Itraconazole solid dispersion with high drug loading capacity and preparation method thereof

Abstract

The invention discloses an itraconazole solid dispersion with high drug loading capacity. The itraconazole solid dispersion is prepared from the following components in percentage by weight: 40-55% of itraconazole, 40-55% of a polymer carrier and 2-6% of a crystallization inhibitor, the polymer carrier is selected from one or a combination of at least two of hydroxypropyl methylcellulose, copovidone and a polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; the crystallization inhibitor is selected from one or a combination of at least two of lauryl sodium sulfate, poloxamer and polysorbate. According to the itraconazole solid dispersion, itraconazole is highly dispersed in the polymer carrier, so that the dissolution rate of itraconazole in the solid dispersion is further improved on the basis of ensuring that the raw materials are stable and are not degraded; the crystallization inhibitor such as lauryl sodium sulfate is used for effectively inhibiting the recrystallization and easy aging and dissolution rate reduction behaviors of itraconazole in the storage process of the high-drug-loading-capacity solid dispersion.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field and relates to a drug and its preparation method, particularly to an itraconazole solid dispersion with high drug loading and its preparation method. Background Technology

[0002] Itraconazole is a triazole class of highly effective broad-spectrum antifungal drug with the chemical formula C. 35 H 38 Cl2N8O4 has a molecular weight of 705.633. Itraconazole's mechanism of action: It inhibits ergosterol synthesis by binding to fungal cytochrome P450 isoenzymes, thereby disrupting the structure and function of fungal cell membranes, achieving its inhibitory and killing effects on fungi. Itraconazole has inhibitory effects on dermatophytes (Trichophyton, Microsporum, Epidermophyton floccosum), yeasts, Cryptococcus neoformans, Malassezia, Candida (including Candida albicans, Candida glabrata, and Candida krusei), Aspergillus, Histoplasma, Paracoccus brasiliensis, Sporothrix schenckii, Chromophytum, Cladosporium, Blastomyces dermatitidis, and various other yeasts and fungi.

[0003] Itraconazole capsules are an antifungal drug developed by Janssen Pharmaceuticals, marketed under the brand name... First launched in the United States in September 1992, in a 100mg strength. Currently, this drug has been domestically produced under the brand name Sporanox, with the marketing authorization holder being Xi'an Janssen Pharmaceutical Co., Ltd. Dosage regimens include both pulse therapy and continuous treatment, and it should be taken immediately after meals to improve absorption. Sporanox is widely used in China due to its excellent antifungal effects.

[0004] Solid dispersion solubilization technology is a technique that improves drug solubility and dissolution rate by uniformly dispersing poorly soluble drugs in a highly dispersed state, such as molecules, colloids, or microcrystalline forms, within a carrier material to form a solid dispersion. Its core principle lies in increasing the surface area of ​​the drug, altering the properties of the environment surrounding the drug molecules, and utilizing the presence of amorphous forms to enhance drug solubility. Various preparation methods exist, primarily including spray drying, hot melt extrusion, freeze drying, and supercritical fluid methods.

[0005] Hot melt extrusion (HME), also known as melt extrusion technology, refers to the technology of mixing drugs, polymers, and extruders such as plasticizers in a molten state and extruding them under certain pressure, speed, and shape to form a pharmaceutical product. This technology uses a rotating screw to further compress the physical mixture, while the extruder jacket is heated to a high temperature. Under the action of intense heat and shear forces, the drug and extruders achieve good compatibility, transforming from a multiphase state at the inlet to a single-phase state at the outlet, and then extruding through the die. This technology can improve the solubility of raw materials, mask flavors, provide sustained-release and controlled-release effects, and target specific release.

[0006] Patent CN106619521A discloses an enteric-coated solid dispersion of itraconazole and its preparation method. The solid dispersion is prepared by hot-melt extrusion technology using itraconazole as the active ingredient, an enteric-coated polymeric carrier, and a surfactant. The itraconazole is amorphously dispersed in the carrier of the solid dispersion. This enteric-coated solid dispersion of itraconazole prevents itraconazole from dissolving in gastric juice, thereby effectively inhibiting recrystallization of the drug before it reaches the intestine. However, itraconazole has very low solubility in the alkaline pH environment of intestinal juice. Even when maintained in an amorphous state, the solubility remains limited, resulting in low dissolution and absorption. Therefore, the bioavailability of this drug in humans is not ideal.

