WO2021120268A1

WO2021120268A1 - Mupirocine ointment and preparation method therefor

Info

Publication number: WO2021120268A1
Application number: PCT/CN2019/128624
Authority: WO
Inventors: 戴小华; 程璐; 朱克旭; 吴剑; 张言君
Original assignee: 福元药业有限公司
Priority date: 2019-12-17
Filing date: 2019-12-26
Publication date: 2021-06-24
Also published as: CN110787128A

Abstract

The present invention relates to a mupirocine ointment. The raw materials thereof by weight comprise: 20-100 parts of mupirocine, 500-700 parts of polyethylene glycol 3350, 400-600 parts of polyethylene glycol 400, 1-2 parts of vitamin E, and 39-58 parts of propylene glycol. The present invention further relates to a preparation method for the described mupirocine ointment, comprising the following steps: taking polyethylene glycol 400, adding polyethylene glycol 3350 and propylene glycol and mixing them uniformly, so as to obtain a solution A; taking polyethylene glycol 400, then adding mupirocin and vitamin E and mixing them uniformly, so as to obtain a suspension B; mixing the solution A and suspension B uniformly at 55-65°C, then lowering the temperature to 35-45°C, grinding, cooling to room temperature, and canning same, so as to obtain a product. The obtained mupirocine ointment has a uniform active ingredient distribution, suitable consistency, easy application and convenient use for patients.

Description

Mupirocin ointment and preparation method thereof

This application claims the priority of a Chinese patent application filed with the Chinese Patent Office on December 17, 2019, the application number is 201911302071.6, the application name is a mupirocin ointment and its preparation method, the entire content of which is incorporated into this by reference Applying.

Technical field

This application relates to the technical field of chemical medicine preparations, in particular to a mupirocin ointment and a preparation method thereof.

Background technique

Mupirocin Ointment, trade name:

It is a new type of topical antibiotic, a metabolite produced in the culture of Pseudomonas fluorescens, namely Pseudomonas A. This product was approved by the FDA in 1987. Mupirocin's chemical structure and mechanism of action are different from other types of antibiotics, and it can avoid the development of drug resistance in the near future; it has high activity against common skin gram-positive bacteria, especially under acidic conditions; it has strong antibacterial effect; it does not produce contact allergies Reaction, non-irritating and toxic, safe to use. It is clinically suitable for primary skin infections such as bacterial infectious impetigo, furunculosis, folliculitis, and secondary infections such as eczema combined infection, ulcer combined infection, trauma combined infection, etc. It can also be used for burn wounds with Staphylococcus aureus Infection etc. In short, mupirocin is a safe and effective new topical antibiotic for clinical use. Mupirocin is produced by the fermentation of Pseudomonas fluorescens. It has antibacterial effect and has a molecular structure with other known antibacterial agents. And metabolites with different mechanisms of action, which are mainly pseudomonas acid A, with a structure similar to isoleucine. However, the affinity to the target site on t-RNA synthetase is stronger than that of isoleucine. Through competitive binding, monosporic acid A can bind to isoleucine transfer RNA synthetase when in contact with bacteria. It inhibits the protein synthesis of bacteria and causes the bacteria to die. In vitro studies have shown that a wide range of microorganisms are sensitive to this drug.

Mupirocin has strong antibacterial activity against various gram-positive cocci related to skin infections, and is also effective against drug-resistant Staphylococcus aureus; it has a certain antibacterial effect against certain gram-negative bacteria, and it is compatible with other antibiotics. No cross-resistance.

At present, the consistency of mupirocin ointment that has been on the market is generally problematic. Its matrix is mainly polyethylene glycol 3350 and polyethylene glycol 400. The specific ratio can be detected by high performance liquid chromatography with a differential detector. , But the prepared ointment base has a very thick consistency. Many manufacturers solve this problem by increasing the ratio of polyethylene glycol 400. The ointment base is thinner when the temperature is high in summer, and it looks watery after extrusion; when the temperature is low in winter, the ointment base It is hard and not easy to squeeze out of the ointment tube, which makes the active ingredient API in mupirocin ointment unevenly distributed in the matrix, which affects the patient's experience and efficacy.

