Solid dispersion of itraconazole as well as preparation method and application of solid dispersion

Abstract

The invention relates to the technical field of western medicine preparations, and discloses an itraconazole solid dispersion as well as a preparation method and application thereof, and the solid dispersion is prepared from itraconazole, a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol grafted copolymer and copovidone in a mass ratio of (0.5-2): (0.1-5): (0.01-5). The preparation method comprises the following steps: mixing the itraconazole, the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol grafted copolymer and the copovidone according to the formula ratio, and adding into a hot melt extruder; the temperature of an extruder is set to be 145-175 DEG C, the rotating speed of a screw of equipment used for hot melt extrusion is 100-250 rpm, and crushing is performed after extrusion to obtain the itraconazole dispersion. The itraconazole solid dispersion prepared by the invention has better dissolution rate in cat gastrointestinal tracts and is easy to disperse, the dissolution rate of the itraconazole solid dispersion is 85-95%, and the complete dispersion time is 1-3 minutes.

Description

Technical Field

[0001] The invention belongs to the technical field of western medicine preparations, and particularly relates to a solid dispersion of itraconazole and a preparation method and application thereof. Background Art

[0002] Itraconazole is a synthetic triazole derivative with a pka of 3.7. It has strong lipophilicity and is almost insoluble in water. It belongs to BCS class II drugs and has the characteristics of high permeability and low solubility. Studies have shown that the absorption site of itraconazole is the anterior small intestine. The small intestine is divided into three segments: the duodenum, jejunum, and ileum. The duodenum is the first segment of the small intestine, that is, the anterior small intestine. For cats, the average pH of the duodenum is 5.7±0.5, and the average pH of the jejunum and ileum is 6.4±0.5 and 6.6±0.8, respectively. However, itraconazole is almost insoluble in an environment with a pH greater than 2. Due to the poor solubility of itraconazole and the long dissolution time, its absorption in cats is poor, which limits the efficacy of itraconazole.

[0003] In addition, the itraconazole dispersible tablets currently on the market were originally designed as human drugs. The gastrointestinal tract of cats is shorter than that of humans. Therefore, the existing itraconazole oral solid preparations are poorly absorbed by cats. Summary of the invention

[0004] In order to solve the above technical problems, the present invention provides a solid dispersion of itraconazole and a preparation method and application thereof.

[0005] A solid dispersion of itraconazole, wherein the solid dispersion is prepared by mixing itraconazole, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and copovidone and then subjecting the mixture to hot melt extrusion;

[0006] The mass ratio of itraconazole, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and copovidone is 0.5-2:0.1-5:0.01-5;

[0007] The temperature of the hot melt extrusion is 145°C to 175°C;

[0008] The screw speed of the hot melt extrusion equipment is 100 rpm to 250 rpm. The hot melt extrusion conditions are determined by measuring the differential thermal scanning of physical mixing to determine the extrusion temperature, and the screw speed is determined during the preparation process according to the change in torque and whether white spots appear in the extrudate due to the change in residence time.

[0009] The solid dispersion of itraconazole in the present invention uses polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as a carrier, loads itraconazole thereon, and improves the dispersibility of the solid dispersion under the action of copolyvidone. After mixing itraconazole, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and copolyvidone in a mass ratio of 0.5-2:0.1-5:0.01-5 and hot-melt extrusion, the obtained solid dispersion of itraconazole has a solubility of at least 85% at 10 minutes, and the dispersion effect is not affected by pH. Under the condition that the pH changes from 1 to 7.4, it can still maintain high solubility, release a large amount of itraconazole in a shorter gastrointestinal tract, so that it can be fully absorbed in the anterior segment of the small intestine, thereby effectively improving the gastrointestinal absorption effect of itraconazole.

[0010] In another preferred embodiment, the copovidone is copovidone VA64.

[0011] The second object of the present invention is to protect the preparation method of the solid dispersion of itraconazole, which specifically comprises the following steps:

[0012] Weigh the raw materials respectively according to the mass ratio, mix them, and obtain a mixture;

[0013] The mixture is hot-melt extruded and pulverized to obtain the itraconazole dispersion.