[0007] Patent CN103622918A discloses an itraconazole microsphere and its preparation method, which is prepared by sequentially coating the surface of the microsphere core with an itraconazole drug-containing layer and an isolation protective layer. This itraconazole microsphere can achieve rapid dissolution; however, the introduction of the organic reagent dichloromethane presents challenges. Firstly, residual dichloromethane may cause significant gastrointestinal irritation in patients. Secondly, the use of the organic reagent and post-processing increase production costs, and the process is complex.

[0008] Patent CN105126110A discloses a solid dispersion of itraconazole, its preparation method, and its applications. Itraconazole is highly dispersed in a blended polymer binary carrier, namely hydroxypropyl methylcellulose acetate succinate and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, forming a stable and uniform solid dispersion. This solid dispersion effectively solves the aging problem during storage and improves bioavailability. However, its drug loading is low, only 25%, which cannot guarantee the stability of the solid dispersion under high drug loading conditions.

[0009] In summary, current solid dispersion technologies for itraconazole either introduce organic reagents, increasing environmental pressure and leading to increased impurities after long-term storage; or have low bioavailability and low absorption and utilization efficiency by the human body; or have low drug loading capacity, failing to meet market demand. Summary of the Invention

[0010] In order to overcome the shortcomings of the prior art, one of the objectives of this invention is to provide an itraconazole solid dispersion with a high drug loading (40-55%). The carrier of this solid dispersion is a composite carrier supplemented with a crystallization inhibitor, which can effectively inhibit the storage aging, impurity growth and dissolution reduction of amorphous itraconazole under high drug loading conditions.

[0011] To achieve the above-mentioned objectives, the technical solution of the present invention is as follows:

[0012] A high-drug-load itraconazole solid dispersion, wherein the itraconazole solid dispersion is prepared from the following components in weight percentage: 40-55% itraconazole, 40-55% polymer carrier, and 2-6% crystallization inhibitor.

[0013] Preferably, the itraconazole solid dispersion is prepared from the following components by weight percentage: 45-55% itraconazole, 43-53% polymer carrier, and 2% crystallization inhibitor.

[0014] Specifically, the itraconazole solid dispersion is prepared from the following components in weight percentage: 50% itraconazole, 48% polymer carrier, and 2% crystallization inhibitor; or 50% itraconazole, 46% polymer carrier, and 4% crystallization inhibitor; or 50% itraconazole, 44% polymer carrier, and 6% crystallization inhibitor; or 45% itraconazole, 53% polymer carrier, and 2% crystallization inhibitor; or 55% itraconazole, 43% polymer carrier, and 2% crystallization inhibitor.

[0015] The polymer carrier is selected from one or a combination of at least two of hydroxypropyl methylcellulose, copovidone, and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0016] Preferably, the polymer carrier is a combination of hydroxypropyl methylcellulose and copovidone.

[0017] More preferably, the polymer carrier is a combination of hydroxypropyl methylcellulose and copovidone in a weight ratio of 3:7 to 7:3.

[0018] Specifically, the polymer carrier is a combination of hydroxypropyl methylcellulose and copovidone in a weight ratio of 3:7, 5:5, and 7:3.

[0019] More preferably, the polymer carrier is a combination of hydroxypropyl methylcellulose and copovidone in a weight ratio of 5:5.

[0020] The crystallization inhibitor is selected from one or a combination of at least two of sodium dodecyl sulfate, poloxamer, and polysorbate.

[0021] Preferably, the crystallization inhibitor is sodium dodecyl sulfate.

[0022] The second objective of this invention is to provide a method for preparing the high-drug-loading itraconazole solid dispersion, comprising the following steps:

[0023] Step (1): Mix itraconazole, polymer carrier and crystallization inhibitor evenly to obtain a physical mixture;

[0024] Step (2), hot melt extrusion: Add the physical mixture into the hot melt extruder, set the extruder temperature to 160-180℃ and the screw speed to 200-500rpm, and extrude to obtain a long strip solid dispersion;

[0025] Step (3) Crushing: Crush the long strip-shaped solid dispersion and sieve itraconazole solid dispersion.

