pH 6.8, the dissolution rate within 30 minutes can reach more than 90%.

Compared with the prior art, the characteristics and beneficial effects of the present invention are:

1. The ritonavir solid dispersion solid preparation provided by the invention, the drug and the carrier material form a solid dispersion, which can keep the drug in a highly dispersed state, and the ritonavir bulk drug is in microcrystalline state, amorphous state, The colloidal dispersion state or molecular dispersion state exists, has a large degree of dispersion, and the dissolution rate of the drug is accelerated, which can promote the absorption of the drug and improve the bioavailability.

2. The polymer carrier material used in the present invention, such as hypromellose succinate (HPMCAS) carrier, has an excellent effect of inhibiting crystallization, which solves the problem that crystallization occurs after the solid dispersion prepared by the carrier material such as copovidone is dissolved. The problem of precipitation, and the prepared solid dispersion is relatively small in hygroscopicity and high in stability.

3. The surfactant used in the present invention such as sodium dodecyl sulfate (SDS) surfactant has excellent solubilization effect, and the ritonavir solid dispersion provided has better dissolution rate and can greatly improve Its dissolution in insoluble media can improve its bioavailability, thereby ensuring drug efficacy.

Description of drawings

Fig.1 Dissolution curves of solid dispersions with different ratios of RTV/HPMCAS-HF(HF)/SDS in pH=6.8 medium;

Fig.2 Dissolution curves of solid dispersions with different ratios of RTV/HPMCAS-HF in pH=6.8 medium;

Fig. 3 Solubilization effect of different polymers on RTV;

Fig. 4 Solubilization effect of different surfactants on RTV;

Fig. 5 Solubilization effect of HPMCAS-HF(HF)/SDS on RTV with different concentrations and combinations;

Fig. 6 Crystal inhibition effect of different polymers on RTV;

Fig.7 Inhibition effect of HPMCAS-HF(HF)/different surfactant binary system on RTV;

Fig. 8 Crystal inhibition effect of different ratios of HPMCAS-HF(HF)/SDS on RTV;

Figure 9 DSC chart of RTV, HPMCAS-HF, SDS, RTV/HPMCAS-HF/SDS physical mixture, RTV/HPMCAS-HF/SDS solid dispersion;

Figure 10 Dissolution of reference formulation RS, physical mixture PM, solid dispersion SD in pH=6.8 medium;

Figure 11. Plasma concentration-time curves of RTV after gavage of reference formulation RS, physical mixture PM, and solid dispersion SD rats.

Detailed ways

The present invention will be further described below with reference to the accompanying drawings and specific embodiments. It should be understood that the following description is only for explaining the present invention, and does not limit the content thereof. Unless otherwise specified, the content of each component used in the following is a weight percentage content.

In the embodiment of the present invention, the dissolution measurement of ritonavir solid dispersion is determined according to the paddle method in the dissolution measurement method of the Chinese Pharmacopoeia 2015 edition, and the dissolution medium is a phosphate buffer solution (500 mL) of pH=6.8, and the rotating speed is At 75 rpm, samples were taken at 15, 30, 60, 90, 120, and 180 min, respectively. After filtering in time, the drug concentration was measured by HPLC method, and the cumulative drug release at each time point was calculated, and the dissolution curve was drawn.

Example 1: Preparation of RTV ternary solid dispersion by solvent method. Weigh a certain amount of RTV API, HPMCAS-HF and SDS, and the ratio of RTV/HPMCAS-HF/SDS is 1:4.5:0.5. Mix well, add 15 mL of methanol, vortex, and sonicate to dissolve. Place in a 60°C blast drying oven for 6 hours, scrape it off for use in in vitro dissolution experiments.

Example 2: Preparation of RTV ternary solid dispersion by solvent method. Weigh a certain amount of RTV API, HPMCAS-HF and SDS, and the ratio of RTV/HPMCAS-HF/SDS is 1:4:1. Mix well, add 15 mL of methanol, vortex, and sonicate to dissolve. Place in a 60°C blast drying oven for 6 hours, scrape it off for use in in vitro dissolution experiments.

Example 3: Preparation of RTV ternary solid dispersion by solvent method. Weigh a certain amount of RTV API, HPMCAS-HF and SDS, and the ratio of RTV/HPMCAS-HF/SDS is 1:3.5:1.5. Mix well, add 15 mL of methanol, vortex, and sonicate to dissolve. Place in a 60°C blast drying oven for 6 hours, scrape it off for use in in vitro dissolution experiments.