[0014] The third object of the present invention is to protect the use of the solid dispersion of itraconazole in the preparation of itraconazole tablets for pets.

[0015] In another preferred embodiment, the preparation method of the pet itraconazole tablets is as follows:

[0016] The itraconazole dispersion is mixed with a filler, a disintegrant, and a lubricant, and then tabletted to obtain the pet itraconazole tablet;

[0017] The mass ratio of itraconazole dispersion, filler, disintegrant and lubricant is 55-65:20-30:6-12:1.5-3.5.

[0018] In another preferred embodiment, the filler is prepared by compounding microcrystalline cellulose and mannitol in a mass ratio of 125-135:10-20.

[0019] In another preferred embodiment, the disintegrant is crospovidone.

[0020] In another preferred embodiment, the lubricant is compounded by fumed silica, talc and magnesium stearate in a mass ratio of 1-5:1-5:0.1-2.

[0021] In another preferred embodiment, the pet is a cat.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] (1) The present invention uses polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as a carrier, loads itraconazole thereon, and improves the dispersibility of the solid dispersion under the action of copolyvidone. By controlling the masses of traconazole, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and copolyvidone, and using the heat and shear force of hot melt extrusion to further improve the solubility under hot melt extrusion, the obtained solid dispersion of itraconazole has the characteristics of high solubility and easy dispersion, and its 10min solubility can reach 85% to 95%, and the time for complete dispersion is 1min to 3min, so that it can be quickly dissolved in a relatively short intestinal tract, thereby promoting the absorption of itraconazole in the front part of the small intestine.

[0024] (2) When the pH value of the pet itraconazole tablets of the present invention changes from 1 to 7.4, the solubility of the pet itraconazole tablets still reaches about 50%. Compared with the commercially available itraconazole dispersible tablets Smik, which have a solubility of less than 20%, the pet itraconazole tablets of the present invention have a higher solubility and can still have a high solubility under high pH conditions, so that they can be used on cats and other pets with shorter gastrointestinal tracts to improve the absorption effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 This is a cumulative dissolution graph of itraconazole dispersions prepared in Examples 1 to 4.

[0026] Figure 2 The X-ray powder diffraction patterns of the itraconazole dispersion, carrier and itraconazole raw material prepared in Example 1 are shown.

[0027] Figure 3 This is a differential thermal scanning spectrum of the itraconazole dispersion, the carrier and the itraconazole bulk drug prepared in Example 1, wherein a is an enlarged view circled in the figure.

[0028] Figure 4 This is a scanning electron microscope image of the itraconazole dispersion prepared in Example 1.

[0029] Figure 5 This is the cumulative dissolution graph of the itraconazole tablets for pets in Example 1, Comparative Example 1, and Comparative Example 2.

[0030] Figure 6 The dissolution performance of itraconazole dispersible tablets prepared in Example 1 and commercially available Hasanlian dispersible tablets under changing pH conditions is shown.

[0031] Figure 7The drug-time curves of the itraconazole dispersible tablets prepared in Example 1 and the commercially available Hasanlian dispersible tablets are shown in FIG. DETAILED DESCRIPTION

[0032] The following will be combined with the specific embodiments of the present invention to clearly and completely describe the technical solutions in the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0033] The methods described in the embodiments of the present invention are conventional methods unless otherwise specified. The materials, reagents, etc. used can be obtained from commercial sources unless otherwise specified.

