Polyethylene glycol matrix preparation and preparation method thereof

Abstract

The invention relates to a polyethylene glycol matrix preparation and a preparation method thereof. The method comprises the following steps: 1) determining prescription dosages of raw material medicines, polyethylene glycol 3350 and / or polyethylene glycol 4000 and polyethylene glycol 400; 2) melting the substrate; 3) cooling the substrate; (4) preparing a raw material medicine polyethylene glycol 400 suspension; (5) preparing ointment; (6) homogenizing; and 7) cooling the paste, and optionally, the method further comprises the steps of standing the paste in the step 7) overnight, and heating and stirring the paste in the second day. Once the polyethylene glycol matrix preparation prepared by the method disclosed by the invention is produced, the polyethylene glycol matrix preparation can reach a composite stable state and presents a peak at 30-60 DEG C in DSC (differential scanning calorimetry), that is, the paste is in a single-phase state, is a stable product, does not change with time or temperature, is fine and smooth in appearance, does not have a gravel feeling, and is good in skin feeling experience of a user.

Description

Technical Field

[0001] The invention belongs to the field of medicine, and in particular, relates to a polyethylene glycol matrix preparation and a preparation method thereof. Background Art

[0002] Usually, topical drugs refer to drugs that are directly applied to the skin surface, including ointments, creams, gels, sprays, patches, etc., which are usually used to relieve symptoms or infections of local skin diseases, such as wound inflammation, atopic dermatitis, eczema, rheumatic or rheumatoid arthritis, silver disease, lupus erythematosus, hair loss, etc. Among them, ointments are generally divided into two categories according to the matrix used. One category is an oily matrix (such as vaseline, liquid paraffin or paraffin, etc.), beeswax, etc. are ointment matrices, such as erythromycin, roxithromycin, and chlortetracycline ointment; the other category is a water-soluble matrix, with water-soluble high molecular weight polyethylene glycol (Polyethylene glycol or Macrogol, polyethylene glycol is referred to as polyethylene glycol) as the matrix, and polyethylene glycol 400 and polyethylene glycol 3350 are often used in combination, or polyethylene glycol 400 and polyethylene glycol 4000 are used in combination, such as Mupirocin Ointment (trade name: Bactroban) is a typical representative of polyethylene glycol ointment. Polyethylene glycol-based ointments are popular because they are not greasy when applied to the skin and the active ingredients of the drug dissolve more easily in them.

[0003] Polyethylene glycol is a polymer material obtained by hydrolysis and polymerization of ethylene oxide. Its structural formula is as follows: HO(CH2CH2O) n H, where n is the degree of polymerization of polyethylene glycol, that is, the number of ethylene glycol units. The larger the value, the higher the degree of polymerization. Polyethylene glycol 400 is a liquid, which is both an ointment base and a solvent, while polyethylene glycol 3350 or polyethylene glycol 4000 is a low-freezing point solid. When heated to about 50-60°C, it will change into a liquid and solidify after cooling. The hardness of the paste can be adjusted. Polyethylene glycol 400 has good miscibility with polyethylene glycol 3350 or polyethylene glycol 4000, so they are used in combination for the preparation of ointments.

[0004] Since polyethylene glycol 400 is a liquid and polyethylene glycol 3350 or polyethylene glycol 4000 is a solid, in the process of preparing polyethylene glycol ointment, if the temperature is raised to about 60-70°C to melt the matrix, polyethylene glycol 3350 or polyethylene glycol 4000 will melt and form a homogeneous phase with polyethylene glycol 400. After the active pharmaceutical ingredient (API) is dissolved or suspended in the matrix, the temperature is lowered. During the cooling process, polyethylene glycol 3350 or polyethylene glycol 4000 may precipitate. The size of the precipitated particles is related to the cooling rate and the stirring homogenization rate. These parameters may affect the properties and microstructure of the final polyethylene glycol ointment, thereby affecting the efficacy.