Example 4: Preparation of RTV ternary solid dispersion by solvent method. Weigh a certain amount of RTV API, HPMCAS-HF and SDS, and the ratio of RTV/HPMCAS-HF/SDS is 1:3:2. Mix well, add 15 mL of methanol, vortex, and sonicate to dissolve. Place in a 60°C blast drying oven for 6 hours, scrape it off for use in in vitro dissolution experiments.

Comparative Example 1: RTV binary solid dispersion was prepared by solvent method. Weigh a certain amount of RTV API and HPMCAS-HF, and the ratio of RTV/HPMCAS-HF is 1:5. Mix well, add 15 mL of methanol, vortex, and sonicate to dissolve. Place in a 60°C blast drying oven for 6 hours, scrape it off for use in in vitro dissolution experiments.

The dissolution results of Examples 1-4 and Comparative Example 1 show that (Fig. 1), when HPMCAS-HF:SDS=4:1, the RTV solid dispersion has the best dissolution effect. That is, RTV:HPMCAS-HF:SDS=1:4:1 is the best formula for preparing RTV solid dispersion by solvent method, and the dissolution of RTV/HPMCAS-HF/SDS ternary solid dispersion is better than that of RTV/HPMCAS-HF binary System solid dispersion.

Comparative Example 2: RTV binary solid dispersion was prepared by hot melt extrusion. The RTV API and HPMCAS-HF were uniformly mixed in a ratio of 1:9 (RTV accounted for 10%) to obtain a physical mixture. A hot-melt extruder was added, the extrusion temperature was set to 140° C., and the rotational speed was set to 30 rpm.

Comparative Example 3: The difference from Comparative Example 2 is that the RTV API and HPMCAS-HF were uniformly mixed in a ratio of 2:8 (RTV accounted for 20%).

Comparative Example 4: The difference from Comparative Example 2 is that the RTV API and HPMCAS-HF were uniformly mixed in a ratio of 3:7 (RTV accounted for 30%).

The dissolution results of Comparative Examples 2-4 (Fig. 2) show that the lower the ratio of RTV, the better the dissolution effect. As the ratio of RTV increases, the dissolution rate decreases. This may be because when the proportion of RTV is high, with the dissolution of HPMCAS-HF, the concentration of RTV in the solid-liquid interface layer is high and crystallization occurs, which further hinders the release of the drug.

Comparative Example 5: 0.5mg/mL of PVP K30, VA64, HPMC E5, HPMC E15, HPMCAS-LF, HPMCAS-MF, HPMCAS-HF polymer solutions were prepared with 50mL each (pH=6.8); 3mg/mL Span 20, Tween 80, 50 mL of SDS solution (pH=6.8); 50 mL of HPMCAS-HF/SDS mixed solutions of different concentrations and ratios (pH=6.8). Add excess RTV bulk drug powder, sonicate for 30min, shake for 24h (37°C, 150rpm). After filtration through a 0.45 μm filter, the samples were injected by HPLC to analyze the RTV concentration.

The test results of Comparative Example 5 show that (Fig. 3-5), the solubility of RTV is not significantly improved after adding each polymer excipient in pH=6.8 medium, that is, the solubilization effect of each polymer on RTV is average, and Little difference. Surfactant has a certain effect on improving the solubility of RTV, and the solubilization effect of SDS is the most significant. The solubilization effect of HPMCAS-HF on RTV with different concentrations was not different, and the solubilization effect was weak; the solubilization effect of SDS was stronger than that of HPMCAS-HF, and with the increase of SDS concentration, the solubility of RTV also increased. It is worth noting that when HPMCAS-HF is added to SDS, the solubility decreases. The more HPMCAS-HF is added, the more the solubility decreases. This may be because the added HPMCAS-HF occupies a part of the micelles formed by SDS, resulting in The solubilizing effect on RTV is reduced. Therefore, the proper HPMCAS-HF/SDS ratio is crucial for the solubilization and crystallization inhibition effect of solid dispersions.

