A topical pharmaceutical composition containing timolol and preparation method thereof

Abstract

The invention discloses a topical pharmaceutical composition containing timolol and a preparation method thereof, and relates to the technical field of timolol topical composition;The raw material of the pharmaceutical composition is composed of timolol 0.1‑5wt%, white vaseline 19‑30wt%, liquid paraffin 46‑54wt%, and beeswax 17‑22wt%;The preparation method is to take liquid paraffin, beeswax, and white vaseline water bath heating and melting, stirring to obtain a mixture;Then add timolol under a specific constant temperature state, continue to stir;Finally, make after cooling to room temperature while stirring. The pharmaceutical composition provided by the invention can promote the active ingredient to penetrate the epidermis (stratum corneum) and dermis of the skin, to provide the active ingredient of a therapeutically effective amount;More importantly, the generation of impurities in the composition during storage is suppressed, and the time for the active ingredient to remain stable in the formula is significantly extended.

Description

Technical Field

[0001] The invention relates to the technical field of timolol external-use compositions, and in particular to a topical pharmaceutical composition containing timolol and a preparation method thereof. Background Art

[0002] Infantile hemangiomas (IH) are one of the most common benign childhood tumors worldwide. Early literature reports that most IHs do not require treatment, but about 12% of high-risk patients may need treatment due to organ function impairment or even life-threatening conditions.

[0003] Timolol is generally used as a first-line drug for the treatment of pediatric glaucoma. Later, clinicians and researchers from various countries reported that timolol is safe and effective in the treatment of IH. In view of the safety and effectiveness of timolol, the American Academy of Dermatology and the American Academy of Pediatrics recommend topical timolol as one of the first-choice options for the treatment of superficial localized infantile hemangiomas (small area) (J Pediatr Ophthalmol Strabismus, 2009, 46 (1): 12-18). At present, there are two main types of timolol preparations that have been marketed in China: timolol maleate eye drops and timolol maleate tablets. Among them, the main indications of timolol maleate tablets are: essential hypertension; treatment of angina pectoris or myocardial infarction; prevention of migraine. Timolol maleate eye drops have a good effect in lowering intraocular pressure for primary open-angle glaucoma; it can further enhance the intraocular pressure-lowering effect for certain secondary glaucoma, ocular hypertension, some primary angle-closure glaucoma, and glaucoma that is not responsive to other drugs and surgery.

[0004] In the existing timolol drug technology for topical external use, for example, the transdermal penetration enhancing composition provided by Chinese authorized patent CN112439071B uses white vaseline, light liquid paraffin, and white beeswax as the transdermal penetration enhancing composition, which is used in combination with timolol to improve the transdermal efficiency of timolol. However, the long-term stability of this timolol composition has not been studied in depth. Summary of the invention

[0005] In view of the above shortcomings of the prior art, the present invention provides a topical pharmaceutical composition containing timolol and a preparation method thereof, wherein the composition can promote the penetration of the active ingredient into the epidermis (stratum corneum) and dermis of the skin to provide a therapeutically effective amount of the active ingredient; more importantly, the generation of impurities in the composition during storage is inhibited, and the time for the active ingredient to remain stable in the formula is significantly prolonged, thereby providing a treatment option that is more conducive to long-term medication. This is specifically achieved through the following technologies.

[0006] A topical pharmaceutical composition containing timolol, wherein the raw materials thereof are composed of 0.1-5wt% of timolol, 25-30wt% of white vaseline, 46-54wt% of liquid paraffin and 17-22wt% of beeswax.