[0005] According to the literature review, there are currently many research papers that use hot melt extrusion technology to prepare polyethylene glycol ointment, such as the hot melt extrusion (HME) preparation process of lidocaine polyethylene glycol ointment (reference: AAPS PharmSciTech, 2016, Volume 17:158, titled Development of an Ointment Formulation Using hot-Melt Extrusion Technology), and the preparation of metronidazole polyethylene glycol ointment (reference: AAPS PharmSciTech, 2020, Volume 21:273, titled A rapid tool to optimize process variables for continuous manufacturing of metronidazole ointment using melt extrusion technique), etc. According to the hot melt extrusion preparation process of lidocaine ointment, AAPS PharmSciTech, 2016, Volume 17:158 disclosed that the polyethylene glycol ointment base prepared by the hot melt extrusion process, including the drug-containing (HME ointment) and the placebo ointment (Placebo ointment, not containing lidocaine active ingredient), both showed double peaks in the differential scanning calorimeter (DSC) test, and the ointment (Conventional ointment) obtained by the conventional process also showed double peaks (see its Figure 3 ).

[0006] Differential Scanning Calorimeter (DSC) is a technical means to study the molecular structure, aggregate structure, and thermal changes of molecular motion of a substance by detecting the changes in the thermophysical properties of the sample itself with temperature. It is used to determine the phase change of a substance, etc. DSC is a classic application for studying the interaction between drugs and excipients. To determine whether there is a mutual influence, it mainly examines whether the characteristic endothermic or exothermic peak of the drug disappears or whether the temperature at which the peak appears changes. In addition, the appearance of new peaks can also be considered as evidence of the interaction between the drug and the excipients. The above-mentioned ointments, including the medicated ointment and the non-medicated placebo ointment, all showed similar double peaks in DSC, indicating that the double peaks were not related to the active ingredient lidocaine, but might be related to the existence of two states of the matrix itself, namely, the ointment prepared in the continuous hot melt extrusion process (HME ointment) and the ointment prepared in the traditional non-continuous tank process (Conventional ointment). Some of the ointment matrices polyethylene glycol 400 and polyethylene glycol 3350 were not truly fused into one phase. It is more likely that some polyethylene glycol 3350 precipitated itself during the cooling process to form microparticles, resulting in another peak in DSC.

[0007] A document published by Shaanxi Provincial Food and Drug Supervision and Inspection Institute (reference: "Chinese Journal of Antibiotics", March 2020, Issue 3, No. 252), titled "Quality Evaluation of Mupirocin Ointment", records that the quality of mupirocin ointment on the market varies greatly.

[0008] Polyethylene glycol 3350 or 4000 is a relatively hard solid at room temperature. After being made into an external ointment with liquid polyethylene glycol 400, if polyethylene glycol 3350 or polyethylene glycol 4000 crystallizes and is not completely compounded with polyethylene glycol 400, it will show double peaks on the DSC, that is, there may be two phases in the paste. This ointment may be whitish in appearance, not round and delicate, and may feel gritty when applied on the hands. Therefore, a preparation process for polyethylene glycol matrix ointment is required, so that the ointment is prepared and completely compounded, and DSC detection shows a peak between 30 and 60°C. For suspension polyethylene glycol ointment, microscopic observation shows that the active ingredients of the raw materials are evenly distributed, and the appearance is round and delicate, not whitish to the naked eye, and the skin feels delicate when applied. Summary of the invention

[0009] Technical Purpose

[0010] One of the technical objectives of the present invention is to provide a method for preparing a polyethylene glycol matrix preparation. The preparation prepared by the method exhibits a single peak in DSC, that is, polyethylene glycol 400 and polyethylene glycol 3350 / 4000 are completely compounded.

[0011] Another technical object of the present invention is to provide a polyethylene glycol matrix preparation prepared by the above method.

[0012] Technical Solution

[0013] In one aspect, the present invention provides a method for preparing a polyethylene glycol matrix formulation, the method comprising the following steps:

[0014] 1) Determine the prescription quantity of the API, PEG 3350 and / or PEG 4000, and PEG 400;

[0015] 2) Matrix melting: Mix the following ingredients:

[0016] ① The total amount of polyethylene glycol 3350 and / or polyethylene glycol 4000, and

[0017] ②55-65% of the prescription amount of polyethylene glycol 400

[0018] Add to the first container, and stir at 65-75°C at 100-200 rpm until the matrix is ​​dissolved and clear;

[0019] 3) Cooling the substrate: cooling the substrate from step 2) to 55-65° C. until the substrate becomes clear and transparent;

[0020] 4) Preparation of the suspension of the API in polyethylene glycol 400: At room temperature, in a second container, add the entire amount of the API to 20-30% of the amount of the polyethylene glycol 400, and stir to disperse for 20-40 minutes;

