External preparation composition, external preparation and preparation method

Abstract

The present invention relates to the field of pharmaceutical preparations, and in particular to an external preparation composition, an external preparation and a preparation method. The external preparation composition comprises a drug, peppermint oil, a stabilizer and a metal stearate, wherein the drug is compound I or a pharmaceutically acceptable salt thereof, and the stabilizer is isopropyl myristate. The external preparation composition provided by the present invention has high stability, effectively avoids or reduces drug precipitation, drug degradation and drug concentration reduction, so that the external preparation containing the external preparation composition has higher effectiveness and stability.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to an external preparation composition, an external preparation and a preparation method. Background Art

[0002] Compound I is a non-steroidal anti-inflammatory drug, and its mechanism of action is to exhibit anti-inflammatory and analgesic effects by strongly inhibiting the activity of cyclooxygenase.

[0003]

[0004] In recent years, with the increase in the number of people suffering from pain-related diseases and the aging of the population, there has been an increase in research on drugs for the treatment of pain-related diseases, especially in the field of topical patches.

[0005] Currently, a patent discloses an external preparation composition containing Compound I and peppermint oil. By adding propylene glycol dicaprylate or tricaprin, it is believed that the decrease in the content of Compound I over time can be inhibited, and Compound I can be stabilized during long-term storage.

[0006] A patent discloses a topical preparation composition containing Compound I, including Compound I or a pharmaceutically acceptable salt thereof, and a stabilizer, wherein the stabilizer includes diisopropyl adipate (DIPA), propylene glycol dicaprylate, diethylene glycol monoethyl ether (Transcutol), caprylic acid capric acid polyethylene glycol glyceride (Labrasol), and polyethylene glycol 400 (PEG400); it is believed that the addition of the stabilizer can effectively inhibit the reduction of the content of Compound I in the prescription. However, the stability of the Compound I topical preparation composition and topical preparation can be further improved. Summary of the invention

[0007] In view of the deficiencies in the prior art, the object of the present invention is to provide an external preparation composition, an external preparation and a preparation method. By introducing isopropyl myristate and a metal stearate and their interaction with a drug, the external preparation composition has higher stability, effectively avoiding or reducing drug precipitation, drug degradation and drug concentration reduction, so that the external preparation containing the same has higher effectiveness and stability.

[0008] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0009] In a first aspect, the present invention provides an external preparation composition, comprising a drug, peppermint oil, a stabilizer and a metal stearate, wherein the drug is Compound I or a pharmaceutically acceptable salt thereof, and the stabilizer is isopropyl myristate.

[0010]

[0011] In some embodiments, in order to achieve a better stabilizing effect, the weight ratio of the drug to the stabilizer is 1:0.2-1:5.

[0012] The weight ratio of the drug to the stabilizer is 1:0.2-1:5, for example, it can be 1:0.2, 1:0.8, 1:1, 1:3, 1:5, and specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range.

[0013] In some embodiments, in order to better inhibit drug crystallization, the metal stearate includes one or more of zinc stearate, calcium stearate, and sodium stearate.

[0014] In some embodiments, the external preparation composition includes, by weight, 1-5 parts of a drug, 0.5-5 parts of peppermint oil, 0.5-11 parts of a stabilizer, and 0.1-10 parts of a metal stearate.

[0015] The weight proportions of the drug are 1-5 parts, for example, 1 part, 3 parts, 4 parts or 5 parts, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range.

[0016] The weight portion of the peppermint oil is 0.5-5 parts, for example, it can be 0.5 parts, 1 parts, 3 parts, 4 parts or 5 parts, as well as specific points between the above points. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific points included in the range.

[0017] The weight portion of the stabilizer is 0.5-11 parts, for example, it can be 0.5 parts, 1 parts, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts or 11 parts, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range.

[0018] The weight portion of the metal stearate is 0.1-10 parts, for example, it can be 0.1 parts, 1 parts, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts or 10 parts, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range.

[0019] In some embodiments, the topical preparation composition further comprises 10-60 parts by weight of a matrix material and 5-25 parts of polyisobutylene; preferably, the matrix material comprises one or more of styrene-isoprene-styrene block copolymer (SIS) and styrene-butadiene-styrene block copolymer (SBS).

[0020] The weight proportion of the matrix material is 10-60 parts, for example, it can be 10 parts, 20 parts, 30 parts, 40 parts, 50 parts or 60 parts, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the said range.

