Medicinal package of isavuconazole sulfate capsule

Abstract

The invention relates to a medicinal package of capsules. In particular to a medicinal package of isavuconazole sulfate capsules, and belongs to the field of biological medicine. According to the medicinal package of the isavuconazole sulfate capsule, on the premise that the stability of a preparation product is better, preparation packaging can be completed through an existing workshop bottling line, a packaging production line does not need to be additionally installed and changed, and the packaging cost is greatly reduced.

Description

Technical Field

[0001] The invention belongs to the field of biomedicine and relates to a medicinal packaging of capsules; specifically, it relates to a medicinal packaging of isavuconazole sulfate capsules. Background Art

[0002] Isavuconazonium Sulfate is a water-soluble prodrug of the triazole antifungal drug isavuconazonium, which is hydrolyzed into the active ingredient isavuconazonium in the body to achieve antifungal activity. Isavuconazonium mainly inhibits the CYP450-mediated demethylation of 14α-lanosterol, hinders the synthesis of ergosterol, a key component of the fungal cell membrane, and weakens the structure and function of the fungal cell membrane, thereby achieving antifungal activity.

[0003] Isavuconazole sulfate was developed by Switzerland-based Basilea Pharmaceutica Ltd. and was first approved by the U.S. FDA in March 2015 under the trade name The dosage forms applied for include oral capsules (specification 100 mg, calculated as isavuconazole) and sterile powder injections (specification 200 mg, calculated as isavuconazole), which are used to treat invasive Aspergillus and invasive Mucor infections in adults. They are azole antibiotics for the treatment of fungal infections.

[0004] Isavuconazole sulfate capsules are very hygroscopic, and related substances grow rapidly after absorbing moisture, which is particularly detrimental to drug preservation. After the original isavuconazole sulfate capsules are filled, they need to be packaged in the preparation through a complex professional packaging line, that is, one capsule corresponds to one piece of molecular sieve desiccant packaged in a double aluminum blister (i.e., herringbone packaging), and the packaging control process is cumbersome. In addition, the installation cost and daily maintenance cost of this professional packaging line are expensive. At present, this packaging technology is not mature in China, and the existing packaging machines in most domestic workshops are difficult to complete this operation.

[0005] In view of this, it is currently urgently needed to provide a medicinal packaging form of isavuconazole sulfate capsules that has low packaging cost, does not require additional installation or change of packaging production lines, and is more suitable for the current enterprise bottling line, while ensuring better stability of the preparation product and addressing the shortcomings of the existing technology. Summary of the invention

[0006] The medicinal packaging of the isavuconazole sulfate capsule of the present invention is as follows: the isavuconazole sulfate capsule and a desiccant are placed in a medicinal high-density polyethylene bottle, which is sealed with aluminum foil and covered with a medicinal high-density polyethylene bottle cap.

[0007] The desiccant is selected from molecular sieve desiccant and silica gel desiccant.

[0008] The desiccant is selected from a cartridge molecular sieve desiccant and a bagged molecular sieve desiccant; preferably a cartridge molecular sieve desiccant.

[0009] In one embodiment of the present invention, the medicinal high-density polyethylene bottle cap contains an aluminum foil gasket, and after the bottle and the bottle cap are closed, the aluminum foil is sealed by an electromagnetic induction sealing machine.

[0010] In one embodiment of the present invention, the usage amount of the desiccant in a single bottle package is 2 to 6 g.

[0011] In one embodiment of the present invention, the usage amount of the desiccant in a single bottle package is 4 to 6 g.

[0012] In one embodiment of the present invention, the usage amount of the desiccant in a single bottle of packaging is 4 g.

[0013] In an embodiment of the present invention, the number of the isavuconazole sulfate capsules in a single bottle is less than or equal to 14 capsules.

[0014] In one embodiment of the present invention, the number of isavuconazole sulfate capsules in a single bottle is 7 to 14 capsules.

[0015] In one embodiment of the present invention, the number of isavuconazole sulfate capsules in a single bottle is 14 capsules.

[0016] Beneficial effects of the present invention:

[0017] 1. The pharmaceutical packaging of the isavuconazole sulfate capsules of the present invention can achieve effective protection for the preparation product during storage. Under the accelerated conditions of 40°C and 75% RH and the long-term conditions of 25°C and 60% RH, the stability of the preparation product is equivalent to that of the reference preparation, or even better than that of the reference preparation.

[0018] 2. The pharmaceutical packaging of the isavuconazole sulfate capsules of the present invention simulates the process of patients taking medicine. After the aluminum foil seal is broken, the bottle is opened once a day, and samples are taken for testing after 7 days. The isavuconazole sulfate capsules basically remain stable during the 7-day use process and meet the quality standards of isavuconazole sulfate.