[0021] 5) Preparation of API ointment: Add the API polyethylene glycol 400 suspension of step 4) to the first container at 55-65°C and stirring at 50-300 rpm, wash the second container with the remaining amount of polyethylene glycol 400, and transfer the washing liquid to the first container to ensure that all the API is transferred completely, and continue stirring for 15-30 minutes;

[0022] 6) Homogenization: Stop stirring in the first container, and homogenize the raw material ointment in step 5) at 55-65° C. and a rotation speed of 10000-20000 rpm for 15-60 minutes;

[0023] 7) Paste cooling: cool the API ointment from step 6) to 30°C-45°C and continue stirring at 50-300 rpm for at least 2 hours.

[0024] In a specific embodiment, in step 1), depending on the type of the API, the prescription amount of the API, polyethylene glycol 3350 or polyethylene glycol 4000, polyethylene glycol 400 can be determined by a technician in the field based on conventional drug formulas or technical information known in the prior art, and the specific prescription amount is not particularly limited in this application.

[0025] In a specific embodiment, the drug substance can be any active drug that does not react with the PEG matrix, such as mupirocin, ciprofloxacin, lidocaine, metronidazole, etc.

[0026] In a specific embodiment, in step 2), component ① is the whole prescription amount of polyethylene glycol 3350 or the whole prescription amount of polyethylene glycol 4000. Preferably, ① is the whole prescription amount of polyethylene glycol 3350.

[0027] In a specific embodiment, in step 2), the first container is a homogenous mixing reactor; in step 4), the second container is any suitable container for preparing the pharmaceutical solution, including a barrel, a kettle or a tank, and preferably, the second container is equipped with a stirring device.

[0028] In a specific embodiment, 60% of the prescribed amount of polyethylene glycol 400 is added in step 2), and 25% of the prescribed amount of polyethylene glycol 400 is added in step 4).

[0029] In a specific embodiment, the paste is stirred for 2-3 hours in step 7), for example, 2 hours.

[0030] The polyethylene glycol paste prepared in the present application is a suspension type. In order to make the microscopic observation of the mixed raw materials reach a steady state, step 8) is included after step 7): the ointment of step 7) is left to stand overnight, heated to 35°C-42°C on the next day, and continued to stir for 15-60 minutes.

[0031] In a specific implementation manner, after step 8), the method further includes a step of filling the product.

[0032] In a specific embodiment, the polyethylene glycol matrix preparation is a polyethylene glycol ointment preparation.

[0033] In another aspect, the present invention also provides a polyethylene glycol matrix preparation prepared by the above method.

[0034] Beneficial Effects

[0035] The present application provides a novel method for producing a polyethylene glycol matrix preparation, in which the inventor unexpectedly discovered that extending the stirring time to more than 2 hours in the paste cooling step can make the prepared product reach a composite stable state once it is produced, which is specifically embodied in DSC as a peak between 30-60 ° C, that is, the paste is in a single-phase state, a stable product, does not change with time or temperature, has a delicate appearance, no gritty feeling, and a good user skin feel experience. Further, in the production of polyethylene glycol matrix preparations, the inventor also added an operation of overnight and continued heating and stirring treatment on the second day after the cooling step. The microscopic observation results confirmed that such an operation can prepare a suspension ointment preparation with a more stable microstructure of the raw material.

[0036] Therefore, the method of the present application can be applied to the preparation of any conventional pharmaceutical ointment preparation based on PEG matrix, and has broad application prospects in the production of these ointment preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 A polarizing micrograph of the 0-day sample in Comparative Example 1 is shown.

[0038] Figure 2 A polarizing micrograph of the 0-day sample in Comparative Example 2 is shown.

[0039] Figure 3 A polarized light micrograph of the 0-day sample in Example 1 is shown.

[0040] Figure 4 A polarized light micrograph of the 0-day sample in Example 2 is shown.

[0041] Figure 5 A polarizing micrograph of commercially available Bactroban is shown.

[0042] Figure 6 The DSC graph of the 0-day sample in Comparative Example 1 is shown.

[0043] Figure 7 The DSC graph of the 0-day sample in Comparative Example 2 is shown.

[0044] Figure 8 The DSC graph of the 0-day sample in Example 1 is shown.

[0045] Fig. 9 The DSC graph of the 0-day sample in Example 2 is shown.

[0046] Fig.10 The DSC graph of commercially available Bactroban is shown.