Application content

Based on the technical problems existing in the background technology, the present application proposes a mupirocin ointment and a preparation method thereof. The active ingredients of the present application are uniformly distributed, have a suitable consistency, are easy to apply, and are convenient for patients to use.

This application proposes a mupirocin ointment. Its raw materials include 20-100 parts by weight of mupirocin, 500-700 parts of polyethylene glycol 3350, 400-600 parts of polyethylene glycol 400, 1- 2 parts vitamin E, 39-58 parts propylene glycol.

Among them, the content of mupirocin is 2-10%.

This application also discloses a method for preparing the above mupirocin ointment, which includes the following steps: taking polyethylene glycol 400, adding polyethylene glycol 3350, and propylene glycol to mix to obtain solution A; taking polyethylene glycol 400, and then adding mopi Mix Luoxing and Vitamin E to obtain suspension B; mix Solution A and Suspension B at 55-65°C, then cool to 35-45°C, grind, cool to room temperature, and canned.

The above mupirocin ointment is 5-10g/stick.

Among them, take polyethylene glycol 400, raise the temperature to 70-75°C, add polyethylene glycol 3350 and propylene glycol to mix well, and lower the temperature to 60-65°C to obtain solution A.

Wherein, the weight ratio of polyethylene glycol 400 in solution A to polyethylene glycol 400 in suspension B is 4-7:3-6.

Among them, grinding 1-3 times.

Among them, use colloid mill to grind.

Among them, the solution A and the suspension B are stirred for 15-25 minutes and mixed evenly.

In this application, vitamin E is added to increase the stability of mupirocin, and the ratio of polyethylene glycol 3350, polyethylene glycol 400 and propylene glycol is adjusted to reduce the proportion of polyethylene glycol 400 to improve the summer temperature. The problem of ointment base is relatively thin, and by adding appropriate amount of propylene glycol, polyethylene glycol 3350, polyethylene glycol 400 to improve the problem of hard ointment base when the temperature is low in winter; and in the preparation process, the polyethylene glycol 3350. Mix propylene glycol and polyethylene glycol 400 to obtain solution A, so that the materials are evenly mixed; adjust the temperature of solution A and suspension B when they are mixed, so that the two are evenly mixed, and the temperature is reduced to 35-45°C for grinding , Instead of cooling to a conventional lower temperature, the cooling speed is slower, so that the temperature of the paste matrix is more uniform, which can avoid the problem of small lumps caused by the rapid cooling of polyethylene glycol 3350, and it is homogeneously ground with a colloid mill Through external extrusion work, the active ingredients in the application can be kept uniformly distributed in the matrix, and the viscosity, kinematic viscosity, and rheological properties are consistent with those of the reference formulation, which is easy to apply and convenient for patients to use.

Detailed ways

Hereinafter, the technical solution of the present application will be described in detail through specific embodiments.

Example 1

A mupirocin ointment, its raw materials include 20 parts by weight of mupirocin, 520 parts of polyethylene glycol 3350, 420 parts of polyethylene glycol 400, 1 part of vitamin E, and 39 parts of propylene glycol.

The preparation method of the above mupirocin ointment includes the following steps:

Take the preparation tank and heat and dry for 30 minutes at 85°C, then add polyethylene glycol 400 to the preparation tank, heat up to 70°C, add polyethylene glycol 3350, propylene glycol and stir slowly to melt and clarify the polyethylene glycol 3350, and cool to 65 ℃ to obtain solution A;

Add polyethylene glycol 400 to a stainless steel bucket, then add mupirocin and vitamin E and mix well to obtain suspension B. Among them, the stainless steel bucket is rinsed twice with polyethylene glycol 400 to obtain a lotion, suspension B includes lotion;

Mix Solution A and Suspension B at 55°C with slow stirring for 25min, then cool to 35°C, grind 3 times with a colloid mill, cool to room temperature, canned 5g/stick to obtain mupirocin ointment, in which, The weight ratio of polyethylene glycol 400 in solution A to polyethylene glycol 400 in suspension B is 7:3.

