Pharmaceutical composition, preparation containing pharmaceutical composition, suite containing pharmaceutical composition, and preparation method and application of pharmaceutical composition

Abstract

The invention discloses a pharmaceutical composition, a preparation containing the pharmaceutical composition, a kit containing the pharmaceutical composition, and a preparation method and application of the pharmaceutical composition. The pharmaceutical composition comprises an active pharmaceutical ingredient and a hot melt adhesive, wherein the active pharmaceutical ingredient is voriconazole, and the hot-melt adhesive is selected from an A-type hot-melt adhesive, namely poloxamer P188 and / or poloxamer P407, and a B-type hot-melt adhesive, namely poloxamer P188 and / or poloxamer P407; or the B-type hot melt adhesive is polyethylene glycol 6000; the mass percent of the B-type hot melt adhesive in the pharmaceutical composition is 12%-25%; the pharmaceutical composition is a pharmaceutical composition in the form of hot-melt granulated particles. According to the pharmaceutical composition and the preparation and the kit containing the pharmaceutical composition, the stability of active pharmaceutical ingredients can be improved, swallowing of a patient can be further improved, and the medicine taking compliance of the patient during actual taking can be improved.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition, a preparation containing the same, a set, and a preparation method and application thereof. Background Art

[0002] Voriconazole is a broad-spectrum triazole antifungal drug indicated for the treatment of invasive aspergillosis and serious infections caused by Candida, Actinomyces, and Fusarium. It is one of the most important drugs for the treatment of invasive fungal diseases. Authoritative guidelines such as the Chinese "Recommendations for the Diagnosis and Treatment of Invasive Fungal Diseases in Children with Hematologic Diseases and Malignancies" recommend voriconazole for the treatment and prevention of invasive aspergillosis in children.

[0003] Currently, the oral preparations of voriconazole available in the market at home and abroad include tablets, dry suspensions and capsules. Among them, the dry suspension has the advantage of being easy to take and is suitable for children and the elderly who have difficulty swallowing. However, the original drug, the voriconazole dry suspension (trade name) developed by Pfizer, USA, ) has deficiencies in stability and cumbersome procedures, potentially impacting patient compliance. The drug should be stored at 2-8°C, and the entire bottle of dry suspension must be reconstituted into a liquid before use, which can only be stored for 14 days. The liquid must be administered using an oral syringe, potentially causing phobia in children.

[0004] Therefore, it is very necessary to develop a voriconazole-containing preparation product that has good stability, is easy to use, and can improve patient compliance. Summary of the Invention

[0005] To address the poor stability and inconvenience of existing voriconazole dry suspensions, the present invention provides a pharmaceutical composition, a formulation containing the same, a kit, and methods for preparing and using the same. The pharmaceutical composition, formulation, and kit exhibit excellent stability, can be transported and stored at room temperature, require no pre-preparation for administration, and can improve dysphagia in patients, offering significant advantages in improving product stability and dosing compliance.

[0006] The present invention provides a pharmaceutical composition comprising an active pharmaceutical ingredient and a hot-melt adhesive; wherein the active pharmaceutical ingredient is voriconazole; and the hot-melt adhesive is selected from:

[0007] Type A hot melt adhesive: Poloxamer P188 and / or Poloxamer P407;

[0008] Or type B hot melt adhesive: polyethylene glycol 6000;

[0009] The mass percentage of the Class B hot melt adhesive in the pharmaceutical composition is 12%-25%;

[0010] The pharmaceutical composition is in the form of hot-melt granules.

[0011] In the present invention, the mass percentage of the active pharmaceutical ingredient in the pharmaceutical composition may be 1%-63%, preferably 8.3%-63%.

[0012] In the present invention, the mass percentage of the Class A hot melt adhesive in the pharmaceutical composition may be 5%-30%, preferably 12%-25%, and more preferably 15.0%-21.6%.

[0013] In the present invention, the mass percentage of the type B hot melt adhesive in the pharmaceutical composition is preferably 15.0%-21.6%.

[0014] In the present invention, the pharmaceutical composition may further include one or more of the following components: a disintegrant, a filler, a lubricant, a glidant, and a flavoring agent.

