Mupirocin ointment and method of preparation

Abstract

The present application relates to a kind of mupirocin ointment and its preparation method, the ointment preparation specifically includes mupirocin, polyethylene glycol 400, polyethylene glycol 3350, cyclodextrin, the prepared preparation can solve mupirocin ointment stability problem, effectively control the period of validity within impurity increase, guarantee preparation quality and clinical curative effect, and the ointment preparation process is simple, easy to operate, suitable for industrialization scale production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, specifically to a mupirocin ointment and its preparation method. Background Technology

[0002] Mupiroci, chemically known as 9-[[(2E)-4-[(2S,3R,4R,5S)-3,4-dihydroxy-5-[[(2S,3S)-3-[(1S,2S)-2-hydroxy-1-methylpropyl]oxy]methyl]tetrahydro-2H-pyran-2-yl]-3-methylbut-2-acyl]oxy]nonanoic acid, has the molecular formula C 26 H 44 O9, molecular weight 500.6, structural formula as follows:

[0003]

[0004] Mupirocin, also known as Pseudomonas aeruginosa acid A, is a bacterial metabolite isolated from *Pseudomonas fluorescens* in 1971 and marketed by GlaxoSmithKline in 1985 under the brand name "Bactroban". Mupirocin is primarily used for the prevention and treatment of skin infections caused by Gram-positive cocci, such as primary skin infections like impetigo, boils, and folliculitis, as well as secondary skin infections such as eczema complicated by infection and superficial wounds not exceeding 10 cm × 10 cm complicated by infection. The main mechanism of mupirocin's antibacterial action lies in inhibiting protein synthesis within bacteria. Specifically, mupirocin acts on the isoleucine-tRNA synthetase binding site within bacteria, thereby inhibiting amino acid synthesis and consuming intracellular tRNA, thus halting RNA and protein synthesis. It is a first-line drug for topical antibacterial treatment in dermatology. The 2020 edition of the Chinese Pharmacopoeia does not yet include mupirocin ointment, but it is included in the National Drug Standards for New Drug Approval, Volume 23, the United States Pharmacopeia 2021, the British Pharmacopoeia 2022, and the Japanese Pharmacopoeia 16th edition (JP16).

[0005] Mupirocin's molecular structure contains epoxy bonds, olefin bonds, and ester bonds. The epoxy bonds are highly prone to ring-opening, combining with adjacent hydroxyl groups to form rings and generate impurities. Mupirocin exhibits significant degradation under high temperature, acidic, and alkaline conditions, making the stability of mupirocin ointment a challenging issue. Patent CN102335122, filed by Beijing Xiehe Pharmaceutical Factory, discloses a mupirocin ointment and its preparation method. This method produces an ointment containing organic acids as stabilizers, improving stability and resulting in low levels of related substances. Patent CN102885763, filed by Hangzhou Zhuyangxin Pharmaceutical Co., Ltd., discloses a novel mupirocin ointment pharmaceutical composition containing a specific ratio of amino acids, exhibiting excellent pharmaceutical characteristics in terms of stability. However, mupirocin is unstable in acidic environments and readily degrades under acidic conditions. Adding organic acids or amino acids to the ointment has not effectively solved the stability problem of mupirocin. Fuyuan Pharmaceutical Co., Ltd.'s patent CN113520994 discloses a mupirocin ointment formulation. This ointment uses a cellulose derivative to encapsulate mupirocin, thereby improving its stability. However, the cellulose derivative used in this patent is generally used as a thickener in topical formulations, and its encapsulation effect on mupirocin is limited, failing to adequately address the stability issue of mupirocin.

[0006] Existing technologies, such as adding organic acids and amino acids to the ointment or encapsulating mupirocin with cellulose derivatives to improve its stability, have failed to effectively solve the stability problem of mupirocin ointment. Therefore, improving the stability of the formulation and controlling the increase of related substances through effective processing methods remain the problems that need to be solved for mupirocin ointment. Summary of the Invention

[0007] This invention provides a mupirocin ointment and its preparation method to solve the stability problem of mupirocin ointment, effectively control the increase of impurities during the shelf life, and ensure the quality of the formulation and its clinical efficacy. The ointment formulation specifically includes mupirocin, polyethylene glycol 400, polyethylene glycol 3350, and cyclodextrin. The process of this ointment formulation is simple, easy to operate, and suitable for industrial-scale production.