[0021] The weight proportion of the polyisobutylene is 5-25 parts, for example, 5 parts, 8 parts, 10 parts, 13 parts, 15 parts, 17 parts, 19 parts, 20 parts or 25 parts, as well as specific values ​​between the above points. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific points included in the range.

[0022] In some embodiments, the topical preparation composition further comprises 8-30 parts by weight of a viscosity enhancer;

[0023] Preferably, the tackifier includes one or more of rosin resin, polyterpene resin, petroleum resin, etc., preferably hydrogenated rosin resin.

[0024] The weight proportion of the tackifier is 8-30 parts, for example, 8 parts, 10 parts, 13 parts, 15 parts, 17 parts, 19 parts, 25 parts or 30 parts, as well as specific values ​​between the above points. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific points included in the range.

[0025] In some embodiments, the topical preparation composition further comprises 0-50 parts by weight of a softener;

[0026] Preferably, the softener includes one or more of liquid paraffin, silicone oil, higher fatty acid, vegetable oil, and polybutene. Preferably, the softener is liquid paraffin.

[0027] The weight proportion of the softener is 0-50 parts, for example, it can be 0 parts, 10 parts, 15 parts, 20 parts, 30 parts, 40 parts or 50 parts, as well as specific values ​​between the above points. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific points included in the range.

[0028] In some embodiments, the topical preparation composition includes the following components in parts by weight:

[0029] Preferably, the external preparation composition comprises the following components by weight:

[0030] Preferably, the external preparation composition comprises the following components by weight:

[0031] Preferably, the external preparation composition comprises the following components by weight:

[0032] Preferably, the external preparation composition comprises the following components by weight:

[0033]

[0034]

[0035] In another aspect, the present invention provides a method for preparing an external preparation composition, the preparation method comprising:

[0036] S1: Add compound I, isopropyl myristate, peppermint oil, etc. to a softener, and stir to disperse the mixture to prepare a suspension.

[0037] S2: Heat and stir the matrix material, polyisobutylene and the remaining softener evenly, add the viscosity enhancer and mix evenly, and when the paste temperature drops below 130° C., add the metal stearate and the suspension prepared in S1 and stir evenly to obtain a drug-containing paste.

[0038] In a third aspect, the present invention provides an external preparation, which comprises a backing layer, a drug storage layer and a protective layer arranged in sequence, and the raw material for preparing the drug storage layer comprises the external preparation composition.

[0039] In some embodiments, the preparation method comprises: coating the external preparation composition on a protective layer to form a drug storage layer; and compounding a backing layer on the drug storage layer to obtain the external preparation.

[0040] The external preparation composition provided by the present invention has high stability, effectively avoids or reduces drug precipitation, drug degradation and reduction of drug concentration, so that the external preparation composition containing the same has higher effectiveness and stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 This is a micrograph of the patch prepared in Example 3 at day 0;

[0042] Figure 2 This is a micrograph of the patch prepared in Example 3 after being placed under 40° C. and 65% RH for 3 months;

[0043] Figure 3 This is a micrograph of the patch prepared in Example 3 after being placed under 30° C. and 60% RH for 6 months;

[0044] Figure 4 This is a micrograph of the patch prepared in Example 4 at day 0;

[0045] Figure 5 This is a micrograph of the patch prepared in Example 4 after being placed under 40° C. and 65% RH for 3 months;

[0046] Figure 6 This is a micrograph of the patch prepared in Example 4 after being placed under 30° C. and 60% RH for 6 months;

[0047] Figure 7 This is a micrograph of the patch prepared in Example 6 at day 0;

[0048] Figure 8 This is a micrograph of the patch prepared in Example 6 after being placed under 40° C. and 65% RH for 3 months;

[0049] Fig. 9 This is a micrograph of the patch prepared in Example 6 after being placed under 30° C. and 60% RH for 6 months;

[0050] Fig.10 This is a micrograph of the patch prepared in Example 7 at day 0;

[0051] Fig.11 This is a micrograph of the patch prepared in Example 7 after being placed under 40° C. and 65% RH for 3 months;

[0052] Fig.12 This is a micrograph of the patch prepared in Example 7 after being placed under 30° C. and 60% RH for 6 months;

[0053] Fig.13 This is a micrograph of the patch prepared in Comparative Example 1 at day 0;