[0015] The disintegrant may be one or more of croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium starch glycolate, microcrystalline cellulose, pregelatinized starch, and cross-linked polyvinylpyrrolidone, preferably croscarmellose sodium and / or low-substituted hydroxypropyl cellulose. The mass percentage of the disintegrant in the pharmaceutical composition may be 0% to 30%, preferably 0% to 20%.

[0016] The filler may be one or more of mannitol, sorbitol and lactose, such as mannitol. The mass percentage of the filler in the pharmaceutical composition may be 0%-50%.

[0017] The lubricant may be one or more of calcium stearate, glyceryl behenate, magnesium stearate, sodium stearyl fumarate, magnesium silicate and calcium silicate, such as magnesium stearate. The mass percentage of the lubricant in the pharmaceutical composition may be 0%-2%.

[0018] The glidant may be talc and / or colloidal silicon dioxide, and the mass percentage of the glidant in the pharmaceutical composition may be 0%-2%.

[0019] The flavoring agent may be one or more of sucrose, maltose, stevioside, mannitol, erythrose, aspartame, citric acid, and essence, preferably one or more of stevioside, mannitol, erythrose, aspartame, and essence. The mass percentage of the flavoring agent in the pharmaceutical composition may be 0%-5%.

[0020] In some embodiments, the pharmaceutical composition includes the following components in mass percentage: 1%-63% of the active drug, "5%-30% of the Class A hot melt adhesive or 12%-25% of the Class B hot melt adhesive", 0%-30% of the disintegrant, 0%-50% of the filler, 0%-2% of the lubricant, 0%-2% of the glidant and 0%-5% of the flavoring agent.

[0021] In some preferred embodiments, the pharmaceutical composition comprises the following components in mass percentage: 8.3%-63% voriconazole, 12%-25% of the hot melt adhesive, 0%-20% of the disintegrant, 0%-50% of the filler, 0%-2% of the lubricant, 0%-2% of the glidant and 0%-5% of the flavoring agent.

[0022] In some more preferred embodiments, the pharmaceutical composition comprises the following components in mass percentage: 33%-55% voriconazole, 15.0%-21.6% of the hot melt adhesive, 5-18% of the disintegrant, 8.5%-36.5% of the filler, 0%-1% of the lubricant, 0.5%-1.5% of the glidant and 0.5%-1.5% of the flavoring.

[0023] The present invention also provides a pharmaceutical preparation, which is a hot-melt granulation granule, and the pharmaceutical preparation comprises the pharmaceutical composition as described above.

[0024] The present invention also provides a method for preparing the pharmaceutical preparation as described above, wherein the method is a hot melt granulation method, which comprises the following steps:

[0025] The hot melt adhesive is crushed into powder, mixed with the active pharmaceutical ingredient, disintegrant, filler, lubricant and glidant, hot melt granulated, and then uniformly mixed with the remaining components of the pharmaceutical composition, and the whole granules are sieved to obtain the powder.

[0026] Wherein, the particle size of the powder may be less than 40 meshes.

[0027] The temperature of the hot melt granulation may be 50-100°C, preferably 55-80°C, such as 60°C, 70°C or 80°C.

[0028] For example, the preparation method comprises the following steps: hot melt granulation is performed using a twin-screw extruder at a granulation temperature of 55-90° C., preferably 60-80° C., a screw speed of 100-800 rpm, and a feed rate of 5-80%, and the obtained granules are passed through a 14 or 16 mesh screen to obtain product granules; alternatively, granulation is performed using a high shear granulator with a heating jacket at a granulation temperature of 70-80° C. until uniform granules are formed, and the hot melt granules are passed through a 14 or 16 mesh screen to obtain product granules; alternatively, a square cone mixer is used to mix the hot melt granules with the remaining components of the pharmaceutical composition at a speed of 10 rpm for 5-30 minutes to obtain product granules.

[0029] The present invention also provides an oral administration delivery preparation set, which includes an oral administration delivery device and the pharmaceutical preparation as described above; the pharmaceutical preparation is provided in the oral delivery device within the drug-carrying space.

[0030] In the present invention, the oral delivery preparation set does not need to be prepared in advance when used. The lower end is immersed in water or beverages and the patient actively sucks it. It is suitable for patients with swallowing difficulties such as children and the elderly. The drug preparation is filled in the oral delivery device. It has higher stability and is convenient for storage and use.