[0008] To obtain a mupirocin ointment with good stability, the inventors, through in-depth research, unexpectedly discovered that adding cyclodextrin to the existing ointment bases of polyethylene glycol 400 and polyethylene glycol 3350, and employing cyclodextrin inclusion technology for mupirocin, can improve the stability of the mupirocin ointment. Furthermore, the resulting ointment has a suitable viscosity, is fine and uniform, spreads easily, and exhibits good patient compliance.

[0009] This invention provides a mupirocin ointment and its preparation method. The ointment formulation specifically comprises mupirocin, polyethylene glycol 400, polyethylene glycol 3350, and cyclodextrin. The cyclodextrin is any one of α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin. More preferably, the cyclodextrin is β-cyclodextrin or γ-cyclodextrin.

[0010] The weight proportions of each component in the above ointment are as follows:

[0011] Raw material names Number of weights Mupiro Star 2-5 Polyethylene glycol 400 50-70 Polyethylene glycol 3350 30-50 Cyclodextrin 1-10

[0012] Furthermore, the preferred weight proportions of each component in the ointment are:

[0013] Raw material names Number of weights Mupiro Star 2-3 Polyethylene glycol 400 50-60 Polyethylene glycol 3350 30-40 Cyclodextrin 1-6

[0014] Furthermore, a method for preparing mupirocin ointment includes the following steps:

[0015] ① Heat 50% to 70% of the prescribed amount of polyethylene glycol 400 to a certain temperature to obtain solution A;

[0016] ② Add the prescribed amount of polyethylene glycol 3350 to solution A and heat it to a certain temperature. Then keep it warm to melt the polyethylene glycol 3350. Stir to mix the two polyethylene glycols evenly to obtain mixture B.

[0017] ③ Heat the remaining amount of polyethylene glycol 400 to a certain temperature, then add cyclodextrin and stir until homogeneous. Then add the prescribed amount of mupirocin and stir to encapsulate the mupirocin with cyclodextrin, thus obtaining drug-containing solution C; ④ Add drug-containing solution C to molten polyethylene glycol mixture B, stir at a certain temperature to mix homogeneously, cool to room temperature, and fill into containers.

[0018] Furthermore, the heating temperature in step ① is 53–55°C.

[0019] Furthermore, the heating temperature in step ② is 63–65°C.

[0020] Furthermore, the heating temperature in step ③ is 55–60°C.

[0021] Furthermore, the stirring temperature in step ④ is 55–60°C.

[0022] Beneficial effects

[0023] Compared with the prior art, the present invention reduces the exposure of mupirocin by using cyclodextrin to encapsulate mupirocin, and reduces its contact with the ointment matrix polyethylene glycol 400 and polyethylene glycol 3350. Moreover, the present invention does not introduce acidic components, thereby achieving the purpose of improving the stability of mupirocin. Detailed Implementation

[0024] The beneficial effects of the present invention are further illustrated by the following experiments. However, the invention is not limited to the following embodiments. Equivalent substitutions or changes made by those skilled in the art based on the present invention without departing from the essential content of the present invention are also within the protection scope of the present invention.

[0025] Example 1

[0026] Raw material names Dosage (g) Mupiro Star 2 Polyethylene glycol 400 55.9 Polyethylene glycol 3350 38.1 α-Cyclodextrin 4

[0027] The process steps are as follows:

[0028] ① Heat 50% of the prescribed amount of polyethylene glycol 400 (27.95g) to 55℃ to obtain solution A;

[0029] ② Add the prescribed amount (38.1g) of polyethylene glycol 3350 to solution A, stir until the temperature rises to 65℃, keep warm to melt polyethylene glycol 3350, stir to mix the two polyethylene glycols evenly, and obtain mixture B for later use;

[0030] ③ Heat the remaining 27.95g of polyethylene glycol 400 to 57℃, add 4g of α-cyclodextrin and stir well, then add 2g of mupirocin and stir to encapsulate mupirocin with cyclodextrin to obtain drug-containing solution C, which is ready for use.

