Method for reducing evapotranspiration rate of volatile solution and specific container and application thereof

Abstract

The invention discloses a method for reducing the evapotranspiration rate of a volatile solution agent and a specific container and application of the volatile solution agent, the volatile solution agent is placed in the container, the container is the specific container made of high-density polyethylene, the density of the specific container is 0.941-0.965 g / cm < 3 >, and the melt mass flow rate of the specific container under the condition of 190 DEG C / 2.16 kg is 0.10-0.35 g / 10 min. The efinaconazole liniment provided by the invention solves the technical problem of evapotranspiration of volatile components in a volatile solution in the prior art, and particularly well solves the technical problems that the content of effective components is reduced and the curative effect of a product is influenced due to the fact that solids are separated out after long-term storage (still in the period of validity) because the efinaconazole liniment sold in the market is relatively high in evapotranspiration rate.

Description

Technical Field

[0001] The present invention relates to the technical field of liquid medicines, in particular to a method for reducing the evaporation rate of a volatile solution, a specific container thereof and an application thereof, and particularly to a method for reducing the evaporation rate of an efinaconazole liniment, a specific container thereof and an application thereof. Background Art

[0002] Volatile solutions refer to liquid preparations containing volatile components (solutes or solvents). These volatile components will quickly change from liquid to gaseous state at room temperature and pressure or when slightly heated. Therefore, this type of solution has the problem of evaporation of volatile components. Specifically in the field of medicine, a volatile solution is a liquid medicine, which refers to a liquid preparation for internal or external use made by dissolving the active ingredients of the drug in a suitable solvent. The solvent is volatile. The solutes in this type of medicine will act locally during or after the solvent evaporates, such as skin disinfectants; or they will exert systemic effects after being inhaled in gaseous form, such as auxiliary treatment drugs for certain respiratory diseases. In order to ensure the efficacy of the drug, for this type of medicine containing volatile components, it is generally required that the evaporation rate (mainly the volatilization of the solvent) does not exceed a certain proportion under storage conditions during the shelf life. This can ensure the stability of the drug quality and the content of the active ingredient is within the qualified range.

[0003] Efinaconazole liniment, also known as ifinaconazole liniment, is a volatile solution in the pharmaceutical field. Currently available on the market, ifinaconazole liniment is the first topical triazole antifungal drug, jointly developed by Kaken Pharmaceutical Co., Ltd. of Japan and Valeant Pharmaceuticals International of Canada. It is marketed under the trade name Jublia. It is a 10% (w / w) topical solution of the active ingredient ifinaconazole dissolved in the volatile solvent ethanol, with each gram containing approximately 538 mg of the volatile ethanol component. The commercially available ifinaconazole liniment is designed to be applied to the affected nails or skin surface from the bottle using a unique, built-in dosage-controlled nail brush. After application, the solvent dries quickly, and ifinaconazole remains on the nail surface, penetrating the nail surface to treat onychomycosis of the hands and feet (i.e., onychomycosis of the nails and toenails) caused by Trichophyton rubrum and Trichophyton mentagrophytes.

[0004] However, in practice, it has been found that solid precipitation often occurs in commercially available efinaconazole ointment after long-term storage (still within the validity period), thereby reducing the content of active ingredients and affecting the efficacy of the product.

[0005] Therefore, how to reduce the evaporation rate of the solution of efinaconazole ointment has become a major problem that needs to be solved urgently. Summary of the Invention

[0006] To address the evaporation problem of volatile components in volatile solutions in the prior art, the present invention provides a method for reducing the evaporation rate of volatile solutions, a specific container thereof, and applications thereof. These methods effectively address the technical problem that volatile solutions, particularly commercially available efinaconazole liniment, have a high evaporation rate, which results in solid precipitation after long-term storage, thereby reducing the content of the active ingredient and affecting the product's efficacy.

[0007] To achieve the above object, the present invention provides the following technical solutions:

[0008] A method for reducing the evaporation rate of a volatile solution. The volatile solution is placed in a container, which is a specific container made of high-density polyethylene. The density of the specific container is 0.941 to 0.965 g / cm3, and the melt mass flow rate (190°C / 2.16 kg) of the specific container is 0.10 to 0.35 g / 10 min.

[0009] The density detection method of a specific bottle provided by the present invention implements the requirements of ISO 1183.

[0010] In one embodiment of the present invention, the density of the specific container is 0.945-

[0011] 0.958g / cm 3 .

[0012] For example, 0.945 g / cm 3 , 0.946g / cm 3 , 0.947g / cm 3 , 0.948g / cm 3 , 0.949g / cm 3 , 0.950g / cm 3 , 0.951g / cm 3 , 0.952g / cm 3 , 0.953g / cm 3 , 0.954g / cm 3 , 0.955g / cm 3 , 0.956g / cm 3 , 0.957g / cm 3 , 0.958g / cm 3 Or any range between any two of the aforementioned points or any point value within the range.