[0031] Preferably, the filling amount of the pharmaceutical preparation is 50-1000 mg.

[0032] Wherein, the oral delivery device It is an existing commercially available oral drug delivery device, which can be an oral drug delivery device protected in the Chinese utility model patent CN201921652286.6. Any of the products in Examples 1-9 described therein can be used in the present invention; at the same time, similar oral drug delivery devices that can achieve the same effect can also be used. Generally speaking, it can include five components, namely, high-density polyethylene (HDPE) pharmaceutical Cap, polypropylene (PP) medicinal Straws, high-density polyethylene (HDPE) for medicinal use Filter housing body, polypropylene (PP) meltblown nonwoven fabric disc and high density polyethylene (HDPE) pharmaceutical Filter housing bottom sheet.

[0033] Wherein, the high density polyethylene (HDPE) medicinal Filter housing body, polypropylene (PP) meltblown nonwoven fabric disc and high density polyethylene (HDPE) pharmaceutical The filter housing bottom sheet is assembled to form Filter; the polypropylene (PP) medicinal Straw with After filter assembly The particles are filled and stored in the body The main body is made of high-density polyethylene (HDPE) Cap seal.

[0034] Wherein, each of the oral delivery preparation sets may further include a packaging layer for sealing the oral delivery device.

[0035] Preferably, the packaging layer is a polyester-aluminum-polyethylene composite film bag.

[0036] Preferably, a desiccant is further provided in the packaging layer, and the desiccant is a bagged desiccant.

[0037] The present invention also provides use of the pharmaceutical composition in preparing a drug for treating or preventing invasive fungal diseases.

[0038] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0039] The reagents and raw materials used in the present invention are commercially available.

[0040] The positive progress effect of the present invention is:

[0041] The present invention uses a specific hot-melt adhesive and a specific active pharmaceutical ingredient in conjunction with a hot-melt granulation process to prepare a pharmaceutical composition. The resulting pharmaceutical composition can rapidly release the active pharmaceutical ingredient to achieve rapid onset of action while ensuring the stability of the active pharmaceutical ingredient. It is particularly suitable for improving the stability of voriconazole dry suspensions for children. Preferably, the resulting pharmaceutical composition is delivered through a specific oral delivery device without the need for pre-preparation and can be actively sucked by the patient. It is suitable for patients with dysphagia, such as children and the elderly, and is conducive to improving patient compliance with medication. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 This is the product appearance of the oral administration delivery preparation set of the present invention.

[0043] 1-Oral drug delivery device 2-Drug particles.

[0044] Figure 2 This is a schematic diagram of the use of the oral administration delivery preparation kit of the present invention.

[0045] Figure 2 a is a schematic diagram of the oral administration delivery preparation set just inserted into water, Figure 2b is a schematic diagram of particles being sucked through a straw in the oral administration delivery formulation set. DETAILED DESCRIPTION

[0046] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0047] Example 1

[0048] According to the prescription in Table 1, voriconazole granules were prepared by the following hot melt granulation process:

[0049] Poloxamer 407 was crushed and passed through a 40-mesh sieve to obtain poloxamer 407 powder. Voriconazole and the remaining excipients were added to a square-cone mixer and mixed at 10 rpm for 10 minutes before discharging. The mixed materials were granulated in a high-shear granulator equipped with a heating jacket at 70-80°C until uniform granules were formed. The hot-melt granules were passed through a 16-mesh sieve to obtain voriconazole granules.

[0050] Table 1. Specific component information of Example 1

[0051] Components mg / vial wt% Voriconazole 50.0 41.7 Mannitol 25.9 21.6 Poloxamer 407 25.9 21.6 Low-substituted hydroxypropyl cellulose 18.1 15.1 total 119.9 100.0

[0052] Example 2

[0053] According to the prescription in Table 2, voriconazole granules were prepared by the following hot melt granulation process:

[0054] Poloxamer 407 was crushed and passed through an 80-mesh sieve to obtain poloxamer 407 powder. Voriconazole and the remaining excipients were added to a square-cone mixer and mixed at 10 rpm for 30 minutes before discharging. Hot-melt granulation was performed using a twin-screw extruder at a granulation temperature of 70-80°C, a screw speed of 200 rpm, and a feed rate of 30%. The hot-melt granules were passed through a 16-mesh sieve to obtain voriconazole granules.