[0019] 3. The pharmaceutical packaging of the isavuconazole sulfate capsules of the present invention has low packaging cost and does not require additional installation or modification of the packaging production line, and is more suitable for the pharmaceutical packaging form of the isavuconazole sulfate capsules of the current enterprise bottling line. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 , double aluminum blister packaging of original isavuconazole sulfate capsules. DETAILED DESCRIPTION

[0021] It should be noted that, in the absence of conflict, the embodiments and features in the embodiments of the present application can be combined with each other. The present invention will be described in detail below in conjunction with the embodiments.

[0022] Example 1. Preparation of Isavuconazole Sulfate Capsules

[0023] The prescription of isavuconazole sulfate capsules is shown in Table 1:

[0024] Table 1

[0025] effect Prescription composition Prescription quantity / 1000 tablets API Isavuconazole sulfate 186.3g Desiccant Magnesium Citrate Anhydrous 180.0g Fillers Microcrystalline Cellulose 183.7g Lubricants Colloidal Silica 2.6g Glidants Stearic acid 17.4g Lubricants talcum powder 10.0g

[0026] Preparation of isavuconazole sulfate capsules: weigh the raw materials and excipients according to the prescription amount, sieve the raw material isavuconazole sulfate, anhydrous magnesium citrate, microcrystalline cellulose, and stearic acid, mix them, add colloidal silicon dioxide and talcum powder, mix them, dry granulate them, and then perform final mixing. Finally, fill them into hollow capsules according to the theoretical value (i.e., 580 mg for a 100 mg specification).

[0027] Example 2: Bottle cap screening experiment

[0028] The isavuconazole sulfate capsules prepared in Example 1 were placed in pharmaceutical high-density polyethylene bottles and packaged according to the packaging forms in Table 2. They were then accelerated at 40° C. and 75% RH for one month. The stability test data are shown in Table 3.

[0029] Table 2

[0030]

[0031] “-” means not used.

[0032] Table 3

[0033]

[0034] Experimental conclusion: Increasing the use of desiccant in the medicinal high-density polyethylene bottle and increasing the amount of desiccant can reduce moisture accordingly and inhibit the growth of related substances to a certain extent. Based on the comparison of the experimental data of packages 2 and 3 with packages 6 and 7, the applicant unexpectedly found that: compared with the medicinal high-density polyethylene bottle cap packaging sealed with aluminum foil, the stability of the preparation packaged with the moisture-proof combination cap with desiccant is worse, and this deviation cannot be eliminated by increasing the amount of desiccant.

[0035] Therefore, the packaging form of the present invention adopts: placing the isavuconazole sulfate capsules and the desiccant in a medicinal high-density polyethylene bottle, sealing it with aluminum foil, and covering it with a medicinal high-density polyethylene bottle cap. The medicinal packaging of the present invention is more moisture-proof and waterproof, ensuring the stability of the isavuconazole sulfate capsules.

[0036] Example 3: Screening of desiccant types and dosages

[0037] The isavuconazole sulfate capsules prepared in Example 1 were placed in pharmaceutical high-density polyethylene bottles and packaged according to the packaging forms in Table 4. They were then accelerated at 40° C. and 75% RH for one month. The stability test data are shown in Table 5.

[0038] Table 4

[0039]

[0040] “-” means not used.

[0041] Table 5

[0042]

[0043] Experimental conclusion: Compared with silica gel desiccant, the same amount of molecular sieve desiccant in the package can ensure low moisture while keeping all impurities and total impurities at a lower level, and the stability of the preparation is better than that of silica gel desiccant. Therefore, molecular sieve desiccant is preferably used in the package of the present invention.

[0044] In the package of the present invention, the amount of the desiccant used is 2 to 6 g, preferably 4 to 6 g.

[0045] Example 4: Screening of molecular sieve models

[0046] The isavuconazole sulfate capsules prepared in Example 1 were placed in pharmaceutical high-density polyethylene bottles and packaged according to the packaging forms in Table 6. They were then accelerated at 40° C. and 75% RH for 180 days. The stability test data are shown in Table 7.

[0047] Table 6

[0048]

[0049] Among them, the specification of bagged molecular sieve desiccant is 1g / bag.

[0050] The cartridge molecular sieve desiccant is specifically a solid pharmaceutical low-density polyethylene cartridge molecular sieve desiccant, with a specification of AdCap-4 / 2.0G (M10).

[0051] Table 7

[0052]

[0053] Experimental conclusion: Compared with the bagged molecular sieve desiccant, the same amount of the cylinder-packed molecular sieve desiccant in the package has lower impurities and total impurities while ensuring low moisture, and the stability of the preparation is better than the bagged molecular sieve desiccant. Therefore, the cylinder-packed molecular sieve desiccant is preferably used in the package of the present invention.

[0054] Example 5: Screening of the number of capsules in packaging

[0055] The isavuconazole sulfate capsules prepared in Example 1 were placed in pharmaceutical high-density polyethylene bottles and packaged according to the packaging forms in Table 8. They were then accelerated at 40° C. and 75% RH for one month. The stability test data are shown in Table 9.