[0026] In step (1), itraconazole, polymer carrier and crystallization inhibitor are first passed through a 40-mesh sieve, and then itraconazole, polymer carrier and crystallization inhibitor are mixed evenly to obtain a physical mixture.

[0027] In step (3), preferably, a hammer mill, needle mill, or air jet mill is used to crush the long strip solid dispersion.

[0028] The itraconazole solid dispersion has a mesh size of 10-80 mesh, preferably 40-80 mesh.

[0029] A third objective of this invention is to provide an itraconazole formulation containing the aforementioned itraconazole solid dispersion with a high drug loading.

[0030] In some embodiments, the itraconazole formulation contains a high-load itraconazole solid dispersion and other pharmaceutically acceptable excipients.

[0031] In some embodiments, the itraconazole formulation is in the form of an oral preparation such as tablets, capsules, or granules.

[0032] Compared with the prior art, the present invention has the following beneficial effects:

[0033] Through extensive and creative experiments, the inventors employed polymer carriers such as hydroxypropyl methylcellulose and copovidone as mixed carriers to highly disperse itraconazole within the polymer carriers. This not only ensured the stability and non-degradation of the raw materials but also further improved the solubility of itraconazole in the solid dispersion. In addition, crystallization inhibitors such as the surfactant sodium dodecyl sulfate were used to effectively inhibit the recrystallization, aging, and reduced solubility of itraconazole in high-drug-load solid dispersions during storage.

[0034] In summary, the present invention can improve the storage stability and dissolution of itraconazole under high drug loading conditions, thereby improving the absorption effect of itraconazole. Attached Figure Description

[0035] Figure 1 The XRD pattern of itraconazole raw material.

[0036] Figure 2 The XRD pattern is for the blank excipient.

[0037] Figure 3 The XRD pattern of itraconazole solid dispersion (Formula 12, 40-80 mesh).

[0038] Figure 4 XRD patterns of itraconazole active pharmaceutical ingredient, blank excipient, and itraconazole solid dispersion are overlaid. Detailed Implementation

[0039] The technical solutions of this invention will be clearly and completely described below with reference to specific embodiments. Obviously, the described embodiments are only some embodiments of this invention, and not all embodiments. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0040] The materials used in the examples are as follows: Reference preparation: itraconazole capsules, purchased from Xian Janssen Pharmaceutical Co., Ltd., trade name Sporanox, specification 100mg, batch number QAJ6122; itraconazole raw material purchased from NOSCH; hydroxypropyl methylcellulose E5 (HPMC E5) purchased from IFF; polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus) purchased from BASF, Germany; copovidone (VA64) purchased from BASF, Germany; sodium dodecyl sulfate purchased from Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd.

[0041] The chemical structure of impurity B is as follows:

[0042]

[0043] Chemical name: (1,2,4-triazol-4-yl)itraconazole; Molecular formula: C 35 H 38 Cl2N8O4.

[0044] The chemical structure of impurity C is as follows:

[0045]

[0046] Chemical name: Propyl itraconazole; Molecular formula: C 34 H36 Cl2N8O4.

[0047] The chemical structure of impurity D is as follows:

[0048]

[0049] Chemical name: Isopropyl itraconazole; Molecular formula: C 34 H 36 Cl2N8O4.

[0050] The chemical structure of impurity G is as follows:

[0051]

[0052] Chemical name: Dehydroxyitraconazole; Molecular formula: C 44 H 41 Cl4N 11 O6.

[0053] Example 1

[0054] Carrier material screening

[0055] The composition of the itraconazole solid dispersion in this embodiment is shown in Table 1.

[0056] Table 1. Carrier Material Screening Formulation

[0057]

[0058] The preparation process of itraconazole solid dispersion includes the following steps:

[0059] Step (1), sieving and weighing: sieve all raw and auxiliary materials through a 40-mesh sieve, weigh itraconazole and polymer carrier according to Table 1, mix itraconazole and polymer carrier evenly to form a physical mixture;

[0060] Step (2), hot melt extrusion: Add the physical mixture to the hot melt extruder, set the extruder temperature of Formula 1 to 170-180℃, the extruder temperature of Formula 2 and Formula 3 to 160-170℃, the screw speed to 300rpm, and extrude to obtain a long strip solid dispersion.