[0013] Melt Mass Flow Rate (MFR), also known as Melt Index (MI), is an indicator widely used in the plastics industry and other fields to characterize the fluidity of thermoplastic melts. It refers to the mass flow rate of the molten polymer flowing out of a test mold with a specific aperture in a standardized melt indexer at a specific temperature and pressure within a certain time (generally 10 minutes), and the unit is g / 10min.

[0014] In one embodiment of the present invention, the melt mass flow rate (190° C. / 2.16 kg) is tested in accordance with ISO 1133.

[0015] In one embodiment of the present invention, the melt mass flow rate (190° C. / 2.16 kg) of the specific container is 0.15 to 0.35 g / 10 min.

[0016] Preferably, the melt mass flow rate (190°C / 2.16kg) of the specific container is 0.20 to 0.30 g / 10 min.

[0017] Preferably, the melt mass flow rate (190°C / 2.16kg) of the specific container is 0.30g / 10min.

[0018] For example, 0.20 g / 10 min, 0.21 g / 10 min, 0.22 g / 10 min, 0.23 g / 10 min, 0.24 g / 10 min, 0.25 g / 10 min, 0.26 g / 10 min, 0.27 g / 10 min, 0.28 g / 10 min, 0.29 g / 10 min, 0.30 g / 10 min or any range between any two of the foregoing points or any point within the range.

[0019] In one embodiment of the present invention, the specific container reduces the evaporation rate of the volatile solution by at least 20% compared to the evaporation rate in existing containers.

[0020] In the method for reducing the evaporation rate of a volatile solution provided by the present invention, the volatile solution refers to a liquid preparation containing a volatile component (solute or solvent).

[0021] Preferably, the volatile solution is a liquid medicine containing a volatile component.

[0022] In one embodiment of the present invention, the volatile solution is a triazole antifungal liquid preparation for external use.

[0023] Preferably, the volatile solution is an efinaconazole liquid external preparation.

[0024] Preferably, the efinaconazole liquid external preparation is an efinaconazole liniment, and the efinaconazole liniment placed in the specific container will not precipitate solids during its validity period.

[0025] The present invention also provides a specific container for reducing the evaporation rate of a volatile solution, wherein the specific container is used to contain the volatile solution and reduces the evaporation rate of the volatile solution by at least 20% compared with the evaporation rate in an existing container. The specific container is made of high-density polyethylene, and the density of the specific container is 0.941 to 0.965 g / cm 3 , the melt mass flow rate (190°C / 2.16kg) of the specific container is 0.10 to 0.35 g / 10 min.

[0026] In one embodiment of the present invention, the specific container is used to contain the volatile solution, and the specific container and the volatile solution have the same definitions as above.

[0027] The present invention also provides a volatile solution package, comprising the aforementioned specific container for reducing the evaporation rate of the volatile solution and the volatile solution packaged in the specific container.

[0028] The present invention also provides a method for reducing the evaporation rate of a volatile solution, or use of the specific container or volatile solution packaging for reducing the evaporation rate of a volatile solution, for reducing the evaporation rate of the volatile solution by at least 20% compared to the evaporation rate in an existing container.

[0029] Preferably, the volatile solution is a triazole antifungal liquid preparation for external use.

[0030] Preferably, the triazole antifungal liquid preparation for external use is efinaconazole liquid preparation for external use.

[0031] More preferably, the triazole antifungal liquid external preparation is efinaconazole liniment, and the application is to prevent solid precipitation of the efinaconazole liniment during its effective period.

[0032] Beneficial effects of the present invention

[0033] 1) The present invention provides a specific container capable of reducing the evaporation rate of a volatile solution. The container has a specific density and a specific melt mass flow rate, which can significantly reduce the evaporation rate of volatile components in the volatile solution, and in particular, can significantly reduce the evaporation rate of efinaconazole liniment.

[0034] 2) The present invention solves the technical problem of evaporation of volatile components in volatile solutions existing in the prior art. In particular, it effectively solves the technical problem that the commercially available efinaconazole liniment has a high evaporation rate, which often leads to solid precipitation after long-term storage (still within the shelf life), thereby reducing the content of the active ingredient and affecting the product's efficacy.

[0035] 3) The present invention demonstrates through the data of the Examples and Comparative Examples that the use of the specific container provided by the present invention to hold the efinaconazole liniment can ensure that solid precipitation does not occur during the shelf life, thereby maintaining a stable content of the active ingredient and ensuring the efficacy of the product. DETAILED DESCRIPTION

[0036] The present invention will be further described in detail below with reference to specific examples and comparative examples. The following examples are intended to explain the present invention, but the present invention is not limited to the following examples.