Example 2

A mupirocin ointment, its raw materials include 100 parts by weight of mupirocin, 700 parts of polyethylene glycol 3350, 600 parts of polyethylene glycol 400, 2 parts of vitamin E, and 58 parts of propylene glycol.

Take the preparation tank and heat and dry it at 85°C for 30 minutes, then add polyethylene glycol 400 to the preparation tank, raise the temperature to 75°C, add polyethylene glycol 3350 and propylene glycol, and stir slowly to melt and clarify the polyethylene glycol 3350, and cool to 60 ℃ to obtain solution A;

Mix Solution A and Suspension B at 65°C with slow stirring for 15min, then cool to 45°C, grind once with a colloid mill, cool to room temperature, canned 10g/stick to obtain mupirocin ointment, in which, The weight ratio of polyethylene glycol 400 in solution A to polyethylene glycol 400 in suspension B is 4:6.

Example 3

A mupirocin ointment, its raw materials include 50 parts by weight of mupirocin, 500 parts of polyethylene glycol 3350, 400 parts of polyethylene glycol 400, 1 part of vitamin E, and 49 parts of propylene glycol.

Take the preparation tank and heat and dry for 30 minutes at 85°C, then add polyethylene glycol 400 to the preparation tank, heat up to 72°C, add polyethylene glycol 3350, propylene glycol and stir slowly to melt and clarify the polyethylene glycol 3350, and cool to 63 ℃ to obtain solution A;

Mix Solution A and Suspension B at 60°C with slow stirring for 20min, then cool to 40°C, grind twice with a colloid mill, cool to room temperature, canned 5g/stick to obtain mupirocin ointment, in which, The weight ratio of polyethylene glycol 400 in solution A to polyethylene glycol 400 in suspension B is 6:4.

Comparison

A mupirocin ointment, its raw materials include 50 parts by weight of mupirocin, 500 parts of polyethylene glycol 3350, and 450 parts of polyethylene glycol 400.

In the preparation method, there is no grinding step, and the others are the same as in Example 3.

Test example

According to Example 3, three batches of mupirocin ointment were produced, and the batch numbers were 190601, 190602, and 190603. A batch of mupirocin ointment was produced according to the comparative example, and the batch number was 190501.

For reference preparations, the batch numbers are 18100585, 18100240, 19040148, 8D9G (British import batch numbers); the performance tests of the above samples were carried out, and the results are as follows:

1. Comparison of kinematic viscosity

Use a Ubbelohde viscometer to detect the outflow time of the solution, and compare the intrinsic viscosity of the high molecular polymers of the above samples. Refer to the second method under the Chinese Pharmacopoeia 2015 edition of the four parts 0633 viscosity measurement method (using Ubbelohde viscometer to determine the intrinsic viscosity) to compare the kinematic viscosity. The results are shown in Table 1.

Table 1 Comparison results of ointment kinematic viscosity

It can be seen from Table 1 that the kinematic viscosity of the batch of self-products of Example 3 is basically the same as that of the reference formulation.

2. Comparison of rotational viscosity

The kinematic viscosity of the paste was measured with a viscosity-temperature control integrated meter, and the apparent viscosity of the above samples was compared with the same instrument and rotor under the same measurement conditions. Refer to the third method (rotor-type rotary viscometer) under the four-part 0633 viscosity measurement method of the Chinese Pharmacopoeia 2015 edition to compare the apparent viscosity. The results are shown in Table 2.