[0034] Solid dispersions typically contain a hydrophobic solid drug uniformly dispersed in a hydrophilic solid matrix. Both the matrix and the dispersed drug particles can be in crystalline or amorphous form. In this simple system, the dissolution of the carrier becomes the rate-limiting step. After the solid dispersion is formed, the particle size of the drug is reduced, especially at the molecular level, the drug changes from crystalline to amorphous, and the wettability of the drug increases, so that the saturated solubility and dissolution rate of the drug are improved. The solid dispersion produces a supersaturated drug solution when exposed to the aqueous environment of the gastrointestinal tract. The drug in this state tends to precipitate quickly before being absorbed, resulting in reduced bioavailability. The polymers commonly used to prepare solid dispersions are the same as those that inhibit drug precipitation, especially some cellulose derivatives such as hydroxypropyl methylcellulose and hydroxypropyl methylcellulose acetate succinate and vinyl polymers such as polyvinyl pyrrolidone and polyvinyl pyrrolidone-covinyl. These polymers are able to maintain supersaturated drug concentrations in the body for a long time to achieve optimal absorption. Polymer-drug interactions may be mainly the result of hydrogen bond formation and / or hydrophobic interactions. For example, studies have shown that hydroxypropyl methylcellulose effectively inhibits the nucleation of drugs rich in hydrogen bond receptors in a concentration-dependent manner. This ability to delay nucleation may be because hydrogen bonds between drug molecules and polymers not only increase the activation energy of nucleation, but also reduce crystal growth. Hydrogen bonds are not the only type of interaction that affects drug precipitation / dissolution in solid dispersions. Studies have also pointed out that the lipophilicity of the polymer has a significant positive correlation with its ability to inhibit or delay the nucleation and growth of crystals. This is because the higher the lipophilicity of the polymer, the easier it is to adsorb on the crystal surface, thereby enhancing the inhibitory effect on further drug attachment. However, there is an upper limit to this ability, beyond which the inhibitory effect on drug attachment will weaken. Studies have shown that other factors that may play a key role in the interaction between polymers and drugs are steric hindrance adsorption, polymer stiffness, and the distribution of functional groups, among which the stiffness of the polymer is believed to affect the adsorption on the crystal surface. Polymers with relatively rigid structures can be more easily adsorbed to inhibit the precipitation of drugs. In the above scenario, the dissolution rate of the solid dispersion is fast and complete, and the supersaturated solution around the solid dispersion determines the concentration of free drugs. In contrast, solid dispersion particles may dissolve slowly due to high drug loading or the nature of the polymer, resulting in a more sustained release profile. As water continues to penetrate into the solid dispersion particles, phase separation will eventually occur. If drug crystallization is still inhibited by the polymer matrix in this case, the drug may form amorphous aggregates and the free drug concentration in the dissolution medium will be equal to the solubility of the amorphous drug. However, if the drug is present in the solid dispersion particles in a crystalline state, the free drug concentration in the solution is reduced to the solubility of the drug crystals, that is, the solubility advantage of the solid dispersion is lost.

[0035] Methods for generating solid dispersions Hot melt extrusion and spray drying are now commonly used in drug production. Hot melt extrusion, introduced in the early 1930s, quickly became the most widely used processing technology in the plastics, rubber and food industries. It was expanded to the pharmaceutical industry in the early 1970s for formulation and product development and manufacturing. Hot melt extrusion is a continuous pharmaceutical process that involves pumping polymer materials with a rotating screw at a temperature above the glass transition temperature Tg and sometimes above the melting temperature Tm to achieve molecular-level mixing of active compounds and thermoplastic binders, polymers or both. In the hot melt extrusion process, the drug is premixed with thermoplastic polymers and other excipients, and then the mixture is loaded into a single-screw or twin-screw extruder. The extruder provides two forces to the mixture, one is heat and the other is shear force generated by the screw. Under the action of heat and shear force, the mixture of drug and polymer melts and mixes. Subsequently, the melt is extruded from the die and processed into different dosage forms through downstream processing equipment. This molecular mixing converts the components into an amorphous product with uniform shape and density, thereby increasing the solubility of poorly water-soluble drugs.

[0036] The embodiment of the present invention provides a solid dispersion of itraconazole, which uses a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as a carrier and improves the dispersibility of the solid dispersion under the action of copovidone. The solid dispersion of itraconazole obtained by loading itraconazole on the carrier and performing hot melt extrusion has better solubility.

[0037] The polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and copovidone VA64 used in the present invention are from BASF China Co., Ltd.; microcrystalline cellulose is from Shanghai Shenmei Pharmaceutical Development Technology Co., Ltd.; mannitol is from Merck China Co., Ltd.; magnesium stearate is from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.; talc is from Guangxi Longsheng Huamei Talc Development Co., Ltd.; fumed silica is from Hubei Huifu Nano Technology Co., Ltd.; itraconazole is from Sichuan Beite Pharmaceutical Co., Ltd.; the model of the hot melt extruder is PPSTSE16p.