[0007] Generally, timolol alone is relatively stable to heat or light. However, the applicant accidentally discovered that, whether it is timolol gel, ointment, cream, etc., which are commercially available or produced in accordance with the authorized patent CN112439071B, it is often found that as the storage time increases, the content of timolol active ingredients in the product decreases significantly and the impurity components increase significantly. Through in-depth research on the degradation mechanism of impurities, it is found that timolol first degrades into impurity D, and then is further oxidized into impurity G. The reaction process is as follows:

[0008]

[0009] In addition, the product also contains impurity B, which is produced by the reaction of the hydroxyl group in intermediate 1 attacking different positions of the epoxy group in R-epichlorohydrin to produce (R)-3-chloro-2-[(4-morpholin-1,2,5-thiadiazol-3-yl)oxy]-1-propanol. The production process is as follows:

[0010]

[0011] Therefore, in order to further inhibit the growth of the above-mentioned impurities B, D and G under long-term storage conditions, the applicant of the present invention accidentally discovered that by adjusting the dosage ratio of white vaseline, liquid paraffin and beeswax, increasing the dosage of liquid paraffin and beeswax, and correspondingly reducing the dosage of white vaseline, the generation of impurities B, G and D under storage conditions can be significantly inhibited. Through further stability tests, the timolol composition prepared by the above-mentioned raw materials and proportions of the present invention is stored in an environment of 40°C for 1 month, and the pharmaceutical composition has a total degradation product of no more than 0.5% content (mass fraction), wherein impurity G does not exceed 0.1%, impurity B does not exceed 0.2%, and impurity D does not exceed 0.05%. Under 45000lx light conditions, the pharmaceutical composition has a total degradation product of no more than 0.5%, wherein the content of impurity G does not exceed 0.1%, impurity B does not exceed 0.1%, and impurity D does not exceed 0.05%. Through further long-term and accelerated stability studies (stored at 30±2°C, RH65±5% for 6 months), it was found that the contents of impurities G, B and D maintained very insignificant growth and were able to meet the limit requirements.

[0012] Preferably, the mass ratio of white vaseline, liquid paraffin and beeswax is 1:(1.6-2.0):(0.7-0.8).

[0013] More preferably, the raw materials of the topical pharmaceutical composition consist of 0.4-1 wt% of timolol, 27-28 wt% of white vaseline, 51-52 wt% of liquid paraffin, and 19-20 wt% of beeswax.

[0014] The present invention also provides a method for preparing the topical pharmaceutical composition containing timolol, comprising the following steps:

[0015] S1. Take liquid paraffin, beeswax and white vaseline, heat them in a water bath until they are liquid and stir evenly;

[0016] S2, adding timolol, stirring until timolol is completely dissolved; then cooling to room temperature while stirring to obtain a finished composition. Preferably, the stirring parameter in step S1 is.

[0017] Preferably, in step S2, after adding timolol, the temperature is controlled to 45-50° C., and the mixture is stirred until timolol is completely dissolved.

[0018] The present invention also provides the use of the topical pharmaceutical composition in preparing a drug for treating infantile hemangioma.

[0019] Compared with the prior art, the present invention is advantageous in that the present invention provides a timolol topical composition having both good transdermal performance and good long-term storage stability by improving and optimizing the dosage composition of timolol, white vaseline, liquid paraffin and beeswax. DETAILED DESCRIPTION

[0020] The technical solution of the present invention will be described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0021] Among the raw materials used in the following examples and comparative examples, white vaseline, liquid paraffin, and beeswax were directly purchased on the market.

[0022] The topical pharmaceutical compositions prepared in the following examples and comparative examples, unless otherwise specified, are prepared by the following method:

[0023] S1. Take liquid paraffin, beeswax and white vaseline, heat them in a water bath until they are liquid (about 80°C) and stir (200-300rpm) evenly;

[0024] S2, adding timolol, controlling the temperature of the mixture to be lowered to 50° C., stirring (200-300 rpm) until the timolol is completely dissolved; then cooling the mixture to room temperature while stirring (200-300 rpm) to obtain a finished composition.

[0025] Example 1

[0026] The topical pharmaceutical composition containing timolol provided in this embodiment is composed of 0.5wt% timolol, 27.5wt% white vaseline, 52wt% liquid paraffin and 20wt% beeswax, that is, the mass ratio of white vaseline, liquid paraffin and beeswax is 1:1.89:0.73.