[0054] Fig.14 This is a micrograph of the patch prepared in Comparative Example 1 after being placed under 40° C. and 65% RH for 3 months;

[0055] Fig.15 This is a micrograph of the patch prepared in Comparative Example 1 after being placed under 30° C. and 60% RH for 3 months;

[0056] Fig.16 This is a micrograph of the patch prepared in Comparative Example 1 after being placed under 30° C. and 60% RH for 6 months. DETAILED DESCRIPTION

[0057] The technical scheme of the present invention is further described below by specific embodiments. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention. The terms "comprise", "include", "have", "contain" or any other variations thereof as used herein are intended to cover non-exclusive inclusions. For example, a composition, step, method, product or device comprising the listed elements need not be limited to those elements, but may also include other elements not explicitly listed or elements inherent to such a composition, step, method, product or device.

[0058] "Optionally" or "either" means that the subsequently described matter or event can or cannot occur, and that the description includes instances where the event occurs and instances where it does not.

[0059] The indefinite articles "a" and "an" before the elements or components of the present invention have no restrictions on the quantity requirements (i.e., the number of occurrences) of the elements or components. Therefore, "a" or "an" should be interpreted as including one or at least one, and elements or components in the singular form also include the plural form, unless the quantity obviously refers only to the singular form. In the present invention, the features defined as "first" and "second" may explicitly or implicitly include one or more of the features, which are used to distinguish and describe the features, without order or importance. In the description of the present invention, unless otherwise specified, the meaning of "plurality" is two or more.

[0060] Example 1-5 Preparation of Compound I Patch

[0061] Table 1 Prescription table of Examples 1-5

[0062]

[0063] Preparation method: Compound I, menthol oil, stabilizer and part of liquid paraffin are stirred and dispersed uniformly to obtain a suspension of Compound I; Styrene isoprene styrene block copolymer, polyisobutylene, hydrogenated rosin glycerol ester and the remaining part of liquid paraffin are heated and dissolved and stirred uniformly; After the paste is cooled (below 130°C), zinc stearate and Compound I suspension are added and stirred uniformly to obtain a drug-containing paste. The paste is applied to a protective layer, and then laminated to a backing layer, and finally cut into a suitable size to obtain a Compound I patch.

[0064] Embodiment 6-7

[0065] Table 2 Prescription table of Examples 6-7

[0066]

[0067]

[0068] Preparation method: Compound I, menthol oil, stabilizer and part of liquid paraffin are stirred and dispersed uniformly to obtain a suspension of Compound I; Styrene isoprene styrene block copolymer, polyisobutylene, hydrogenated rosin glycerol ester and the remaining part of liquid paraffin are heated and dissolved and stirred uniformly; After the paste is cooled (below 130°C), zinc stearate and Compound I suspension are added and stirred uniformly to obtain a drug-containing paste. The paste is applied to a protective layer, and then laminated to a backing layer, and finally cut into a suitable size to obtain a Compound I patch.

[0069] Comparative Example 1-4 Preparation of Compound I Patch

[0070] Table 3 Prescription table of comparative examples 1-4

[0071]

[0072] Preparation method: Compound I, menthol oil, stabilizer and part of liquid paraffin are stirred and dispersed uniformly to obtain a suspension of Compound I; Styrene isoprene styrene block copolymer, polyisobutylene, hydrogenated rosin glycerol ester and the remaining part of liquid paraffin are heated and dissolved and stirred uniformly; After the paste is cooled (below 130°C), zinc stearate and Compound I suspension are added and stirred uniformly to obtain a drug-containing paste. The paste is applied to a protective layer, and then laminated to a backing layer, and finally cut into a suitable size to obtain a Compound I patch.

[0073] Example 8 Stability Test

[0074] The compound I patch samples prepared in each embodiment and comparative example were placed under accelerated conditions (40°C, 65% RH) and long-term conditions (30°C, 60% RH), sealed with paper-aluminum or aluminum-plastic, and placed for 6 months. The content of compound I in the compound I patch was detected, and the results were as follows:

[0075] Table 4 Stability data of Examples 1-5 and Comparative Examples 1-4

[0076]

[0077] Table 5 Stability data of Examples 6-7

[0078]