[0047] Fig.11 The DSC chart of the 30-day sample in Comparative Example 1 is shown.

[0048] Fig.12 The DSC chart of the 30-day sample in Comparative Example 2 is shown. DETAILED DESCRIPTION

[0049] Hereinafter, the present invention will be described in detail. Before describing, it should be understood that the terms used in this specification and the appended claims should not be interpreted as being limited to the general meaning and dictionary meaning, but should be interpreted according to the meaning and concept corresponding to the technical aspects of the present invention on the basis of the principle that the inventor is allowed to appropriately define the terms for the best interpretation. Therefore, the descriptions presented here are only preferred examples for illustrative purposes and are not intended to limit the scope of the present invention, so that it should be understood that other equivalents or improvements can be obtained therefrom without departing from the spirit and scope of the present invention.

[0050] the term

[0051] In this application, PEG and polyethylene glycol are used interchangeably.

[0052] In the present application, "suspension polyethylene glycol ointment" means that the active ingredient, namely the raw material drug (API for short), cannot be completely dissolved in the polyethylene glycol matrix, and exists in the ointment in the form of suspension, which may be completely suspended or partially suspended and partially dissolved.

[0053] In the present application, "room temperature" refers to a temperature of 18-28°C, typically, room temperature is 20-25°C, preferably, room temperature is 24°C.

[0054] The following examples are merely listed as examples of embodiments of the present invention and do not constitute any limitation to the present invention. Those skilled in the art will appreciate that modifications within the scope of the spirit and concept of the present invention fall within the protection scope of the present invention.

[0055] In order to verify the technical improvement effect of the present invention, in the following examples, mupirocin was used as a research model compound, different cooling schemes were adopted, and DSC analysis and microscopic observation were performed on the obtained polyethylene glycol ointment, and then the effects of these methods on the performance of the final product were compared.

[0056] Materials and Equipment:

[0057] Unless otherwise specified, the reagents and instruments used in the following examples are commercially available products.

[0058] Mupirocin: purchased from Hangzhou Sino-US Huadong Pharmaceutical Jiangdong Co., Ltd.

[0059] Polyethylene glycol 400: purchased from Oxiteno, Brazil.

[0060] Polyethylene glycol 3350: purchased from Dow Chemical.

[0061] BDO: Sino-US Tianjin SmithKline Pharmaceutical Co., Ltd.

[0062] Homogeneous mixing reactor (referred to as "homogenizer"): Fluker, model Fisco-1S;

[0063] DSC testing instrument: NETZSCH Instrument Manufacturing Co., Ltd., Germany, model: DSC 200F3 Maia.

[0064] Polarized light microscope (PLM): Olympus, model BX53M.

[0065] Example 1

[0066] The ointment preparation was prepared by showing the prescription and batch size of the ointment preparation in Table 1 below.

[0067] Table 1. Prescription and batch size

[0068]

[0069]

[0070] 1) Matrix melting: Add the prescribed amount of polyethylene glycol 3350 and 60% of the prescribed amount of polyethylene glycol 400 into a 1L homogenizing mixing reactor, start stirring at a speed of 150±50rpm, and stir at 70±5°C until dissolved and clarified.

[0071] 2) Substrate cooling: Turn off the heating of the homogeneous mixing reactor, circulate cooling water, and cool the temperature of the substrate to 60±5°C. The substrate is clear and transparent.

[0072] 3) Preparation of Mupirocin PEG 400 suspension: At room temperature, add the prescribed amount of API to 25% of the prescribed amount of PEG 400, and disperse it fully by magnetic stirring for 30±10 minutes. Phenomenon description: Opaque suspension, evenly dispersed.

[0073] 4) Preparation of mupirocin ointment: At 60±5°C, under stirring conditions, the stirring speed is about 150 rpm, the drug-containing polyethylene glycol 400 suspension is slowly added to the homogenizer, and the remaining 15% of the prescription amount of polyethylene glycol 400 solution is rinsed twice in the container, and added together to the homogenizing mixing reactor, and stirring is continued for 15-30 minutes.

[0074] 5) Homogenization: Turn off stirring, turn on homogenization, homogenization speed 15000±5000rpm, homogenize at 60±5℃ for 30±15 minutes.