[0055] Table 2. Specific component information of Example 2

[0056] Components mg / vial wt% Voriconazole 50.0 8.3 Mannitol 301.2 50.0 Poloxamer 407 130.7 21.7 Low-substituted hydroxypropyl cellulose 120.5 20.0 total 602.4 100.0

[0057] Example 3

[0058] According to the prescription in Table 3, voriconazole granules were prepared by the hot melt granulation process of Example 2.

[0059] Table 3. Specific component information of Example 3

[0060] Components mg / vial wt% Voriconazole 200.0 41.7 Mannitol 107.0 22.3 Poloxamer 407 86.3 18.0 Low-substituted hydroxypropyl cellulose 86.3 18.0 total 479.6 100.0

[0061] Example 4

[0062] According to the prescription in Table 4, 0.5% magnesium stearate and 0.5% strawberry essence were added to the granules of Example 3, and then placed in a square cone mixer and mixed at 10 rpm for 5 minutes to obtain voriconazole granules.

[0063] Table 4. Specific component information of Example 4

[0064] Components mg / vial wt% Voriconazole 200.0 41.3 Mannitol 107.0 22.1 Poloxamer 407 86.3 17.8 Low-substituted hydroxypropyl cellulose 86.3 17.8 magnesium stearate 2.4 0.5 strawberry flavor 2.4 0.5 total 484.4 100.0

[0065] Example 5

[0066] According to the prescription in Table 5, voriconazole granules were prepared by the hot melt granulation process of Example 1.

[0067] Table 5. Specific component information of Example 5

[0068]

[0069]

[0070] Example 6

[0071] According to the prescription in Table 6, voriconazole granules were prepared by the following hot melt granulation process:

[0072] Poloxamer 407 was crushed and passed through a 40-mesh sieve to obtain poloxamer 407 powder. Voriconazole and the remaining excipients were added to a square-cone mixer and mixed at 10 rpm for 10 minutes before discharging. The mixed materials were granulated in a high-shear granulator equipped with a heating jacket at 80-90°C until uniform granules were formed. The hot-melt granules were passed through a 14-mesh sieve to obtain voriconazole granules.

[0073] Table 6. Specific component information of Example 6

[0074] Components mg / vial wt% Voriconazole 300.0 54.5 Mannitol 102.9 18.7 Poloxamer 407 66.1 12.0 Low-substituted hydroxypropyl cellulose 76.0 13.8 Colloidal silica 5.5 1.0 total 550.5 100.0

[0075] Example 7

[0076] According to the prescription in Table 7, voriconazole granules were prepared by the following hot melt granulation process:

[0077] Poloxamer 188 was crushed and passed through an 80-mesh sieve to obtain poloxamer 188 powder. Voriconazole and the remaining excipients were added to a square-cone mixer and mixed at 10 rpm for 30 minutes before discharging. Hot-melt granulation was performed using a twin-screw extruder at a granulation temperature of 60-70°C, a screw speed of 400 rpm, and a feed rate of 40%. The hot-melt granules were passed through a 16-mesh sieve to obtain voriconazole granules.

[0078] Table 7. Specific component information of Example 7

[0079]

[0080]

[0081] Example 8

[0082] According to the prescription in Table 8, poloxamer 407 was crushed and passed through an 80-mesh sieve to obtain poloxamer 407 powder, and voriconazole granules were prepared using the hot-melt granulation process of Example 7.

[0083] Table 8. Specific component information of Example 8

[0084] Components mg / vial wt% Voriconazole 50.0 51.6 Mannitol 18.3 18.9 Poloxamer 407 17.9 18.5 microcrystalline cellulose 9.7 10.0 Colloidal silica 1.0 1.0 total 96.9 100.0

[0085] Example 9

[0086] According to the prescription in Table 9, poloxamer 407 was crushed and passed through an 80-mesh sieve to obtain poloxamer 407 powder, and voriconazole granules were prepared using the hot-melt granulation process of Example 7.