[0031] ④ Add the above-mentioned drug-containing liquid C to the molten polyethylene glycol mixture B, stir at 57°C to mix evenly, cool to room temperature, and then fill into the container.

[0032] Example 2

[0033] Raw material names Dosage (g) Mupiro Star 4 Polyethylene glycol 400 53 Polyethylene glycol 3350 37 β-Cyclodextrin 6

[0034] The process steps are as follows:

[0035] ① 65% of the prescribed amount of polyethylene glycol 400 (34.45g) was heated to 55℃ to obtain solution A;

[0036] ② Add the prescribed amount (37g) of polyethylene glycol 3350 to solution A, stir until the temperature rises to 64℃, keep warm to melt polyethylene glycol 3350, stir to mix the two polyethylene glycols evenly, and obtain mixture B for later use;

[0037] ③ Heat the remaining 18.55g of polyethylene glycol 400 to 60℃, add 6g of β-cyclodextrin and stir well, then add 4g of mupirocin and stir to encapsulate mupirocin with cyclodextrin to obtain drug-containing solution C, which is ready for use.

[0038] ④ Add the above-mentioned drug-containing liquid C to the molten polyethylene glycol mixture B, stir at 60°C to mix evenly, cool to room temperature, and then fill into the container.

[0039] Example 3

[0040] Raw material names Dosage (g) Mupiro Star 5 Polyethylene glycol 400 53 Polyethylene glycol 3350 36 γ-Cyclodextrin 6

[0041] The process steps are as follows:

[0042] ① 70% of the prescribed amount of polyethylene glycol 400 (37.1g) was heated to 55℃ to obtain solution A;

[0043] ② Add the prescribed amount (36g) of polyethylene glycol 3350 to solution A, stir until the temperature rises to 63℃, keep warm to melt polyethylene glycol 3350, stir to mix the two polyethylene glycols evenly, and obtain mixture B for later use;

[0044] ③ Heat the remaining 15.9g of polyethylene glycol 400 to 55℃, add 6g of γ-cyclodextrin and stir well, then add 5g of mupirocin and stir to encapsulate mupirocin with cyclodextrin to obtain drug-containing solution C, which is ready for use.

[0045] ④ Add the above-mentioned drug-containing liquid C to the molten polyethylene glycol mixture B, stir at 55°C to mix evenly, cool to room temperature, and then fill into the container.

[0046] Example 4

[0047] Raw material names Dosage (g) Mupiro Star 2 Polyethylene glycol 400 57.7 Polyethylene glycol 3350 38.1 β-Cyclodextrin 2.2

[0048] The process steps are as follows:

[0049] ① 60% of the prescribed amount of polyethylene glycol 400 (34.62 g) was heated to 53°C to obtain solution A;

[0050] ② Add the prescribed amount (38.1g) of polyethylene glycol 3350 to solution A, stir until the temperature rises to 65℃, keep warm to melt polyethylene glycol 3350, stir to mix the two polyethylene glycols evenly, and obtain mixture B for later use;

[0051] ③ Heat the remaining 23.08g of polyethylene glycol 400 to 55℃, add 2.2g of β-cyclodextrin and stir well, then add 2g of mupirocin and stir to encapsulate mupirocin with cyclodextrin to obtain drug-containing solution C, which is ready for use.

[0052] ④ Add the above-mentioned drug-containing liquid to the molten polyethylene glycol mixture B, stir at 55°C to mix evenly, cool to room temperature, and then fill into the container.

[0053] Example 5

[0054] Raw material names Dosage (g) Mupiro Star 3 Polyethylene glycol 400 54 Polyethylene glycol 3350 37 β-Cyclodextrin 6

[0055] The process steps are as follows:

[0056] ① 65% of the prescribed amount of polyethylene glycol 400 (35.1g) was heated to 54℃ to obtain solution A;

[0057] ② Add the prescribed amount (37g) of polyethylene glycol 3350 to solution A, stir until the temperature rises to 63℃, keep warm to melt polyethylene glycol 3350, stir to mix the two polyethylene glycols evenly, and obtain mixture B for later use;

[0058] ③ Heat the remaining 18.9g of polyethylene glycol 400 to 60℃, add 6g of β-cyclodextrin and stir well, then add 3g of mupirocin and stir to encapsulate mupirocin with cyclodextrin to obtain drug-containing solution C, which is ready for use.