[0061] Step (3), crushing: The long strip extruded material is crushed by a hammer mill and passed through a 40-mesh sieve to obtain fine powder, which is itraconazole solid dispersion.

[0062] The dissolution rate of the itraconazole solid dispersions prepared by the three formulations in this example was tested according to Method II of General Chapter 0931 of the Chinese Pharmacopoeia. Specifically, 1000 mL of 0.1 mol / L hydrochloric acid was used as the dissolution medium, and the rotation speed was 75 rpm. Samples were taken at 30 minutes and 60 minutes to test the dissolution rate. The results are shown in Table 2. The impurity growth of the itraconazole solid dispersions prepared by the three formulations in this example was also tested under accelerated stability (40℃, 75% RH) conditions. The results are shown in Table 3.

[0063] Table 2. Dissolution rates of itraconazole solid dispersions prepared with different carrier materials

[0064]

[0065] Table 3. Accelerated stability study results of itraconazole solid dispersions prepared with different carrier materials

[0066]

[0067] The results showed that the dissolution rate of itraconazole solid dispersions prepared with hydroxypropyl methylcellulose as a carrier was significantly higher than that of commercially available formulations, and the related substances were within acceptable limits during the stability period, although there was an upward trend. The dissolution rate of itraconazole capsules prepared with copovidone as a carrier was similar to that of commercially available formulations, but copovidone showed good compatibility with the raw material itraconazole, and the related substances did not increase significantly during the stability period. The dissolution rate of itraconazole capsules prepared with polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as a carrier was lower than that of commercially available formulations, and the related substances were higher. However, the dissolution rate of all three formulations of itraconazole solid dispersions decreased significantly during the stability period. Therefore, hydroxypropyl methylcellulose, with its high dissolution rate, and copovidone, with its good compatibility, were selected as alternative carriers for further research.

[0068] Example 2

[0069] Combined carrier investigation

[0070] The composition of the itraconazole solid dispersion is shown in Table 4.

[0071] Table 4. Screening formulations using combined vectors

[0072] Raw material names Prescription 4 Prescription 5 Prescription 6 itraconazole 50.00g 50.00g 50.00g Hydroxypropyl methylcellulose 15.00g 25.00g 35.00g Copolyvinylpyrrolidone 35.00g 25.00g 15.00g total 100.00g 100.00g 100.00g

[0073] The preparation process of itraconazole solid dispersion includes the following steps:

[0074] Step (1), sieving and weighing: Sieve all raw and auxiliary materials through a 40-mesh sieve, weigh itraconazole, hydroxypropyl methylcellulose and copovidone according to Table 4, mix the three evenly to form a physical mixture;

[0075] Step (2), hot melt extrusion: Add the physical mixture into the hot melt extruder, set the extruder temperature to 170-180℃ and the screw speed to 300rpm, and extrude to obtain a long strip solid dispersion;

[0076] Step (3), crushing: The long strip extruded material is crushed by hammer mill, passed through a 40-mesh sieve, and the fine powder is itraconazole solid dispersion.

[0077] The dissolution rate of the itraconazole solid dispersion prepared in this example was investigated according to Method II of General Chapter 0931 of the Chinese Pharmacopoeia. Specifically, 1000 mL of 0.1 mol / L hydrochloric acid was used as the dissolution medium, and the rotation speed was 75 rpm. Samples were taken at 30 minutes and 60 minutes to detect the dissolution rate. The results are shown in Table 5. The impurity growth of the itraconazole solid dispersion prepared in this example under accelerated stability (40℃, 75% RH) conditions was also detected. The results are shown in Table 6.

[0078] Table 5. Dissolution rate of itraconazole solid dispersions prepared using combined carrier materials

[0079]

[0080] Table 6. Results of accelerated stability study of itraconazole solid dispersions prepared with combined carrier materials

[0081]

[0082] The results showed that in the formulation of the combined carrier, the higher the proportion of hydroxypropyl methylcellulose, the higher the dissolution rate of itraconazole solid dispersion, but the faster the impurity growth during the stability period; the higher the proportion of copovidone, the lower the dissolution rate of solid dispersion, but the slower the impurity growth during the stability period; when the weight ratio of hydroxypropyl methylcellulose to copovidone in the combined carrier was 1:1, it could both improve the high dissolution rate of itraconazole and reduce the degradation of raw materials during the stability period.