Table 2 Comparison results of ointment rotational viscosity

It can be seen from Table 2 that the rotational viscosity of the batch of self-products of Example 3 is basically the same as that of the reference formulation.

3. Comparison of rheology

A DHR-1 rheometer was used to detect the rheology of the paste. The same instrument and a 25mm rotor were used to compare the apparent viscosity of the above samples under the same measurement conditions.

For the measurement method, first select a 25mm clamp and perform zero calibration, take an appropriate amount of mupirocin ointment sample to the center of the clamp, touch Bearing lock to lock the bearing, and then touch Trim gap to wait for intermittent closing to the trimming gap, use a suitable scraping tool Remove the excess sample spilling to the periphery of the fixture. Click the Go to Geometry gap button and wait for the completion of setting the test gap to start the test. In the test, the linear viscoelastic region of the sample is measured at a strain of 0.01-100% under the oscillation mode, and the rheological curve of the sample is measured at 0.01-100s-1 under the flow test.

Take an appropriate amount of the above sample to measure the rheology. The results are shown in Table 3.

Table 3 Rheological comparison results of ointment

It can be seen from Table 3 that the rheological properties of the self-made batch of Example 3 are basically the same as those of the reference formulation.

4. Comparison of spreadability

Randomly 20 people in each group, a total of 5 groups, take appropriate amount of the above samples and apply them to the outer skin of the arm to compare the spreadability. The results are shown in Table 4.

Table 4 Comparison results of spreadability

From Table 4, it can be seen that the spreadability of the 3 batches of self-products of Example 3 is basically the same as that of the reference formulation.

5. Comparison of content uniformity

The content uniformity of samples with batch numbers of 190501 and 190601 was tested, and the results are shown in Table 5:

Table 5 Results of uniformity inspection of mupirocin content

It can be seen from Table 5 that the active ingredients are added by suspension. Due to equipment and process reasons, there is uneven mixing. Homogenizing with a colloid mill for 1-3 times can make the active ingredients evenly distributed and achieve the expected curative effect during use. , Mupirocin ointment is mixed evenly after colloid milling.

The above are only preferred specific implementations of this application, but the protection scope of this application is not limited to this. Anyone familiar with the technical field within the technical scope disclosed in this application, according to the technical solution of this application The equivalent replacement or change of its application concept shall be covered by the scope of protection of this application.

Claims

A mupirocin ointment, the raw materials of which include 20-100 parts by weight of mupirocin, 500-700 parts of polyethylene glycol 3350, 400-600 parts of polyethylene glycol 400, and 1-2 parts of vitamin E , 39-58 parts of propylene glycol.
The mupirocin ointment according to claim 1, wherein the content of mupirocin is 2-10%.
A method for preparing mupirocin ointment according to claim 1 or 2, which comprises the following steps: taking polyethylene glycol 400, adding polyethylene glycol 3350 and propylene glycol to dissolve to obtain solution A; taking polyethylene glycol 400, then add mupirocin and vitamin E and mix well to obtain suspension B; mix solution A and suspension B at 55-65℃, then cool to 35-45℃, grind, cool to room temperature, tank Install it and get it.
The method for preparing mupirocin ointment according to claim 3, wherein polyethylene glycol 400 is taken, the temperature is raised to 70-75°C, polyethylene glycol 3350 and propylene glycol are added to mix, and the temperature is lowered to 60-65°C to obtain solution A.
The method for preparing mupirocin ointment according to claim 3 or 4, wherein the weight ratio of polyethylene glycol 400 in solution A to polyethylene glycol 400 in suspension B is 4-7:3-6.
The method for preparing mupirocin ointment according to any one of claims 3 to 5, wherein the grinding is performed 1-3 times.
The preparation method of mupirocin ointment according to claim 3-6, wherein the grinding is carried out with a colloid mill.
The method for preparing mupirocin ointment according to any one of claims 3-7, wherein the solution A and the suspension B are stirred for 15-25 minutes and mixed evenly.