[0059] ④ Add the above-mentioned drug-containing liquid C to the molten polyethylene glycol mixture B, stir at 60°C to mix evenly, cool to room temperature, and then fill into the container.

[0060] Example 6

[0061] Raw material names Dosage (g) Mupiro Star 2.5 Polyethylene glycol 400 56 Polyethylene glycol 3350 38 β-Cyclodextrin 3.5

[0062] The process steps are as follows:

[0063] ① Heat 50% of the prescribed amount of polyethylene glycol 400 (28g) to 55℃ to obtain solution A;

[0064] ② Add the prescribed amount (38g) of polyethylene glycol 3350 to solution A, stir until the temperature rises to 64℃, keep warm to melt polyethylene glycol 3350, stir to mix the two polyethylene glycols evenly, and obtain mixture B for later use;

[0065] ③ Heat the remaining 28g of polyethylene glycol 400 to 56℃, add 3.5g of β-cyclodextrin and stir well, then add 2.5g of mupirocin and stir to encapsulate mupirocin with cyclodextrin to obtain drug-containing solution C, which is ready for use.

[0066] ④ Add the above-mentioned drug-containing liquid C to the molten polyethylene glycol mixture B, stir at 56°C to mix evenly, cool to room temperature, and then fill into containers.

[0067] Comparative Example 1

[0068] Raw material names Dosage (g) Mupiro Star 2 Polyethylene glycol 400 58.9 Polyethylene glycol 3350 39.1

[0069] The preparation process is the same as in Example 1.

[0070] Comparative Example 2

[0071] Samples were prepared according to Example 1 of patent CN113520994 of Fuyuan Pharmaceutical Co., Ltd.

[0072] Raw material names Dosage (g) Mupiro Star 2 Sodium carboxymethyl cellulose 1 Polyethylene glycol 400 58.6 Polyethylene glycol 3350 38.4

[0073] The process steps are as follows:

[0074] ① Heat 50% of the prescribed amount of polyethylene glycol 400 (29.3g) to 55℃, add polyethylene glycol 3350 and stir, continue to heat to 75℃ until polyethylene glycol 400 and polyethylene glycol 3350 melt to obtain a mixed solution, and set aside;

[0075] ② Mix mupirocin and sodium carboxymethyl cellulose evenly to obtain a mixture, and add the mixture to 29.3g of polyethylene glycol 400 at 55℃ and mix well to obtain a drug-containing solution.

[0076] ③ At 55℃, mix the mixed solution and the drug-containing liquid evenly, cool to 40℃, and then fill.

[0077] Comparative Example 3

[0078] Samples were prepared according to Example 1 of Beijing Union Medical College Pharmaceutical Factory Patent CN102335122 (one-tenth of each component was taken).

[0079] Raw material names Dosage (g) Mupiro Star 1 Citric acid 0.1 Polyethylene glycol 400 39.1 Polyethylene glycol 4000 9.8

[0080] The process steps are as follows:

[0081] Dissolve 0.1g of citric acid in 39.1g of polyethylene glycol 400, then add 9.8g of polyethylene glycol 4000, heat in a 60°C water bath until melted, then add 1g of mupirocin, stir in a 60°C water bath to dissolve the mupirocin, mix evenly, and cool to room temperature to obtain mupirocin ointment.

[0082] Comparative Example 4

[0083] The sample was prepared according to Example 1 in patent CN102885763 of Hangzhou Zhuyangxin Pharmaceutical Co., Ltd.

[0084] Raw material names Dosage (g) Mupiro Star 1.5 Arginine 1 Polyethylene glycol 400 79.5 Polyethylene glycol 4000 18

[0085] The process steps are as follows:

[0086] ① Dissolve 1g of arginine in 55.65g of 70% polyethylene glycol 400 to obtain a mixture;

[0087] ② Add 1.5g of mupirocin to the mixture from step ① and stir to dissolve;

[0088] ③ Heat 18g of polyethylene glycol 4000 until it melts, then add it to the material obtained in step ② while stirring, and stir evenly;

[0089] ④ Add the remaining amount of polyethylene glycol 400 (23.85g), mix well, and cool to room temperature to obtain mupirocin ointment.