[0038] The abbreviation of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer is Soluplus; the abbreviation of crospovidone is CL-F; abbreviation of copolyvidone VA64 VA64.

[0039] Example 1

[0040] A method for preparing a solid dispersion of itraconazole comprises the following steps:

[0041] S1, 80g of itraconazole, 80g of Soluplus and 80g of After VA64 is mixed evenly, a mixture is obtained.

[0042] S2. Add the mixture into a hot melt extruder, set the hot melt extrusion temperature to 155° C., set the screw speed of the hot melt extruder to 200 rpm, extrude into a rod-like object, and use a hammer mill to crush the rod-like object to obtain a solid dispersion of itraconazole with a particle size of 280 μm.

[0043] The specific process of preparing pet itraconazole tablets from the above-mentioned solid dispersion tablets of itraconazole is as follows:

[0044] 75 g of itraconazole dispersion, 11 g of mannitol, 80 g of microcrystalline cellulose, 24 g of CL-F, 2 g of magnesium stearate, 4 g of talc and 4 g of fumed silicon dioxide were mixed evenly and compressed with a tablet press to obtain pet itraconazole tablets with a tablet weight of 200 mg, a diameter of 10 mm, a thickness of 5 mm and a hardness of 70±10N.

[0045] Example 2

[0046] A method for preparing a solid dispersion of itraconazole comprises the following steps:

[0047] S1, 60g of itraconazole, 90g of Soluplus and 90g of VA64 was mixed uniformly to obtain a mixture.

[0048] S2. Add the mixture into a hot melt extruder, set the hot melt extrusion temperature to 155° C., set the screw speed of the hot melt extruder to 200 rpm, extrude into a rod-like object, and crush the obtained rod-like object using a hammer mill to obtain a solid dispersion of itraconazole with a particle size of 280 μm.

[0049] The specific process of preparing pet itraconazole tablets from the solid dispersion of itraconazole is as follows:

[0050] 100 g of itraconazole solid dispersion, 24 g of CL-F, 7 g of mannitol, 59 g of microcrystalline cellulose, 2 g of magnesium stearate, 4 g of talc and 4 g of fumed silicon dioxide were mixed evenly and tableted with a tablet press to obtain pet itraconazole tablets with a tablet weight of 200 mg, a diameter of 10 mm, a thickness of 5 mm and a hardness controlled at 70±10N.

[0051] Example 3

[0052] A method for preparing a solid dispersion of itraconazole comprises the following steps:

[0053] S1 Mix 60g of itraconazole, 120g of Soluplus and 120g of VA64 was mixed uniformly to obtain a mixture.

[0054] S2. Add the mixture into a hot melt extruder, set the hot melt extrusion temperature to 155° C., set the screw speed of the hot melt extruder to 200 rpm, extrude into a rod-like object, and use a hammer mill to crush the rod-like object to obtain a solid dispersion of itraconazole with a particle size of 280 μm.

[0055] The specific process of preparing pet itraconazole tablets from the solid dispersion of itraconazole is as follows:

[0056] 125 g of itraconazole solid dispersion, 24 g of CL-F, 5 g of mannitol, 36 g of microcrystalline cellulose, 2 g of magnesium stearate, 4 g of talc and 4 g of fumed silicon dioxide were mixed evenly and tableted with a tablet press to obtain pet itraconazole tablets with a tablet weight of 200 mg, a diameter of 10 mm, a thickness of 5 mm and a hardness controlled at 70±10N.

[0057] Example 4

[0058] A method for preparing a solid dispersion of itraconazole comprises the following steps:

[0059] S1, 20g of itraconazole, 40g of Soluplus and 4g of After VA is mixed uniformly, a mixture is obtained.