[0075] 6) Paste cooling: Lower the paste temperature to 35°C-42°C, and keep stirring during the cooling process. After the paste temperature reaches 35°C-42°C, continue stirring for about 2 hours at a stirring speed of 150±50rpm, and then stop stirring.

[0076] 7) Filling: Take about 200 grams of the paste and fill it into a medicinal aluminum tube, with a filling amount of 10 g / tube, and fill about 20 tubes in total, which is the sample of "Example 1".

[0077] Example 2

[0078] The remaining paste from step 7) of Example 1 was left to stand overnight, and heated to 35°C-42°C on the next day. After reaching 35°C-42°C, stirring was continued for about 30 minutes. A pharmaceutical aluminum tube was used for filling, with a filling amount of 10 g / tube, and a total of about 20 tubes were filled, which was the sample of "Example 2".

[0079] Comparative Example 1:

[0080] The operation process is the same as that in Example 1, except that in step 6), the stirring time is 10-20 minutes.

[0081] Comparative Example 2

[0082] The operation process is the same as that in Example 2, except that in step 6), the stirring time is 10-20 minutes.

[0083] Test Example 1:

[0084] The samples of the above Examples 1-2 and Comparative Examples 1-2 were sent for inspection to observe their properties, evaluate the skin feel after application, and perform DSC analysis and polarizing microscope observation.

[0085] 1)DSC analysis method:

[0086] Instruments and equipment

[0087] Differential Scanning Calorimeter (NETZSCH DSC 200F3)

[0088] Method Parameters

[0089] Starting temperature: 5°C

[0090] Final temperature: 100°C

[0091] Heating rate: 10K / min

[0092] Acquisition rate: 30.0 points / K

[0093] Testing process

[0094] Take about 2-5 mg of the test sample, place it in an aluminum crucible and cover it (the aluminum crucible is pressed together with the crucible after holes are punched in the cover). For reference, use an empty crucible and place it on the left side of the sensor, and the sample crucible on the right side. In the workstation, set the protective gas flow rate to 70 ml / min, the purge gas to 30 ml / min, and the temperature program to start at 5 °C and rise to 100 °C at 10 K / min. Select DSC signal for data processing, set the temperature as the horizontal axis, and select the peak value, starting point, end point and peak area for annotation.

[0095] 2) High-end microscope observation method:

[0096] Instruments and equipment

[0097] Microscope (Manufacturer: OLYMPUS; Model: BX53M)

[0098] Microanalytical balance (manufacturer: Sartorius; model: MCA6.6S-2CCN-M)

[0099] Glass slide (Specifications: 25.4×76.2mm; Thickness: 1-1.2mm)

[0100] Cover glass (specification: 24×24mm; thickness: 0.13-0.16mm)

[0101] Method Parameters

[0102] Objective lens magnification: 10 times

[0103] Eyepiece magnification: 10 times

[0104] Testing process

[0105] Take one tube of this product, squeeze out about 10 mg of the paste and place it in the middle of the slide, cover the slide with a cover glass, press lightly with your fingers and slide the cover glass in a clockwise circle to evenly disperse the sample. Immediately examine it under a microscope with orthogonal polarized light, adjust the focus to make the field of view clear, and save the picture.

[0106] The samples of the above-mentioned Example 1 and Example 2, as well as Comparative Example 1 and Comparative Example 2, on the day when they were prepared were recorded as "0-day samples", and their test results are detailed in Table 2 below.

[0107] Table 2. Test results of 0-day samples

[0108]

[0109] Result analysis:

[0110] Comparative Example 1 and Comparative Example 2, and the four 0-day samples of Example 1 and Example 2, the polarized light micrographs are shown respectively. Figures 1 to 4 , see the polarized light micrograph of Bactroban Figure 5Comparing the above figures, it can be seen that the polarized light micrograph of the 0-day sample of Example 2 ( Figure 4 ) and Baiduobang ( Figure 5 ), that is, the suspension ointment preparation prepared by the process of Example 2 is consistent with that of Bactroban in microscopic observation.

[0111] The DSC diagrams of the 0-day samples of Comparative Example 1 and Comparative Example 2, and Example 1 and Example 2 are shown in FIG. Figures 6 to 9 ; DSC diagram of BDOBON Fig.10 As can be seen from the above figures, the DSC graphs of Comparative Example 1 and Comparative Example 2 show double peaks, while the DSC graphs of Example 1 and Example 2 show single peaks. In addition, the property tests of Comparative Example 1 and Comparative Example 2 show that both are slightly whitish in appearance, while the property tests of Example 1 and Example 2 show that both are delicate in appearance and not whitish. These results indicate that the ointment preparations prepared by Implementation 1 and 2 of the present application are consistent with the original mupirocin ointment - Bactroban.