[0090] Key quality attribute assessment: Key quality attributes of mupirocin ointment prepared in Examples 1, 2, 3, 4, 5, 6 and Comparative Examples 1, 2, 3, 4 were assessed: appearance, uniformity, viscosity, and stability (related substances). The determination methods and acceptable standards are as follows:

[0091]

[0092]

[0093] The results of the tests on properties, uniformity, and viscosity are as follows:

[0094]

[0095]

[0096] Stability (related substances) test results:

[0097] The samples prepared in Examples 1, 2, 3, 4, 5, and 6 and Comparative Examples 1, 2, 3, and 4 were examined under accelerated conditions (30℃±2℃, relative humidity: 65%±5%) for 6 months. The total impurity (%) of each sample after 6 months of accelerated testing is shown in the table below:

[0098]

[0099] As can be seen from the above stability results, the inclusion technology of mupirocin by cyclodextrin in the embodiments of the present invention can reduce the exposure of mupirocin and reduce its contact with the ointment matrix polyethylene glycol 400 and polyethylene glycol 3350, thereby improving the stability of mupirocin. Compared with the stability of the samples prepared by Comparative Example 1 without cyclodextrin, Comparative Example 2 with cellulose derivatives to encapsulate mupirocin, Comparative Example 3 with citric acid, and Comparative Example 4 with arginine, the sample prepared according to the present invention has better stability.

Claims

1. A mupirocin ointment characterized in that, The ointment contains mupirocin, polyethylene glycol 400, polyethylene glycol 3350, and cyclodextrin; The weight proportions of each component in the ointment are as follows: The mupirocin ointment is prepared by the following process steps: ① Heat 50% to 70% of the prescribed amount of polyethylene glycol 400 to a certain temperature to obtain solution A; ② Add the prescribed amount of polyethylene glycol 3350 to solution A and heat it to a certain temperature. Then keep it warm to melt the polyethylene glycol 3350. Stir to mix the two polyethylene glycols evenly to obtain mixture B. ③ Heat the remaining amount of polyethylene glycol 400 to a certain temperature, then add cyclodextrin and stir evenly, then add the prescribed amount of mupirocin and stir to encapsulate mupirocin with cyclodextrin to obtain drug-containing solution C. ④ Add the drug-containing liquid C to the molten polyethylene glycol mixture B, stir at a certain temperature to make it evenly mixed, cool to room temperature, and then fill into the container.

2. A mupirocin ointment according to claim 1, wherein The cyclodextrin is any one of α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin.

3. A mupirocin ointment according to claim 2, wherein The cyclodextrin is β-cyclodextrin or γ-cyclodextrin.

4. The mupirocin ointment of claim 1, wherein, The weight proportions of each component in the ointment are as follows: 。 5. The method for preparing mupirocin ointment as described in claim 1, characterized in that, The process includes the following steps: ① Heat 50% to 70% of the prescribed amount of polyethylene glycol 400 to a certain temperature to obtain solution A; ② Add the prescribed amount of polyethylene glycol 3350 to solution A and heat it to a certain temperature. Then keep it warm to melt the polyethylene glycol 3350. Stir to mix the two polyethylene glycols evenly to obtain mixture B. ③ Heat the remaining amount of polyethylene glycol 400 to a certain temperature, then add cyclodextrin and stir evenly, then add the prescribed amount of mupirocin and stir to encapsulate mupirocin with cyclodextrin to obtain drug-containing solution C. ④ Add the drug-containing liquid C to the molten polyethylene glycol mixture B, stir at a certain temperature to make it evenly mixed, cool to room temperature, and then fill into the container.

6. The method for preparing mupirocin ointment according to claim 5, characterized in that, The heating temperature in process step ① is 53-55℃.

7. The method for preparing mupirocin ointment according to claim 5, characterized in that, The heating temperature in process step ② is 63-65℃.

8. The method for preparing mupirocin ointment according to claim 5, characterized in that, The heating temperature in process step ③ is 55-60℃.

9. The method for preparing mupirocin ointment according to claim 5, characterized in that, The stirring temperature in process step ④ is 55-60℃.

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