Comparative Example 6: 50 mL (pH=6.8) of polymer solutions of 0.5 mg/mL PVP K30, PVP VA64, HPMC E5, HPMC E15, HPMCAS-LF, HPMCAS-MF, and HPMCAS-HF were prepared respectively. Add 250 μL of RTV organic solution (20 mg/mL), stir at 37° C., 150 rpm, take samples at specific time points, filter through 0.45 μm membrane, and analyze RTV concentration by HPLC.

The test results of Comparative Example 6 show that (Figure 6), HPMCAS-HF has the best anti-crystal effect, and can keep RTV at a high concentration for a long time; HPMCAS-MF, HPMC E5, HPMC E15, HPMCAS-LF also have certain effects. The crystallization inhibition effect of PVP K30 and PVP VA64 is weak, and the crystallization inhibition effect of the four is close.

Comparative Example 7: 50 mL of HPMCAS-HF/SDS, HPMCAS-HF/Tween 80, and HPMCAS-HF/Span 20 were prepared respectively (pH=6.8), in which RTV accounted for 16.7%, HPMCAS-HF/surfactant= 4.5:0.5. Add 250 μL of RTV organic solution (20 mg/mL), stir at 37° C., 150 rpm, take samples at specific time points, filter with 0.45 μm filter, and analyze RTV concentration by HPLC.

The test results of Comparative Example 7 showed that (Figure 7), after adding SDS, the effect of HPMCAS-HF on RTV was improved; when Tween 80 was added, the effect of HPMCAS-HF on RTV was not changed; compared with SDS and Tween 80 , the addition of Span 20 reduced the crystallization inhibition effect of HPMCAS-HF on RTV.

Comparative Example 8: 50 mL of solutions of HPMCAS-HF and SDS in different ratios (4.5:0.5, 4:1, 3.5:1.5, 3:2) were prepared respectively, and the HPMCAS-HF solution without SDS was used as a control. Add 250 μL of RTV organic solution (20 mg/mL), stir at 37° C., 150 rpm, take samples at specific time points, filter with 0.45 μm filter, and analyze RTV concentration by HPLC.

The test results of Comparative Example 8 showed that (Figure 8), with the increase of the proportion of SDS, the crystallization inhibition effect of HPMCAS-HF on RTV was first enhanced and then weakened. When HPMCAS-HF:SDS=4:1, its crystal inhibition effect on RTV is the best. This may be because the proper ratio of HPMCAS-HF and SDS assembles into a complex, which affects the solubility and inhibition of RTV.

Comparative Example 9: Weigh RTV API, HPMCAS-HF, SDS, RTV/HPMCAS-HF/SDS (1:4:1) physical mixture (PM), RTV/HPMCAS-HF/SDS (1:4:1) ) solid dispersion (SD) 3-5 mg. The samples were evenly placed in an aluminum pan, and tested by DSC. The heating rate was 10°C·min ^-1 , and the scanning range was 30-140°C.

The DSC results of Comparative Example 9 showed ( FIG. 9 ) that RTV exhibited a sharp and single endothermic peak at about 124° C., indicating that RTV was in a crystalline state. SDS showed an endothermic peak at about 110 °C, which was consistent with literature reports. For the RTV/HPMCAS-HF/SDS ternary solid dispersion, the endothermic peak of RTV at around 124 °C disappeared, and only a weak endothermic peak belonging to SDS at 110 °C was observed, indicating that RTV is indeterminate in the solid dispersion. type exists. In the physical mixture, the endothermic peak of RTV still exists, indicating that RTV exists as a crystal in the physical mixture.

利托那韦片(参比制剂，RS)、RTV/HPMCAS-HF/SDS(1:4:1)固体分散体(SD)若干(均含RTV 50mg)，用于体外溶出实验。Comparative Example 10: Weigh RTV/HPMCAS-HF/SDS (1:4:1) physical mixture (PM),

Several ritonavir tablets (reference preparation, RS), RTV/HPMCAS-HF/SDS (1:4:1) solid dispersion (SD) (both containing RTV 50mg) were used for in vitro dissolution experiments.

The results of the dissolution test of Comparative Example 10 (Fig. 10) showed that in the pH=6.8 medium, the dissolution rate of SD was higher, and the drug concentration could be maintained at a higher level for a long time without obvious crystallization trend. The dissolution rate of the reference preparation is not as high as that of SD, and the drug concentration gradually decreases after dissolution, indicating that the anti-crystal effect of the reference preparation excipients is weak. The physical mixture has a lower dissolution rate because the RTV is present in the physical mixture in a crystalline state.