[0112] Based on the above analysis, the method of the present application allows polyethylene glycol 400 to be fully compounded with polyethylene glycol 3350. For the preparation of suspension-type polyethylene glycol ointment, in addition to the complete compounding of the matrix, the suspension of the raw material drug is also required to reach a steady state. Therefore, the method of the present application is suitable for the preparation of suspension-type polyethylene glycol ointment.

[0113] Test Example 2: Ointment Stability Study

[0114] The samples of Example 1 and Example 2, as well as the samples of Comparative Example 1 and Comparative Example 2, a total of 4 groups of samples, were placed in an accelerated environment at 40°C and 75% humidity for 30 days (referred to as "30-day samples") and then sent for inspection, and the properties were observed and DSC analysis was performed. The test results are shown in Table 3 below. Fig.11 and 12 shown.

[0115] Table 3. Test results of samples placed at 40°C and 75% humidity for 30 days

[0116]

[0117] From the data in Table 3 and Fig.11 and 12 It can be seen that after being placed at 40°C and 75% humidity for 30 days, the samples of Comparative Example 1 and Comparative Example 2 changed from two peaks to one peak, that is, the samples of Comparative Example 1 and Comparative Example 2 were not stable enough at the microscopic level and further turned into a more stable state at 40°C.

Claims

1. A method for preparing a polyethylene glycol matrix formulation, the method comprising the following steps: 1) Determine the prescription quantity of the API, PEG 3350 and / or PEG 4000, and PEG 400; 2) Matrix melting: Mix the following ingredients: ① The total amount of polyethylene glycol 3350 and / or polyethylene glycol 4000, and ②55-65% of the prescription amount of polyethylene glycol 400 Add to the first container, and stir at 65-75°C at 100-200 rpm until the matrix is ​​dissolved and clear; 3) Cooling the substrate: cooling the substrate from step 2) to 55-65° C. until the substrate becomes clear and transparent; 4) Preparation of the suspension of the API in polyethylene glycol 400: At room temperature, in a second container, add the entire amount of the API to 20-30% of the amount of polyethylene glycol 400, and stir to disperse for 20-40 minutes; 5) Preparation of ointment: Add the polyethylene glycol 400 suspension of the API in step 4) to the first container at 55-65°C and stirring at 50-300 rpm, wash the second container with the remaining amount of polyethylene glycol 400, and transfer the washing liquid to the first container to ensure that all the API is transferred completely, and continue stirring for 15-30 minutes; 6) Homogenization: Stop stirring in the first container, and homogenize the raw material ointment in step 5) at 55-65° C. and a rotation speed of 10000-20000 rpm for 15-60 minutes; as well as 7) Paste cooling: cool the API ointment from step 6) to 30°C-45°C and continue stirring at 50-300 rpm for at least 2 hours.

2. The method according to claim 1, wherein: In step 1), the drug substance is any active drug that does not react with the PEG matrix.

3. The method according to claim 1, wherein: In step 1), the drug substance is selected from mupirocin, ciprofloxacin, lidocaine and metronidazole.

4. The method according to claim 1, wherein: In step 2), component ① is the total prescribed amount of polyethylene glycol 3350 or polyethylene glycol 4000.

5. The method according to claim 1, wherein: In step 2), the first container is a homogeneous mixing reactor; and / or In step 4), the second container is a barrel, kettle or tank with a stirring device.

6. The method according to claim 1, wherein: In step 2), 60% of the prescribed amount of polyethylene glycol 400 is added, and in step 4), 25% of the prescribed amount of polyethylene glycol 400 is added.

7. The method according to claim 1, wherein: In step 7), the paste is stirred for 2 hours.

8. The method according to claim 1, wherein: After step 7), the method further comprises step 8): leaving the ointment of step 7) to stand overnight, heating to 35° C.-42° C. on the next day, and continuing stirring for 15-60 minutes.

9. The method according to claims 1-8, wherein: After step 7) or step 8), the method further comprises the step of filling the product.

10. A polyethylene glycol matrix preparation prepared by the method according to any one of claims 1 to 9.

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