[0027] Example 2

[0028] The topical pharmaceutical composition containing timolol provided in this embodiment comprises 0.5wt% timolol, 30wt% white vaseline, 47.5wt% liquid paraffin and 22wt% beeswax, that is, the mass ratio of white vaseline, liquid paraffin and beeswax is 1:1.58:0.73.

[0029] Example 3

[0030] The topical pharmaceutical composition containing timolol provided in this embodiment comprises 0.5wt% timolol, 28.5wt% white vaseline, 54wt% liquid paraffin and 17wt% beeswax, that is, the mass ratio of white vaseline, liquid paraffin and beeswax is 1:1.89:0.60.

[0031] Example 4

[0032] The topical pharmaceutical composition containing timolol provided in this embodiment comprises 0.5wt% timolol, 26wt% white vaseline, 52wt% liquid paraffin and 21.5wt% beeswax, that is, the mass ratio of white vaseline, liquid paraffin and beeswax is 1:2.0:0.83.

[0033] Example 5

[0034] The topical pharmaceutical composition containing timolol provided in this embodiment comprises 0.5wt% timolol, 30wt% white vaseline, 48wt% liquid paraffin and 21.5wt% beeswax, that is, the mass ratio of white vaseline, liquid paraffin and beeswax is 1:1.6:0.72.

[0035] Comparative Example 1

[0036] The topical pharmaceutical composition containing timolol provided in this comparative example is composed of 0.5wt% timolol, 34.5wt% white vaseline, and 65wt% liquid paraffin, that is, it does not contain beeswax, and the mass ratio of white vaseline to liquid paraffin is 1:1.884 (basically the same as the ratio of the two in Example 1).

[0037] Comparative Example 2

[0038] The topical pharmaceutical composition containing timolol provided in this comparative example is composed of 0.5wt% timolol, 79.5wt% white vaseline, 15wt% liquid paraffin and 5wt% beeswax, that is, the prescription of 20161220-1 disclosed in paragraph 0056 of the specification of the authorized patent CN112439071B is adopted.

[0039] Comparative Example 3

[0040] The topical pharmaceutical composition containing timolol provided in this comparative example is composed of 0.5wt% timolol, 69.5wt% white vaseline, 25wt% liquid paraffin and 5wt% beeswax, that is, the prescription of 20161220-2 disclosed in paragraph 0056 of the specification of the authorized patent CN112439071B is adopted.

[0041] Test Example 1: Stability Study of the Pharmaceutical Compositions Prepared in Examples and Comparative Examples

[0042] The above examples and comparative examples were placed at 40°C for 1 month, 4500lx for 10 days, 30°C for 3 months, and 25°C for 3 months for stability testing, and the content and related substances were tested. The test results are shown in Table 1 below, in which total impurities refer to the sum of impurities B and impurities D, as well as some other unknown impurities.

[0043] Table 1 Stability test results of the pharmaceutical compositions prepared in Examples and Comparative Examples

[0044]

[0045]

[0046] As can be seen from Table 1 above, under the above-mentioned 40°C high temperature, light and accelerated test conditions, the degradation impurities of the pharmaceutical composition obtained by the present invention did not show a significant increase. In the products prepared in Comparative Examples 1-3, impurities B, impurity D, and impurity G all increased to a greater or lesser extent, ultimately resulting in a significant increase in the total impurity content. Test Example 2: Investigation of the in vitro release performance of the pharmaceutical compositions prepared in the Examples and Comparative Examples

[0047] The in vitro release rate was determined using an improved Franz vertical diffusion cell. The stirrer was placed in the receiving cell. The pretreated nylon membrane (pore size 0.45 μm) was placed between the supply chamber and the receiving chamber, with the smooth side facing the receiving liquid. It was fixed with an iron clamp. 200 mg of the sample was evenly spread on the membrane and the supply cell port was closed. The diffusion cell was placed in a water tank with a water bath temperature of 32°C ± 0.5°C and a stirring speed of 600 r / min. 2 ml of the receiving liquid was taken out at 0.5, 1, 2, 4, and 6 h, and the same volume of blank receiving liquid was added at the same time. The obtained sample was centrifuged, the supernatant was taken, and the concentration was determined by HPLC. The results are shown in Table 2 below.