[0087] Table 9. Specific component information of Example 9

[0088] Components mg / vial wt% Voriconazole 50.0 51.6 Mannitol 18.3 18.9 Poloxamer 407 17.9 18.5 Pregelatinized starch 9.7 10.0 Colloidal silica 1.0 1.0 total 96.9 100.0

[0089] Example 10

[0090] According to the prescription in Table 10, voriconazole granules were prepared by the following hot melt granulation process:

[0091] Poloxamer 407 was crushed and passed through an 80-mesh sieve to obtain poloxamer 407 powder. Voriconazole and the remaining excipients were added to a square-cone mixer and mixed at 10 rpm for 30 minutes before discharging. Hot-melt granulation was performed using a twin-screw extruder at a granulation temperature of 70-80°C, a screw speed of 400 rpm, and a feed rate of 25%. The hot-melt granules were passed through a 16-mesh sieve to obtain voriconazole granules.

[0092] Table 10. Specific component information of Example 10

[0093] Components mg / vial wt% Voriconazole 300.0 54.5 Mannitol 82.6 15.0 Poloxamer 407 107.3 19.5 Low-substituted hydroxypropyl cellulose 55.1 10.0 Colloidal silica 5.5 1.0 total 550.5 100.0

[0094] Example 11

[0095] According to the prescription in Table 11, voriconazole granules were prepared using the hot melt granulation process of Example 10.

[0096] Table 11. Specific component information of Example 11

[0097] Components mg / vial wt% Voriconazole 300.0 54.5 Mannitol 94.7 17.2 Poloxamer 407 82.6 15.0 Low-substituted hydroxypropyl cellulose 67.7 12.3 Colloidal silica 5.5 1.0 total 550.5 100.0

[0098] Example 12

[0099] According to the prescription in Table 12, 0.5% colloidal silicon dioxide, 0.3% aspartame and 0.7% orange flavor were added to the granules of Example 10, and then placed in a square cone mixer and mixed at 10 rpm for 5 minutes to obtain voriconazole granules.

[0100] Table 12. Specific component information of Example 12

[0101]

[0102]

[0103] Example 13

[0104] According to the prescription in Table 13, voriconazole granules were prepared by the following hot melt granulation process:

[0105] Poloxamer 407 was crushed and passed through an 80-mesh sieve to obtain poloxamer 407 powder. Voriconazole and the remaining excipients were added to a square-cone mixer and mixed at 10 rpm for 30 minutes before discharging. Hot-melt granulation was performed using a twin-screw extruder at a granulation temperature of 60-70°C, a screw speed of 400 rpm, and a feed rate of 30%. The hot-melt granules were passed through a 16-mesh sieve to obtain voriconazole granules.

[0106] Table 13. Specific component information of Example 13

[0107] Components mg / vial wt% Voriconazole 300.0 33.0 Mannitol 255.5 28.1 Poloxamer 407 162.7 17.9 Low-substituted hydroxypropyl cellulose 181.8 20.0 Colloidal silica 9.1 1.0 total 909.1 100.0

[0108] Example 14

[0109] According to the prescription in Table 14, 0.5% aspartame and 0.5% orange flavor were added to the granules of Example 13, and then placed in a square cone mixer and mixed at 10 rpm for 5 minutes to obtain voriconazole granules.

[0110] Table 14. Specific component information of Example 14

[0111]

[0112]

[0113] Example 15

[0114] According to the prescription in Table 15, voriconazole granules were prepared by the following hot melt granulation process:

[0115] Poloxamer 407 was crushed and passed through an 80-mesh sieve to obtain poloxamer 407 powder. Voriconazole and the remaining excipients were added to a square-cone mixer and mixed at 10 rpm for 20 minutes before discharging. Hot-melt granulation was performed using a twin-screw extruder at a granulation temperature of 60-70°C, a screw speed of 800 rpm, and a feed rate of 80%. The hot-melt granules were passed through a 16-mesh sieve to obtain voriconazole granules.