[0083] Example 3

[0084] Investigation of crystallization inhibitors

[0085] Since the itraconazole solid dispersions prepared according to formulations one through six all exhibited a decrease in dissolution during the stability period, sodium dodecyl sulfate, a crystallization inhibitor, was added to the formulations. The composition of the itraconazole solid dispersion in this example is shown in Table 7.

[0086] Table 7. Formulas for investigating crystallization inhibitors

[0087] Raw material names Prescription 7 Prescription 8 Prescription Nine itraconazole 50.00g 50.00g 50.00g Hydroxypropyl methylcellulose E5 24.00g 23.00g 22.00g Copolyvinylpyrrolidone 24.00g 23.00g 22.00g Sodium dodecyl sulfate 2.00g 4.00g 6.00g total 100.00g 100.00g 100.00g

[0088] The preparation process of itraconazole solid dispersion includes the following steps:

[0089] Step (1), sieving and weighing: Sieve all raw and auxiliary materials through a 40-mesh sieve, weigh itraconazole, hydroxypropyl methylcellulose, copovidone and sodium dodecyl sulfate according to Table 7, mix the four evenly to form a physical mixture;

[0090] Step (2), hot melt extrusion: Add the physical mixture into the hot melt extruder, set the extruder temperature to 170-180℃ and the screw speed to 300rpm, and extrude to obtain a long strip solid dispersion;

[0091] Step (3), crushing: The long strip extruded material is crushed by hammer mill, passed through a 40-mesh sieve, and the fine powder is itraconazole solid dispersion.

[0092] The dissolution rate of the itraconazole solid dispersion prepared in this example in 0.1 mol / L hydrochloric acid medium was tested according to Method II of General Chapter 0931 of the Chinese Pharmacopoeia. Specifically, 1000 mL of 0.1 mol / L hydrochloric acid was used as the dissolution medium, and the rotation speed was 75 rpm. Samples were taken at 30 minutes and 60 minutes to test the dissolution rate. The results are shown in Table 8. The impurity growth of the itraconazole solid dispersion prepared in this example during accelerated stability testing (40°C, 75% RH) was also tested. The results are shown in Table 9.

[0093] Table 8. Dissolution rate of itraconazole solid dispersions with added crystallization inhibitors

[0094]

[0095] Table 9. Results of accelerated stability study of itraconazole solid dispersions with added crystallization inhibitors

[0096]

[0097] The results showed that the addition of sodium dodecyl sulfate, a crystallization inhibitor, could effectively inhibit the storage aging of itraconazole solid dispersion and prevent the decrease in dissolution during stability testing. In addition, the addition ratio of crystallization inhibitor was 2-6%, which could effectively inhibit the decrease in dissolution. Therefore, the addition ratio of crystallization inhibitor was tentatively set at 2%.

[0098] Example 4

[0099] Drug loading study

[0100] The composition of the itraconazole solid dispersion in this embodiment is shown in Table 10.

[0101] Table 10. Prescriptions for Drug Loading Assessment

[0102] Raw material names Prescription 10 Prescription 11 itraconazole 45.00g 55.00g Hydroxypropyl methylcellulose E5 26.50g 21.50g Copolyvinylpyrrolidone 26.50g 21.50g Sodium dodecyl sulfate 2.00g 2.00g total 100.00g 100.00g

[0103] The preparation process of itraconazole solid dispersion includes the following steps:

[0104] Step (1) Sieving and weighing: Sieve all raw and auxiliary materials through a 40-mesh sieve, weigh itraconazole, hydroxypropyl methylcellulose, copovidone and sodium dodecyl sulfate according to Table 10, mix the four evenly to form a physical mixture;

[0105] Step (2), hot melt extrusion: Add the physical mixture into the hot melt extruder, set the extruder temperature to 170-180℃ and the screw speed to 300rpm, and extrude to obtain a long strip solid dispersion;

[0106] Step (3), crushing: The long strip extruded material is crushed by hammer mill, passed through a 40-mesh sieve, and the fine powder is itraconazole solid dispersion.