[0048] Table 2 In vitro release of drug samples of Examples and Comparative Examples

[0049]

[0050] It can be seen from Table 2 above that the drug samples of Examples 1-5 prepared by the method of the present invention have better transdermal penetration enhancing effects than those of Comparative Examples 1-3.

[0051] Test Example 3: In vitro skin permeation test

[0052] The in vitro transdermal test was conducted using a modified Franz vertical diffusion cell. The stirring bar was placed in the receiving cell. The pretreated pig skin (back) was placed between the supply chamber and the receiving chamber, with the dermis facing the receiving liquid. It was fixed with an iron clamp, and about 35 mg of the sample was evenly spread on the epidermis. The diffusion cell was placed in a water tank with a water bath temperature of 32°C ± 0.5°C and a stirring speed of 600r / min. The receiving liquid was completely removed at 1, 2, 4, 6, and 8 hours, and supplemented with fresh blank receiving liquid. The obtained samples were centrifuged, the supernatant was taken, the concentration was determined by HPLC, and the cumulative retention rate of subcutaneous, intercutaneous and epidermal was calculated.

[0053] Table 3 Cumulative retention rate of drugs in the subcutaneous, intradermal and epidermal regions

[0054] Subcutaneous Leather Room On the skin Example 1 0.43％ 10.95％ 85.30％ Example 2 0.38％ 9.90％ 87.26％ Example 3 0.11％ 8.36％ 88.40％ Example 4 1.53％ 7.97％ 88.20％ Example 5 1.49％ 7.89％ 88.80％ Comparative Example 1 0.17％ 5.44％ 90.30％ Comparative Example 2 0.05％ 4.01％ 92.80％ Comparative Example 3 0.03％ 3.82％ 94.10％

[0055] It can be seen from Table 3 above that the drug samples prepared in Examples 1-5 have significantly higher intercutaneous drug retention and significantly less subcutaneous permeation, which indicates that the amount of drug that enters the systemic circulation through the skin is reduced. The increase in intercutaneous retention means better local efficacy.

[0056] The above specific embodiments describe the implementation of the present invention in detail, but the present invention is not limited to the specific details in the above embodiments. Within the scope of the claims and technical concept of the present invention, the technical solution of the present invention can be modified and changed in many simple ways, and these simple modifications all belong to the protection scope of the present invention.

Claims

1. A topical pharmaceutical composition containing timolol, characterized in that The raw materials consist of 0.5wt% of timolol, 25-30wt% of white vaseline, 46-54wt% of liquid paraffin and 17-22wt% of beeswax.

2. The topical pharmaceutical composition containing timolol according to claim 1, characterized in that The mass ratio of the white vaseline, liquid paraffin and beeswax is 1:(1.6-2.0):(0.7-0.8).

3. The topical pharmaceutical composition containing timolol according to claim 2, characterized in that The raw materials consist of 0.5wt% of timolol, 27-28wt% of white vaseline, 51-52wt% of liquid paraffin and 19-20wt% of beeswax.

4. A method for preparing a topical pharmaceutical composition containing timolol according to any one of claims 1 to 3, characterized in that: The following steps are involved: S1. Take liquid paraffin, beeswax and white vaseline, heat them in a water bath until they are liquid and stir evenly; S2, adding timolol, stirring until timolol is completely dissolved; then cooling to room temperature while stirring to obtain a finished composition.

5. The method for preparing a topical pharmaceutical composition containing timolol according to claim 4, characterized in that: In step S2, after adding timolol, the temperature is controlled to 45-50° C. and stirred until timolol is completely dissolved.

6. Use of the topical pharmaceutical composition according to any one of claims 1 to 3 in the preparation of a drug for treating infantile hemangioma.

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