[0116] Table 15. Specific component information of Example 15

[0117] Components mg / vial wt% Voriconazole 300.0 43.9 Mannitol 192.0 28.1 Poloxamer 407 95.7 14.0 Low-substituted hydroxypropyl cellulose 88.8 13.0 Colloidal silica 6.8 1.0 total 683.3 100.0

[0118] Example 16

[0119] According to the prescription in Table 16, voriconazole granules were prepared by the following hot melt granulation process:

[0120] Poloxamer 407 was crushed and passed through a 40-mesh sieve to obtain poloxamer 407 powder. Voriconazole and the remaining excipients were added to a square-cone mixer and mixed at 10 rpm for 20 minutes before discharging. Hot-melt granulation was performed using a twin-screw extruder at a granulation temperature of 60-70°C, a screw speed of 100 rpm, and a feed rate of 10%. The hot-melt granules were passed through a 16-mesh sieve to obtain voriconazole granules.

[0121] Table 16. Specific component information of Example 16

[0122]

[0123]

[0124] Example 17

[0125] According to the prescription in Table 17, voriconazole granules were prepared by the following hot melt granulation process:

[0126] Poloxamer 407 was crushed and passed through an 80-mesh sieve to obtain poloxamer 407 powder. Voriconazole, mannitol, poloxamer 407 powder, low-substituted hydroxypropyl cellulose, and colloidal silicon dioxide were added to a square-cone mixer and mixed at 10 rpm for 30 minutes before discharging. Hot-melt granulation was performed using a twin-screw extruder at a granulation temperature of 70-80°C, a screw speed of 200 rpm, and a feed rate of 20%. The hot-melt granules were passed through a 16-mesh sieve. The sieved granules were added to the remaining excipients and placed in a square-cone mixer. Mixing was performed at 10 rpm for 5 minutes to obtain voriconazole granules.

[0127] Table 17. Specific component information of Example 17

[0128] Components mg / vial wt% Voriconazole 300.0 39.0 Mannitol 153.8 20.0 Poloxamer 407 165.4 21.5 Low-substituted hydroxypropyl cellulose 133.1 17.3 Colloidal silica 3.8 0.5 magnesium stearate 3.8 0.5 Aspartame 4.6 0.6 Orange flavor 4.6 0.6 total 769.1 100.0

[0129] Example 18

[0130] like Figure 1 As shown, the voriconazole granules obtained in Example 3 were filled into The oral delivery preparation kit containing voriconazole is obtained:

[0131] The polypropylene meltblown nonwoven fabric disc is loaded into the high density polyethylene pharmaceutical The filter housing bottom sheet is then filled with high-density polyethylene medicinal The filter housing and the bottom sheet are buckled together to form Filter; Polypropylene medicinal Straw with After filter assembly The voriconazole granules obtained in Example 1 are filled into The main body is made of high-density polyethylene Cap seal.

[0132] Example 19

[0133] The voriconazole granules obtained in Example 4 were filled into the The oral delivery preparation set containing voriconazole is obtained. The filled Seal the bag and add a 0.25g desiccant bag into the composite film bag.

[0134] like Figure 2 As shown, when using the product of this embodiment, there is no need to prepare it in advance, just open the polyester / aluminum / polyethylene composite film bag and take out Remove the cap and place it in water, milk or juice. When the patient inhales it, the medicine is instantly dispersed in the liquid and then swallowed.

[0135] Example 20

[0136] According to the prescription in Table 18, voriconazole granules were prepared using the hot melt adhesive polyethylene glycol 6000 and the hot melt granulation process in Example 10.

[0137] Table 18. Specific component information of Example 20

[0138] Components wt% Voriconazole 54.5 Mannitol 15.0 Polyethylene glycol 6000 19.5 Low-substituted hydroxypropyl cellulose 10.0 Colloidal silica 1.0 total 100.0

[0139] Comparative Example 1

[0140] According to the prescription in Table 19, voriconazole granules were prepared using the hot melt adhesive glyceryl behenate 888ATO and the hot melt granulation process in Example 10.

[0141] Table 19. Specific component information of Comparative Example 1

[0142]

[0143]

[0144] Effect Example 1

[0145] The voriconazole granules obtained in Example 10, Example 20, and Comparative Example 1 were tested for dissolution and related substances. The results are shown in Table 20. The dissolution method used USP Method 2 (paddle method) at a speed of 50 rpm, the dissolution medium was 0.1N hydrochloric acid at pH 1.0, and the volume was 900 mL. Samples were taken for testing at 5, 10, 20, 30, 45, and 60 minutes.