[0060] S2. Add the mixture into a hot melt extruder, set the hot melt extrusion temperature to 155° C., set the screw speed of the hot melt extruder to 200 rpm, extrude into a rod-like object, and use a hammer mill to crush the rod-like object to obtain a solid dispersion of itraconazole with a particle size of 280 μm.

[0061] The specific process of preparing pet itraconazole tablets from the solid dispersion of itraconazole is as follows:

[0062] 50 g of itraconazole solid dispersion, 24 g of CL-F, 13 g of mannitol, 103 g of microcrystalline cellulose, 2 g of magnesium stearate, 4 g of talc and 4 g of fumed silicon dioxide were mixed evenly and tableted with a tablet press to obtain pet itraconazole tablets with a tablet weight of 200 mg, a diameter of 10 mm, a thickness of 5 mm and a hardness controlled at 70±10N.

[0063] Comparative Example 1

[0064] A method for preparing a solid dispersion of itraconazole comprises the following steps:

[0065] S1. Mix 100 g of itraconazole and 400 g of Soluplus evenly to obtain a mixture.

[0066] S2. Add the mixture into a hot melt extruder, set the hot melt extrusion temperature to 155° C., set the screw speed of the hot melt extruder to 200 rpm, extrude into a rod-like object, and crush the obtained rod-like object using a hammer mill to obtain a solid dispersion of itraconazole with a particle size of 280 μm.

[0067] The specific process of preparing pet itraconazole tablets from the solid dispersion of itraconazole is as follows:

[0068] 300g of itraconazole dispersion, 12g of mannitol, 129g of microcrystalline cellulose, 24g of CL-F, 2 g of magnesium stearate, 4 g of talc, and 4 g of fumed silicon dioxide are mixed evenly and compressed with a tablet press to obtain pet itraconazole tablets with a tablet weight of 200 mg, a diameter of 10 mm, a thickness of 5 mm, and a hardness of 70±10N.

[0069] Comparative Example 2

[0070] A method for preparing a solid dispersion of itraconazole comprises the following steps:

[0071] S1, 100g of itraconazole and 400g of After VA64 is mixed evenly, a mixture is obtained.

[0072] S2. Add the mixture into a hot melt extruder, set the hot melt extrusion temperature to 155° C., set the screw speed of the hot melt extruder to 200 rpm, extrude into a rod-like object, and crush the obtained rod-like object using a hammer mill to obtain a solid dispersion of itraconazole with a particle size of 280 μm.

[0073] The specific process of preparing pet itraconazole tablets from the solid dispersion of itraconazole is as follows:

[0074] 300g of itraconazole dispersion, 12g of mannitol, 129g of microcrystalline cellulose, 24g of CL-F, 2 g of magnesium stearate, 4 g of talc, and 4 g of fumed silicon dioxide are mixed evenly and compressed with a tablet press to obtain pet itraconazole tablets with a tablet weight of 200 mg, a diameter of 10 mm, a thickness of 5 mm, and a hardness of 70±10N.

[0075] The solid dispersions of itraconazole in Examples 1 to 4 were respectively subjected to cumulative dissolution tests. The results are as follows: Figure 1 As shown. Figure 1It can be seen that the solid dispersions of itraconazole in Examples 1 to 3 all reached a cumulative dissolution rate of more than 80% in 10 minutes, while the solid dispersion of itraconazole in Example 4 had a lower solubility, with a cumulative dissolution rate of only 50% in 10 minutes. Since the cumulative dissolution curves of the solid dispersions of itraconazole prepared in Examples 2 to 3 are basically the same as those of the solid dispersions of itraconazole prepared in Example 1, the solid dispersions of itraconazole prepared in Example 1 are used as an example for testing below.

[0076] The itraconazole dispersion in Example 1 was subjected to X-ray powder diffraction analysis. Figure 2 As shown, from Figure 2 It can be seen that after itraconazole is prepared into a hot-melt extrudate, the characteristic diffraction peak of the active pharmaceutical ingredient disappears, indicating that the active pharmaceutical ingredient has been completely transformed into an amorphous form.