[0079] As can be seen from the above table, when Examples 1 to 5 were placed under accelerated conditions (40°C, 65% RH) and long-term conditions (30°C, 60% RH) for 6 months, the degradation trend of Compound I in the preparation was significantly weaker than that of Comparative Examples 2 to 4, and as the proportion of isopropyl myristate increased, its inhibitory effect increased. The composition of isopropyl myristate increased from 0.5 parts to 2.5 parts to 7.0 parts, and the inhibitory effect on the stability process of Compound I gradually increased, but 7.0 parts and 11.0 parts had no significant change in the inhibitory effect on the stability process of Compound I, that is, there was a threshold value for the stability effect of isopropyl myristate on Compound I in the Compound I patch, that is: 11 parts ≈ 7.0 parts > 2.5 parts > 0.5 parts. When the addition ratio of isopropyl myristate was low, the inhibitory effect on the stability process of Compound I was not significant; when the addition ratio of isopropyl myristate was greater than 1:5, isopropyl myristate would destroy the pressure-sensitive adhesive matrix and affect the adhesion of the patch.

[0080] Example 9

[0081] Comparing the appearance of the Compound I patches prepared in Example 2, Example 3, Example 4, Example 6, Example 7, and Comparative Example 1, it was found that the preparation prepared in the Examples containing both zinc stearate and isopropyl myristate did not show crystal precipitation, but Comparative Example 1 to which zinc stearate was not added showed varying degrees of crystal precipitation as the stability placement time increased.

[0082] Table 6 Summary of crystal precipitation during stability process

[0083]

Claims

1. An external preparation composition, characterized in that: The invention comprises a drug, a peppermint oil, a stabilizer and a metal stearate, wherein the drug is compound I or a pharmaceutically acceptable salt thereof, and the stabilizer is isopropyl myristate.

2. The external preparation composition according to claim 1, characterized in that The weight ratio of the drug to the stabilizer is 1:0.2-1:

5.

3. The external preparation composition according to claim 1, characterized in that The metal stearate includes one or more of zinc stearate, calcium stearate and sodium stearate.

4. The external preparation composition according to any one of claims 1 to 3, characterized in that The external preparation composition comprises, by weight, 1-5 parts of a drug, 0.5-5 parts of peppermint oil, 0.5-11 parts of a stabilizer and 0.1-10 parts of a metal stearate.

5. The external preparation composition according to any one of claims 1 to 4, characterized in that: The external preparation composition further comprises 10-60 parts by weight of a matrix material and 5-25 parts by weight of polyisobutylene; Preferably, the matrix material comprises one or more of styrene-isoprene-styrene block copolymer and styrene-butadiene-styrene block copolymer.

6. The external preparation composition according to any one of claims 1 to 5, characterized in that: The external preparation composition further comprises 8-30 parts by weight of a viscosity enhancer; Preferably, the tackifier includes one or more of rosin resin, polyterpene resin, petroleum resin, etc., preferably hydrogenated rosin resin.

7. The external preparation composition according to any one of claims 1 to 6, characterized in that: The external preparation composition further comprises 0-50 parts by weight of a softener; Preferably, the softener includes one or more of liquid paraffin, silicone oil, higher fatty acid, vegetable oil, and polybutene. Preferably, the softener is liquid paraffin.

8. The external preparation composition according to any one of claims 1 to 7, characterized in that: The external preparation composition comprises the following components by weight:

9. The external preparation composition according to claim 8, characterized in that The external preparation composition comprises the following components by weight: Preferably, the external preparation composition comprises the following components by weight:

10. A method for preparing the external preparation composition according to any one of claims 1 to 9, characterized in that: The preparation method comprises: Step 1: Add compound I, isopropyl myristate and peppermint oil to a softener, and stir to disperse the prepared suspension evenly. Step 2: Heat and stir the matrix material, polyisobutylene and the remaining softener evenly, add the viscosity enhancer and mix evenly, wait until the paste temperature drops below 130° C., add the metal stearate and the suspension prepared in step 1, and stir evenly to obtain a drug-containing paste.

11. A compound I external preparation, characterized in that: The compound I external preparation comprises a backing layer, a drug storage layer and a protective layer arranged in sequence, and the raw material for preparing the drug storage layer comprises the external preparation composition according to any one of claims 1 to 9.

12. A method for preparing the external preparation of Compound I as claimed in claim 11, characterized in that: The preparation method comprises: coating the external preparation composition on a protective layer to form a drug storage layer; and compounding a backing layer on the drug storage layer to obtain the compound I external preparation.

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