[0056] Table 8

[0057]

[0058] Table 9

[0059]

[0060] Experimental conclusion: When the amount of molecular sieve desiccant used in the package is constant, the more capsules there are in the medicinal high-density polyethylene bottle, the more unfavorable the control of moisture is, and the impurities and total impurities increase with the increase of the number of capsules. Therefore, the preferred number of capsules in the package is 7 to 14, and more preferably 14.

[0061] Example 6 Accelerated stability test of reference preparation and packaging of the present invention

[0062] 14 capsules of isavuconazole sulfate capsules prepared in Example 1 and 4 g of molecular sieve in a tube were put into a medicinal high-density polyethylene bottle, and covered with a medicinal high-density polyethylene bottle cap containing an aluminum foil gasket inside, and the aluminum foil was sealed by an electromagnetic induction sealing machine. Four bottles were prepared for standby use. Together with the reference preparation packaging (i.e., one capsule corresponds to one molecular sieve desiccant packaged in a double aluminum blister), the stability test data was accelerated for 180 days at 40°C and 75% RH. The stability test data are shown in Table 10.

[0063] Table 10

[0064]

[0065] Example 7: Long-term stability test of reference preparation and packaging of the present invention

[0066] 14 capsules of isavuconazole sulfate capsules prepared in Example 1 and 4 g of molecular sieve in a tube were placed in a medicinal high-density polyethylene bottle, and covered with a medicinal high-density polyethylene bottle cap containing an aluminum foil gasket inside, and the aluminum foil was sealed by an electromagnetic induction sealing machine. Four bottles were prepared for standby use. The bottles were placed together with the reference preparation package (i.e., one capsule corresponds to one molecular sieve desiccant packaged in a double aluminum blister) under the conditions of 25° C. and 60% RH for 1 year, and the stability test data are shown in Table 11.

[0067] Table 11

[0068]

[0069] Experimental conclusion: According to Examples 6 and 7, the capsule pharmaceutical packaging of the present invention can achieve effective protection for the preparation product. Under the accelerated conditions of 40°C and 75% RH and the long-term conditions of 25°C and 60% RH, the preparation stability is equivalent to the reference quality, or even better than the reference preparation.

[0070] Example 8: Investigation of the stability of the packaging of the present invention

[0071] 14 capsules of isavuconazole sulfate capsules prepared in Example 1 and 4 g of molecular sieve in a tube were put into a medicinal high-density polyethylene bottle, and the bottle was covered with a medicinal high-density polyethylene bottle cap containing an aluminum foil gasket inside. The aluminum foil was sealed by an electromagnetic induction sealing machine. After 2 bottles were made, the aluminum foil seal was broken for standby use and placed at 25° C. and 60% RH for 7 days. The medication instructions were simulated, the bottle was opened once a day, and the samples were sent for testing in 7 days. The stability experimental data are shown in Table 12.

[0072] Table 12

[0073]

[0074] Experimental conclusion: The capsule medicinal packaging of the present invention simulates the patient's medication process. After the aluminum foil seal is broken, the bottle is opened once a day, and samples are taken for testing after 7 days. The isavuconazole sulfate capsules basically remain stable during the 7-day use process and meet the quality standards of isavuconazole sulfate.

Claims

1. A medicinal packaging of isavuconazole sulfate capsules, characterized in that: Place isavuconazole sulfate capsules and desiccant in a medicinal high-density polyethylene bottle, seal it with aluminum foil, and cover it with a medicinal high-density polyethylene bottle cap.

2. The pharmaceutical packaging of isavuconazole sulfate capsules according to claim 1, characterized in that: The desiccant is selected from molecular sieve desiccant and silica gel desiccant.

3. The pharmaceutical packaging of isavuconazole sulfate capsules according to claim 2, characterized in that: The desiccant is selected from a cylinder-packed molecular sieve desiccant and a bag-packed molecular sieve desiccant.

4. The pharmaceutical packaging of isavuconazole sulfate capsules according to claim 3, characterized in that: The desiccant is selected from a cartridge molecular sieve desiccant.

5. The pharmaceutical packaging of isavuconazole sulfate capsules according to claim 1, characterized in that: The usage amount of the desiccant in a single bottle package is 2 to 6 g.

6. The pharmaceutical packaging of isavuconazole sulfate capsules according to claim 5, characterized in that: The usage amount of the desiccant in a single bottle package is 4 to 6 g.

7. The pharmaceutical packaging of isavuconazole sulfate capsules according to claim 6, characterized in that: The amount of desiccant used in a single bottle is 4 g.

8. The pharmaceutical packaging of isavuconazole sulfate capsules according to claim 1, characterized in that: The number of isavuconazole sulfate capsules in a single bottle is less than or equal to 14 capsules.

9. The pharmaceutical packaging of isavuconazole sulfate capsules according to claim 8, characterized in that: The number of isavuconazole sulfate capsules in a single bottle is 7 to 14 capsules.

10. The pharmaceutical packaging of isavuconazole sulfate capsules according to claim 9, characterized in that: The number of isavuconazole sulfate capsules in a single bottle package is 14 capsules.

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