[0077] The crystal form of the itraconazole dispersion in Example 1 was studied to determine the conditions for subsequent production. Differential thermal scanning analysis was performed on the dispersion. Figure 3 The results showed that the characteristic endothermic peak of itraconazole disappeared after it was prepared into hot-melt extrudate, indicating that the active pharmaceutical ingredient had completely transformed into an amorphous state. Scanning electron microscopy revealed that the prepared itraconazole hot-melt extrudate was waxy and had no crystalline state, confirming that itraconazole had completely transformed from crystalline to amorphous state. Figure 4 shown.

[0078] 1. Dissolution of itraconazole tablets for different pets

[0079] Using 1000 mL of 9 mL / 1000 mL hydrochloric acid solution as the dissolution medium and a rotation speed of 75 revolutions per minute, the dissolution of the pet itraconazole tablets in Example 1, Comparative Example 1 and Comparative Example 2 was determined by referring to the dissolution determination method of itraconazole capsules in the Chinese Pharmacopoeia 2015 edition.

[0080] Take 10 mg of each of the pet itraconazole tablets in Example 1, Comparative Example 1, and Comparative Example 2, use 1000 mL of 9 mL / 1000 mL hydrochloric acid solution as the dissolution medium, rotate at 75 revolutions per minute, take 5 ml of solution at 5 min, 10 min, 15 min, 30 min, 45 min, and 60 min, add the same volume of dissolution medium after each liquid taking, filter, and take the filtrate to obtain 3 test samples. Take 10 mg of itraconazole standard as a reference substance, place it in a 100 ml volumetric flask, dissolve it with 30 ml of acetonitrile by ultrasonication, dilute it to the scale with the dissolution medium, shake it well, accurately measure an appropriate amount and filter it, and take the filtrate as the reference substance solution.

[0081] Take the above three test samples and the reference substance and dissolve them. Use high performance liquid chromatography to measure the dissolution rate. The measurement wavelength is 261nm, the temperature is 35℃, the injection volume is 20μL, and the running time is 20 minutes. Calculate the cumulative dissolution rate of each tablet. The results are as follows: Figure 5 As shown. Figure 5 It can be seen that the cumulative dissolution rate of the solid dispersion of itraconazole in Example 1 reaches more than 90% in 10 minutes, while the cumulative dissolution rate of the solid dispersion of itraconazole in Comparative Example 1 is about 70%, and the cumulative dissolution rate of the solid dispersion of itraconazole in Comparative Example 2 is only more than 50%. It can be seen that the present invention uses the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as a carrier, and under the action of copovidone, the dispersibility of the solid dispersion of itraconazole can be effectively improved by combining the two.

[0082] 2. pH dissolution of itraconazole tablets for different pets

[0083] Since itraconazole itself can only be dissolved at extremely low pH and its absorption site is mainly in the anterior small intestine, it is necessary to study its absorption method in the gastrointestinal tract.

[0084] Take 10 mg of each of the pet itraconazole tablets and the commercially available Smacker dispersible tablets in Example 1, respectively, and mix them with 750 ml of a hydrochloric acid solution with a concentration of 9 mL / 1000 mL and a pH of 1 at a speed of 75 revolutions per minute. Sampling is performed at 30 minutes and 60 minutes, respectively, and then 250 mL of a 0.2 mol / L trisodium phosphate solution is added to make the pH 7.4 similar to the anterior segment of the small intestine, thereby simulating the absorption of itraconazole in vitro. Subsequently, sampling is performed at 10 minutes, 20 minutes, 30 minutes, and 60 minutes after the addition of the trisodium phosphate solution, filtered, and the dissolution is calculated. The results are as follows: Figure 6 As shown. Figure 6 It can be seen that compared with the commercially available Smiker dispersible tablets, the pet itraconazole tablets prepared in Example 1 of the present invention can still maintain a higher solubility after the pH is changed.

[0085] 3. Pharmacokinetic analysis of different itraconazole tablets

[0086] The pharmacokinetic study was conducted on the pet itraconazole tablets prepared in Example 1 and the commercially available Smik dispersible tablets.

[0087] Four normal and healthy British shorthair cats, male and female, over one year old, weighing 2.6-4.2kg, were fed adaptively for one week, with room temperature maintained at 20℃-25℃, humidity maintained at 50-60%, light-dark cycle of 12h, and the same amount of cat food fed daily, with unlimited water.