[0146] Comparing Example 10 and Example 20 with Comparative Example 1, when the hot-melt adhesive was glyceryl behenate 888ATO, the dissolution of voriconazole granules in the first 20 minutes was significantly slower than that of granules using poloxamer 407 or polyethylene glycol 6000 as the adhesive. When polyethylene glycol 6000 was used as the adhesive, the dissolution of voriconazole granules was not significantly different from that of granules using poloxamer 407 as the adhesive. When the three hot-melt adhesives were used in the same proportions to prepare voriconazole granules, no significant differences in related substances were observed.

[0147] Table 20. Dissolution and related substance detection results of Example 10, Example 20 and Comparative Example 1

[0148]

[0149] Effect Example 2

[0150] A compatibility study of raw and excipients was conducted on the formulation of voriconazole granules in Example 6 at 40°C / RH75%. As shown in Table 21, among all the excipients, poloxamer 407 had poor compatibility with voriconazole. After preparation into a formulation, there was a risk of excessive levels of related substances in terms of stability.

[0151] The oral delivery formulation set containing voriconazole obtained in Example 19 was placed under 40°C / RH75% and sampled for testing at 1 month, 3 months and 6 months, respectively. The test indicators were dissolution and related substances. The results are shown in Table 22. The dissolution method adopted USP Method 2 (paddle method), the rotation speed was 50 rpm, the dissolution medium was 0.1N hydrochloric acid at pH 1.0, the volume was 900 mL, and samples were taken for testing at 5, 10, 20, 30, 45 and 60 minutes. After 6 months of accelerated sampling, the dissolution of voriconazole granules did not change significantly, and the related substances were far below the limit. This shows that the use of hot melt granulation process and moisture-proof packaging can significantly improve the compatibility of voriconazole and poloxamer 407 and increase the stability of the granules. Compared with the original drug (voriconazole dry suspension) which needs to be stored at 2-8°C, the oral delivery preparation set containing voriconazole in this embodiment can be stored for a long time at room temperature, which has obvious advantages in improving stability and storage conditions.

[0152] Table 21. Compatibility study results of voriconazole granules raw materials

[0153]

[0154] Table 22. Stability test results of Example 19

[0155]

[0156] Effect Example 3

[0157] The oral delivery preparation kit containing voriconazole obtained in Example 19 was compared with a commercially available voriconazole dry suspension. Ten respondents were surveyed and their preferences for the two products in terms of preparation before use, usage, storage conditions, appearance, and comprehensive factors were summarized as follows:

[0158] Table 23. Biased statistical results of the oral delivery formulation set of the present invention and the commercially available voriconazole dry suspension

[0159]

[0160] (The values in the table indicate the number of people who preferred the examples or the commercially available products. For example, when considering "preparation before use," 8 people preferred the oral delivery formulation set of Example 19, no one preferred the commercially available dry suspension, and 2 people thought both products were acceptable.)

[0161] It can be seen that the majority of the respondents believe that the oral administration delivery preparation set containing voriconazole of the present invention is more convenient to use and store, and has a more attractive appearance, and tend to choose the product of the present invention; only a few believe that both products are acceptable in terms of preparation before use, usage method and appearance; taking all factors into consideration, the vast majority of respondents believe that the oral administration delivery preparation set containing voriconazole of the present invention is more advantageous than the commercially available dry suspension.

Claims

1. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises an active pharmaceutical ingredient and a hot melt adhesive; wherein the active pharmaceutical ingredient is voriconazole, and the hot melt adhesive is selected from: Type A hot melt adhesive: Poloxamer P188 and / or Poloxamer P407; Or type B hot melt adhesive: polyethylene glycol 6000; The mass percentage of the Class B hot melt adhesive in the pharmaceutical composition is 12%-25%; The pharmaceutical composition is in the form of hot-melt granules.