[0037] The specific bottles provided in the following examples and comparative examples 1-4 are all produced by Cangzhou Shengli Pharmaceutical Packaging Co., Ltd. using the conventional production process of high-density polyethylene bottles in the existing technology (mainly including weighing of raw and auxiliary materials → mixing → molding by fully automatic extrusion / injection blow molding machine → finished product). The raw materials used are HDPE pellets with model HE2581 produced by Borealis AG, and the auxiliary materials are masterbatches with model PE12309 produced by Guangdong Meilian New Materials Co., Ltd. The amount of raw and auxiliary materials used is 97-98:2-3.

[0038] The shape, size, wall thickness, and light transmittance of the specific bottles provided in the following Examples and Comparative Examples 1-4 are consistent with those of the bottles of the commercially available efinaconazole liniment under the trade name Jublia, developed by Japan Research Institute Co., Ltd., and all specific bottles meet the quality requirements of the standard YBB00392003-2015, "High-density polyethylene bottles for external liquid medicine." In the following Examples and Comparative Examples 1-4, the density of the specific bottles was tested in accordance with ISO 1183, and the melt mass flow rate was tested in accordance with ISO 1133.

[0039] The following examples are only used to illustrate the present invention, and the experimental methods described therein, unless otherwise defined, are conventional methods.

[0040] Examples 1-4

[0041] The following Examples 1-4 provide specific bottles made of high-density polyethylene in this application, and the physical properties of the corresponding bottles are shown in Table 1.

[0042] Table 1 Physical properties of the specific bottle provided by the present invention

[0043]

[0044] Examples 5-8

[0045] The following Examples 5-8 provide specific bottles made of high-density polyethylene of the present invention. The physical properties of the corresponding bottles are shown in Table 2.

[0046] Table 2 Physical properties of the specific bottle provided by the present invention

[0047]

[0048] Comparative Examples 1-4

[0049] The following comparative examples 1-4 provide specific bottles made of high-density polyethylene. The physical properties of the corresponding bottles are shown in Table 3.

[0050] Table 3 Physical properties of the corresponding bottles

[0051]

[0052] Comparative Example 5

[0053] The bottle of commercially available efinaconazole liniment is prepared by pouring out the original liquid from the commercially available efinaconazole liniment under the trade name Jublia, developed by Nippon Kagaku Seiyaku Co., Ltd., etc., and washing and drying the bottle.

[0054] Experimental example Study on Evaporation Rate of Efluconazole Liniment

[0055] Test samples: the specific bottles of Examples 1-8 and Comparative Examples 1-4, the bottle of Comparative Example 5, and efinaconazole liniment (prepared by pouring out the original liquid from several bottles of Jublia, a commercially available efinaconazole liniment developed by Nippon Kenken Pharmaceutical Co., Ltd., and uniformly mixing them).

[0056] Test method:

[0057] 1) 3 mL of efinaconazole liniment was added to the bottle of Comparative Example 5, and the bottle mouth was heat-sealed with an aluminum pad.

[0058] 2) 3 mL of efinaconazole liniment solution was added to the specific bottles of Examples 1-8 and Comparative Examples 1-4, and the bottle openings were heat-sealed with aluminum pads.

[0059] 3) Place the samples treated in 1) and 2) in a constant temperature and humidity chamber at 40±2°C and 25±5% RH for 3 months. Calculate the evaporation rate of the samples at the 7th, 14th, 21st, 28th day, 2nd month, and 3rd month of storage.

[0060] The formula for calculating evaporation rate is: evaporation rate (%) = (weight of the bottle containing the drug solution before the test - weight of the bottle containing the drug solution at different time points after the test) / (weight of the bottle containing the drug solution before the test - weight of the bottle without the drug solution before the test)

[0061] Evaluation Criteria: Compare the evaporation rate data of Examples 1-8 and Comparative Examples 1-4 with the evaporation rate data of Comparative Example 5 at the same time points. Samples are considered qualified when the evaporation rate data at the aforementioned six time points are all 20% or more lower than the evaporation rate data of Comparative Example 5 at the same time points. (A comparative stability test revealed that when the evaporation rate data of the efinaconazole liniment at the aforementioned six time points are all 20% or more lower than the evaporation rate data of the commercially available efinaconazole liniment under the trade name Jublia, developed by Japan Science and Technology Pharmaceutical Co., Ltd., at the corresponding time points under the same conditions, the efinaconazole liniment is guaranteed to have no visible solid precipitation during its shelf life.) The test results are shown in Table 4.