[0088] Eight male and female cats were randomly divided into two groups: Group A and Group C, and numbered, and water and food were cut off one night in advance. In the first cycle, Group A was fed with 70 mg / kg body weight of Smiker dispersible tablets, containing 10 mg of itraconazole, and Group C was fed with 80 mg / kg body weight of pet itraconazole tablets in Example 1, containing 10 mg of itraconazole. After administration, 1.5 mL of blood was collected with a sodium heparin tube at 1h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, and 72h, respectively, and each cycle was 20 days apart to ensure that all drugs were eliminated. In the second cycle, Group A was fed with 80 mg / kg body weight of pet itraconazole tablets in Example 1, containing 10 mg of itraconazole, and Group C was fed with 70 mg / kg body weight of Smiker dispersible tablets, containing 10 mg of itraconazole, and 1.5 mL of blood was collected at the same time and collected in a sodium heparin tube. Method for determination of itraconazole content in plasma: chromatographic column: Waters ACQUITY UPLC BEHC18 (1.7 μm, 2.1×100 mm); mobile phase: A acetonitrile, B 0.2% trifluoroacetic acid solution, flow rate of 0.2 mL / min, elution mode of gradient elution, elution program as shown in Table 1, data collection time of 0 to 5 min; injection volume 10 μl; wavelength 261 nm; column temperature 35°C.

[0089] Table 1 UPLC elution program

[0090]

[0091] Example 1 was used to conduct a pharmacokinetic study with commercially available Smiker dispersible tablets, and the results were processed using DAS 2.0 software. Figure 7 As shown, the results show that the pet itraconazole tablets in Example 1 have a huge improvement in absorption compared with the commercially available Smiker.

[0092] Table 2 Pharmacokinetic parameter results

[0093]

[0094]

[0095] Note: AUC represents the area enclosed by the horizontal axis and the time-volume curve, which reflects the degree of drug exposure in the body. For oral drugs, it reflects the degree of absorption.

[0096] Although the preferred embodiments of the present invention have been described, those skilled in the art may make other changes and modifications to these embodiments once they have learned the basic creative concept. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments and all changes and modifications that fall within the scope of the present invention.

[0097] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. A solid dispersion of itraconazole, characterized in that: The solid dispersion is prepared by mixing itraconazole, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and copovidone and then hot-melt extruding; The mass ratio of itraconazole, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and copovidone is 0.5-2:0.1-5:0.01-5; The temperature of the hot melt extrusion is 145°C to 175°C; The screw speed of the equipment used for hot melt extrusion is 100rpm to 250rpm.

2. The solid dispersion of itraconazole according to claim 1, characterized in that The copolyvidone is copolyvidone VA64.

3. A method for preparing the solid dispersion of itraconazole according to any one of claims 1 to 2, characterized in that: The following steps are involved: Weigh the raw materials respectively according to the mass ratio, mix them, and obtain a mixture; The mixture is hot-melt extruded and pulverized to obtain the itraconazole dispersion.

4. Use of the solid dispersion of itraconazole according to any one of claims 1 to 2 in the preparation of itraconazole tablets for pets.

5. The use according to claim 4, characterized in that: The preparation method of the pet itraconazole tablet is as follows: The itraconazole dispersion is mixed with a filler, a disintegrant, and a lubricant, and then tabletted to obtain the pet itraconazole tablet; The mass ratio of itraconazole dispersion, filler, disintegrant and lubricant is 50-125:41-116:23-24:9-10.

6. The use according to claim 5, characterized in that: The filler is prepared by compounding microcrystalline cellulose and mannitol in a mass ratio of 36-80:5-11.

7. The use according to claim 5, characterized in that: The disintegrant is crospovidone.

8. The use according to claim 5, characterized in that: The lubricant is prepared by compounding fumed silicon dioxide, talcum powder and magnesium stearate in a mass ratio of 1-5:1-5:0.1-2.

9. The use according to claim 5, characterized in that: The pet is a cat.

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