2. The pharmaceutical composition according to claim 1, characterized in that The mass percentage of the active pharmaceutical ingredient is 1%-63%; The mass percentage of the Class A hot melt adhesive in the pharmaceutical composition is 5%-30%.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that The pharmaceutical composition meets one or more of the following conditions: The mass percentage of the active pharmaceutical ingredient in the pharmaceutical composition is 8.3%-63%; The mass percentage of the Class A hot melt adhesive in the pharmaceutical composition is 12%-25%, preferably 15.0%-21.6%; The mass percentage of the Class B hot melt adhesive in the pharmaceutical composition is preferably 15.0%-21.6%; The pharmaceutical composition may further comprise one or more of the following components: a disintegrant, a filler, a lubricant, a glidant, and a flavoring agent.

4. The pharmaceutical composition according to claim 3, characterized in that The pharmaceutical composition meets one or more of the following conditions: The disintegrant is one or more of cross-linked carboxymethyl cellulose sodium, low-substituted hydroxypropyl cellulose, sodium starch glycolate, microcrystalline cellulose, pregelatinized starch and cross-linked polyvinylpyrrolidone, preferably cross-linked carboxymethyl cellulose sodium and / or low-substituted hydroxypropyl cellulose; The mass percentage of the disintegrant in the pharmaceutical composition is 0%-30%, preferably 0%-20%; The filler is one or more of mannitol, sorbitol and lactose; The mass percentage of the filler in the pharmaceutical composition is 0%-50%; The lubricant is one or more of calcium stearate, glyceryl behenate, magnesium stearate, sodium stearyl fumarate, magnesium silicate and calcium silicate; The mass percentage of the lubricant in the pharmaceutical composition is 0%-2%; The glidant is talc and / or colloidal silicon dioxide; The mass percentage of the glidant in the pharmaceutical composition is 0%-2%; The flavoring agent is one or more of sucrose, maltose, stevioside, mannitol, erythrose, aspartame, citric acid and essence, preferably one or more of stevioside, mannitol, erythrose, aspartame and essence; The mass percentage of the flavoring agent in the pharmaceutical composition is 0%-5%.

5. The pharmaceutical composition according to claim 4, characterized in that The pharmaceutical composition comprises the following components by mass percentage: 1%-63% of the active drug, "5%-30% of the Class A hot melt adhesive or 12%-25% of the Class B hot melt adhesive", 0%-30% of the disintegrant, 0%-50% of the filler, 0%-2% of the lubricant, 0%-2% of the glidant and 0%-5% of the flavoring agent; Preferably, the pharmaceutical composition comprises the following components in mass percentage: 8.3%-63% voriconazole, 12%-25% of the hot melt adhesive, 0%-20% of the disintegrant, 0%-50% of the filler, 0%-2% of the lubricant, 0%-2% of the glidant and 0%-5% of the flavoring agent; More preferably, the pharmaceutical composition comprises the following components in the following mass fractions: 33%-55% voriconazole, 15.0%-21.6% of the hot-melt adhesive, 5%-18% of the disintegrant, 8.5%-36.5% of the filler, 0%-1% of the lubricant, 0.5%-1.5% of the glidant and 0.5%-1.5% of the flavoring agent.

6. A pharmaceutical preparation, characterized in that The invention relates to a hot-melt granulation granule, wherein the pharmaceutical preparation comprises the pharmaceutical composition according to any one of claims 1 to 5.

7. A method for preparing the pharmaceutical preparation according to claim 6, characterized in that: The preparation method is a hot melt granulation method, which comprises the following steps: The hot melt adhesive is crushed into powder, mixed with the active pharmaceutical ingredient, disintegrant, filler and glidant, hot melt granulated, and then uniformly mixed with the remaining components of the pharmaceutical composition, and the whole granules are sieved to obtain the powder.

8. An oral delivery preparation kit, characterized in that: The oral administration delivery preparation kit includes an oral administration delivery device and the pharmaceutical preparation according to claim 6; wherein the pharmaceutical preparation is provided in the oral administration delivery device preferably, the filling amount of the drug preparation is 50-1000 mg.

9. The oral delivery preparation set according to claim 8, wherein: Each of the oral administration delivery preparation sets further comprises a sealing layer for sealing the oral administration delivery device. Preferably, the packaging layer is a polyester-aluminum-polyethylene composite film bag; Preferably, a desiccant is further provided in the packaging layer, and the desiccant is a bagged desiccant.

10. Use of the pharmaceutical composition according to any one of claims 1 to 5 in the preparation of a medicament for treating or preventing invasive fungal diseases.

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