[0062] Table 4. Sample evaporation rate data results at different time points

[0063]

[0064] As can be seen from Table 4, the evaporation rates of the specific bottles in Examples 1-8 provided by the present invention on the 7th day, 14th day, 21st day, 28th day, 2nd month, and 3rd month were all more than 20% lower than the evaporation rates of the bottle in Comparative Example 5 at the same time points. These samples are qualified and have significant advantages. They can ensure that the efinaconazole liniment will not precipitate solids during its shelf life, thereby maintaining a stable content of the active ingredient and guaranteeing the efficacy of the product.

[0065] Among them, the specific bottles in Example 3 and Example 7 have the best effect of reducing the evaporation rate of volatile solution.

[0066] The transpiration rates of the specific bottles of Comparative Examples 1-4 were comparable to or worse than the transpiration rate of the bottle of the commercially available efinaconazole liniment developed by Nippon Kakaku Seiyaku Co., Ltd. in Comparative Example 5, and were unqualified samples.

[0067] In summary, the comparative experiments of the embodiments and comparative examples of the present application confirmed that a sealed bottle filled with 3 ml of efinaconazole liniment was placed at 40±2°C and 25±5% RH for 3 months. Compared with the bottle of commercially available efinaconazole liniment developed by Japan Science and Pharmaceutical Co., Ltd. in Comparative Example 5 (a sealed bottle filled with 3 ml of efinaconazole liniment was placed at 40±2°C and 25±5% RH for 3 months, the evaporation rate of the solution in the third month was 4.29% compared with that in the 0th month), the specific bottle provided by the present invention had an evaporation rate of more than 20% less on the 7th day, 14th day, 21st day, 28th day, 2nd month and 3rd month, which has a significant advantage and can ensure that the efinaconazole liniment will not precipitate solids during the shelf life, thereby maintaining the stable content of the active ingredient and ensuring the efficacy of the product.

[0068] The above is only a preferred specific implementation method of the present application, but the scope of protection of the present application is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes based on the technical solution and concept of the present application within the technical scope disclosed in the present application, and they should be covered by the scope of protection of the present application.

Claims

1. A method for reducing the evaporation rate of a volatile solution, wherein the volatile solution is placed in a container, characterized in that: The container is a specific container made of high-density polyethylene, the density of the specific container is 0.941-0.965 g / cm3, and the melt mass flow rate of the specific container under the conditions of 190°C / 2.16 kg is 0.10-0.35 g / 10 min.

2. The method according to claim 1, wherein: The density of the specific container is 0.945 to 0.958 g / cm3.

3. The method according to claim 1 or 2, characterized in that: The melt mass flow rate of the specific container under the conditions of 190° C. / 2.16 kg is 0.15 to 0.35 g / 10 min.

4. The method according to claim 3, wherein: The melt mass flow rate of the specific container at 190°C / 2.16kg is 0.20-0.30g / 10min; Preferably, the melt mass flow rate of the specific container under the conditions of 190° C. / 2.16 kg is 0.30 g / 10 min.

5. The method according to claim 4, characterized in that: The specific container reduces the evaporation rate of volatile liquid agents by at least 20% compared to the evaporation rate in existing containers.

6. The method according to claim 1, wherein: The volatile solution is a triazole antifungal liquid external preparation.

7. The method according to claim 6, characterized in that: The volatile solution is a liquid external preparation of efinaconazole; Preferably, the efinaconazole liquid external preparation is an efinaconazole liniment, and the efinaconazole liniment placed in the specific container will not precipitate solids during its validity period.

8. A container for reducing the evaporation rate of a volatile solution, characterized in that: The specific container is used to contain the volatile solution and reduces the evaporation rate of the volatile solution by at least 20% compared with the evaporation rate in the existing container. The specific container is made of high-density polyethylene, and the density of the container is 0.941-0.965 g / cm 3 The melt mass flow rate of the specific container at 190°C / 2.16kg is 0.10-0.35g / 10min.

9. A volatile solution package, characterized in that: The invention comprises the specific container for reducing the evaporation rate of the volatile solution according to claim 8 and the volatile solution packaged in the specific container.

10. Use of the method for reducing the evaporation rate of a volatile solution according to any one of claims 1 to 7, the specific container for reducing the evaporation rate of a volatile solution according to claim 8, or the volatile solution packaging according to claim 9 in a volatile solution, characterized in that: The application is to reduce the evaporation rate of the volatile solution by at least 20% compared to the evaporation rate in the existing container; Preferably, the volatile solution is a triazole antifungal liquid external preparation; Preferably, the triazole antifungal liquid external preparation is an efinaconazole liquid external preparation; More preferably, the triazole antifungal liquid external preparation is efinaconazole liniment, and the application is to prevent solid precipitation from occurring in the efinaconazole liniment during its effective period.

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