[0107] The drug loading does not affect the impurities of the itraconazole solid dispersion, but only the dissolution. The dissolution rate of the itraconazole solid dispersion prepared in this example in 0.1 mol / L hydrochloric acid was tested. The specific method was as follows: 1000 mL of 0.1 mol / L hydrochloric acid was used as the dissolution medium, and the rotation speed was 75 rpm. Samples were taken at 30 minutes and 60 minutes to test the dissolution rate. The results are shown in Table 11.

[0108] Table 11. Dissolution results of itraconazole solid dispersions with different drug loadings

[0109]

[0110] The results showed that a drug loading of 45-55% could effectively ensure stability and the dissolution rate did not decrease during the sample release period. Therefore, the drug loading was tentatively set at 45-55%.

[0111] Example 5

[0112] Solid dispersion particle size investigation

[0113] The composition of the itraconazole solid dispersion in this embodiment is shown in Table 12.

[0114] Table 12. Formulations for Particle Size Determination of Solid Dispersions

[0115] Raw material names Prescription Twelve itraconazole 250.00g Hydroxypropyl methylcellulose E5 120.00g Copolyvinylpyrrolidone 120.00g Sodium dodecyl sulfate 10.00g total 500.00g

[0116] The preparation process of itraconazole solid dispersion includes the following steps:

[0117] Step (1), sieving and weighing: sieve all raw and auxiliary materials through a 40-mesh sieve, weigh itraconazole, hydroxypropyl methylcellulose, copovidone and sodium dodecyl sulfate according to Table 12, mix the four evenly to form a physical mixture;

[0118] Step (2), hot melt extrusion: Add the obtained physical mixture into a hot melt extruder, set the extruder temperature to 170-180℃ and the screw speed to 300rpm, and extrude to obtain a long strip solid dispersion;

[0119] Step (3), crushing: crush the long strip extruded material with a hammer mill, and pass it through 10 mesh, 40 mesh and 80 mesh sieves in sequence to obtain 10-40 mesh particles, 40-80 mesh particles and fine powder below 80 mesh.

[0120] Particle size does not affect the impurities of itraconazole solid dispersions, but only the dissolution. The dissolution of itraconazole solid dispersions with different particle sizes prepared in this example in 0.1 mol / L hydrochloric acid was tested according to the second method of General Chapter 0931 of the Chinese Pharmacopoeia. The specific method was as follows: 1000 mL of 0.1 mol / L hydrochloric acid was used as the dissolution medium, and the rotation speed was 75 rpm. Samples were taken at 30 minutes and 60 minutes to test the dissolution. The results are shown in Table 13 below.

[0121] Table 13. Dissolution rate study results of itraconazole solid dispersions with different particle sizes

[0122]

[0123] The results show that the dissolution rate of 40-80 mesh solid dispersions is better than that of 10-40 mesh, but the dissolution rate is lower for particles smaller than 80 mesh. This is because when the particle size is too small, the true density decreases significantly, resulting in poor flowability. The powder floats on the surface of the medium and cannot be wetted, leading to a significant decrease in dissolution rate. Therefore, the preferred particle size for solid dispersions is 40-80 mesh fine powder.

[0124] X-ray diffraction (XRD) was used to characterize itraconazole raw material, blank excipients (a composition of hydroxypropyl methylcellulose, copovidone, and sodium dodecyl sulfate in a weight ratio of 12:12:1), and itraconazole solid dispersion (40-80 mesh). The XRD pattern of itraconazole raw material is shown in [image missing]. Figure 1 The XRD pattern of the blank excipient is shown in [reference needed]. Figure 2 The XRD pattern of itraconazole solid dispersion is shown in [reference needed]. Figure 3 The XRD patterns of the three samples are overlaid. Figure 4 Obvious crystal diffraction peaks can be observed in the itraconazole raw material. The characteristic crystal peaks of the raw material in the itraconazole solid dispersion all disappear, indicating that an amorphous solid dispersion has been formed.