利托那韦片(参比制剂，RS)、RTV/HPMCAS-HF/SDS(1:4:1)固体分散体(SD)若干(均含RTV 20mg)，加入10mL生理盐水，配制成均一的混悬液。选择18只雌性SD大鼠(n＝6)，体重200g左右，随机平均分为三组(每组六只)进行编号。给药前禁食12h，整个实验期间自由饮水。大鼠灌胃给药，剂量10mg/kg，于给药后5min，15min，30min，1h，1.5h，2h，3h，4h，6h，8h，12h，24h从大鼠眼底静脉丛取血0.5mL于肝素化离心管中，随即5000转离心5分钟，取血浆0.2mL于1.5mL离心管，处理后测定血浆中RTV浓度。Experimental Example 1: Weigh RTV/HPMCAS-HF/SDS (1:4:1) physical mixture (PM),

Ritonavir tablets (reference preparation, RS), RTV/HPMCAS-HF/SDS (1:4:1) solid dispersion (SD) several (both containing RTV 20mg), add 10mL of normal saline to prepare a uniform suspension. Eighteen female SD rats (n=6) with a body weight of about 200 g were selected and randomly divided into three groups (six in each group) for numbering. They were fasted for 12 hours before administration and had free access to water throughout the experimental period. Rats were given intragastric administration at a dose of 10 mg/kg, and 0.5 mL of blood was collected from the fundus venous plexus of rats at 5min, 15min, 30min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, and 24h after administration. In a heparinized centrifuge tube, centrifuge at 5000 rpm for 5 minutes, take 0.2 mL of plasma into a 1.5 mL centrifuge tube, and measure the RTV concentration in plasma after treatment.

The results of the pharmacokinetic experiment in Experimental Example 1 (Fig. 11) showed that the peak time of different preparations in vivo was different, PM peaked at around 2 hours, RS peaked at around 4 hours, and SD peaked at around 5 hours. The plasma concentration of PM was low and decreased rapidly after reaching the peak, indicating that the release and absorption effects of the drug were general. RS has higher blood drug concentration, but also has the problem of short duration of peak drug concentration. SD not only has a higher blood drug concentration, but also can maintain the peak drug concentration for a long time, indicating that the drug release and absorption effect is better. The main pharmacokinetic parameters are shown in Table 1. Compared with PM, SD and RS have no statistically significant difference in T _max , but there are significant differences in C _max and AUC. There is a significant difference among the three MRT, and the SD has the longest time, indicating that the SD drug has the longest effective time. The AUC _(0-t) of SD was the highest, indicating that the formulation was better absorbed in vivo, while the AUC _(0-t) of PM was lower, possibly due to the lower drug release content. The above results indicated that the bioavailability of RTV was the highest in SD.

Table 1. Pharmacokinetic parameters of RTV after gavage in rats

Each value represents the mean±S.D. (n=6).

^* P<0.05 compared to PM.

^# P<0.05 compared to SD.

The above-mentioned embodiments of the present invention are only examples for illustrating the present invention, and are not intended to limit the specific embodiments of the present invention. For those of ordinary skill in the art, changes or modifications in other different forms can also be made on the basis of the above examples. Not all embodiments can be exemplified in detail here. Any obvious changes or changes derived from the technical solutions of the present invention are still within the protection scope of the present invention.

Claims (2)

1. a ritonavir solid dispersion having both solubilization and anti-crystal effect, is characterized in that, described solid dispersion is made of ritonavir, macromolecular carrier material hypromellose acetate succinate HF type , the surfactant is prepared from sodium lauryl sulfate, and the weight ratio of the ritonavir: polymer carrier material: surfactant is 1:4:1. 2. the preparation method of ritonavir solid dispersion as claimed in claim 1, is characterized in that, described preparation method is solvent method, comprises the following steps: respectively take by weighing the ritonavir crude drug of recipe quantity, high Molecular carrier material and surfactant, and mix them evenly to obtain a physical mixture, add 15 mL of methanol, vortex, ultrasonically dissolve, place in a 60 ° C blast drying oven for 6 hours, scrape off, and get the Ritona Wei solid dispersion.

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