[0125] Example 6

[0126] Preparation of itraconazole capsules

[0127] The composition of the itraconazole capsules in this embodiment is shown in Table 14.

[0128] Table 14. Prescription Table for Itraconazole Capsules

[0129]

[0130] The preparation process of itraconazole capsules is as follows:

[0131] The itraconazole solid dispersion (40-80 mesh) prepared in Example 5 was mixed evenly with the prescribed amounts of sodium carboxymethyl starch, colloidal silica and magnesium stearate to obtain a total mixture intermediate. The total mixture intermediate was then filled into No. 0 gelatin capsule shells to obtain itraconazole capsules.

[0132] In summary, the drug loading and dissolution properties of the itraconazole solid dispersion of the present invention are superior to those of commercially available formulations, and it also exhibits good stability.

[0133] The above-described embodiments merely illustrate several implementation methods of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity, not all possible combinations of the technical features in the above embodiments have been described. As long as these combinations of technical features do not contradict each other, they should be considered within the scope of this specification. It should be noted that those skilled in the art can make several modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A high-drug-loading itraconazole solid dispersion, characterized in that: The itraconazole solid dispersion is prepared from the following components by weight percentage: 40-55% itraconazole, 40-55% polymer carrier, and 2-6% crystallization inhibitor; wherein the polymer carrier is selected from one or a combination of at least two of hydroxypropyl methylcellulose, copovidone, and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; and the crystallization inhibitor is selected from one or a combination of at least two of sodium dodecyl sulfate, poloxamer, and polysorbate.

2. The itraconazole solid dispersion according to claim 1, characterized in that: The itraconazole solid dispersion is prepared from the following components by weight percentage: 45-55% itraconazole, 43-53% polymer carrier, and 2% crystallization inhibitor.

3. The itraconazole solid dispersion according to claim 1, characterized in that: The itraconazole solid dispersion is prepared from the following components in weight percentage: 50% itraconazole, 48% polymer carrier, and 2% crystallization inhibitor; or 50% itraconazole, 46% polymer carrier, and 4% crystallization inhibitor; or 50% itraconazole, 44% polymer carrier, and 6% crystallization inhibitor; or 45% itraconazole, 53% polymer carrier, and 2% crystallization inhibitor; or 55% itraconazole, 43% polymer carrier, and 2% crystallization inhibitor.

4. The itraconazole solid dispersion according to any one of claims 1-3, characterized in that: The polymer carrier is a combination of hydroxypropyl methylcellulose and copovidone in a weight ratio of 3:7 to 7:

3.

5. The itraconazole solid dispersion according to claim 4, characterized in that: The polymer carrier is a combination of hydroxypropyl methylcellulose and copovidone in a weight ratio of 5:

5.

6. The itraconazole solid dispersion according to any one of claims 1-3, characterized in that: The crystallization inhibitor is sodium dodecyl sulfate.

7. The itraconazole solid dispersion according to any one of claims 1-3, characterized in that: The itraconazole solid dispersion has a mesh size of 10-80 mesh, preferably 40-80 mesh.

8. A method for preparing the high-drug-loading itraconazole solid dispersion, characterized in that: Includes the following steps: Step (1): Mix itraconazole, polymer carrier and crystallization inhibitor evenly to obtain a physical mixture; Step (2), hot melt extrusion: Add the physical mixture into the hot melt extruder, set the extruder temperature to 160-180℃ and the screw speed to 200-500rpm, and extrude to obtain a long strip solid dispersion; Step (3) Crushing: Crush the long strip-shaped solid dispersion and sieve itraconazole solid dispersion.

9. The method for preparing itraconazole solid dispersion according to claim 8, characterized in that: In step (1), itraconazole, polymer carrier and crystallization inhibitor are first passed through a 40-mesh sieve, and then itraconazole, polymer carrier and crystallization inhibitor are mixed evenly to obtain a physical mixture; in step (3), the long strip solid dispersion is crushed by hammer mill, needle mill or air jet mill.

10. An itraconazole formulation, characterized in that: The itraconazole formulation contains the high-drug-loading itraconazole solid dispersion as described in any one of claims 1-3; the dosage form of the itraconazole formulation is one of tablets, capsules or granules.

Images