A minocycline sterile ointment and preparation method

Abstract

The present invention provides a method for removing epimers (i.e., epi-minocycline) from minocycline hydrochloride, and further provides a method for purifying minocycline hydrochloride, as well as a minocycline hydrochloride API produced by the method of the present invention. In particular, the present invention provides a sterile minocycline hydrochloride API produced by the method of the present invention, and a sterile minocycline hydrochloride ointment produced from the API. Compared with existing minocycline hydrochloride APIs, the minocycline hydrochloride API produced by the method of the present invention significantly reduces the epimer content, thereby improving the quality and safety of the API and its preparation.

Description

Technical Field

[0001] The present invention provides a method for removing epimers from minocycline hydrochloride, further provides a method for purifying minocycline hydrochloride, and produces high-quality sterile minocycline hydrochloride bulk drug and sterile ointment preparation thereof. The present invention belongs to the field of medicine. Background Art

[0002] Minocycline hydrochloride, namely [4S-(4a, 4aa, 5aa, 12aa)]-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide hydrochloride, is a semi-synthetic tetracycline. It is considered the first choice for the treatment of periodontal disease due to its broad antibacterial spectrum, strong antibacterial activity, high efficiency, long-term effect, easy penetration, and high sensitivity to various periodontitis pathogens.

[0003] US4701320 discloses a pharmaceutical composition containing minocycline hydrochloride for periodontal disease, and the drug Palio was developed and marketed based on this composition. The applicant's earlier patent application CN202010785369.3 also discloses a minocycline hydrochloride ointment and a preparation method. The minocycline hydrochloride preparations disclosed in the prior art are not sterile APIs. In particular, minocycline hydrochloride ointment is used as a topical dental medication, and the administration site is the gums or inflamed areas. Non-sterile preparations are prone to secondary infections, etc.

[0004] In addition, the minocycline hydrochloride API contains diastereomers (i.e., diastereomers) as impurities. Currently, the purification or refining processes for the minocycline hydrochloride API often use recrystallization with ethanol as the solvent. Example 22 of CN112574057A discloses the preparation of minocycline hydrochloride (HPLC purity 98.9%) using ethanol as the solvent; Example 5 of CN101679218A discloses the preparation of Form III of minocycline base using ethanol as the solvent. The concentration of the solvent ethanol used is not specified, but the industry generally refers to 95% ethanol. In fact, the limit requirements for relevant substances in minocycline hydrochloride APIs are currently stipulated in the US and Chinese pharmacopoeias as 1.2% diastereomers. This shows that the content of diastereomers in the minocycline hydrochloride APIs prepared by the existing technology is still relatively high.

[0005] Active Pharmaceutical Ingredients (APIs) are the active ingredients used in the production of various pharmaceutical preparations. The quality of these APIs directly impacts the quality of the finished product. Summary of the Invention

[0006] The present invention surprisingly found that using anhydrous ethanol as a solvent in the recrystallization of minocycline hydrochloride can significantly reduce the content of diastereomers in minocycline hydrochloride.

[0007] To this end, the present invention provides a method for removing epimers (i.e., epiminocycline) from minocycline hydrochloride, and further provides a method for purifying minocycline hydrochloride, as well as a minocycline hydrochloride API prepared by the method of the present invention (having a significantly reduced epimer content compared to existing minocycline hydrochloride APIs). In particular, provided are a sterile minocycline hydrochloride API prepared by the method of the present invention, and a sterile minocycline hydrochloride ointment prepared from the API. Compared to existing minocycline hydrochloride APIs and their preparations, the minocycline hydrochloride API and its sterile ointment of the present invention are not only sterile products but also have significantly reduced impurity content, particularly the content of epimers (i.e., epiminocycline), thereby significantly improving the quality and safety of the API and its preparation.

[0008] The technical solutions of the present invention are as follows:

[0009] The invention provides a method for removing diastereomers (i.e., diastereomers) from minocycline hydrochloride, comprising the step of crystallizing minocycline hydrochloride, characterized in that anhydrous ethanol is used as a solvent for the crystallization.

[0010] The invention also provides a method for purifying minocycline hydrochloride, comprising the step of crystallizing minocycline hydrochloride, characterized in that anhydrous ethanol is used as a solvent for the crystallization.

[0011] Preferably, the above method is characterized in that the solution is sterile filtered before crystallization, and after crystallization, it is passed through a three-in-one sterile filter dryer to obtain sterile minocycline hydrochloride.

[0012] As another object of the present invention, minocycline hydrochloride prepared by the above method is also provided.

[0013] Preferably, the minocycline hydrochloride described above, calculated as anhydrous, contains minocycline (C 23 H 27 N3O7) is 89.0% to 95.0%, and is characterized in that the content of the diastereomer (i.e., diastereomer minocycline) does not exceed 0.3%.

[0014] Preferably, the minocycline hydrochloride described above is characterized in that the content of other single impurities except diastereomers does not exceed 0.2%, and the total content of other impurities except diastereomers does not exceed 1.0%.

[0015] Preferably, the minocycline hydrochloride described above is characterized by being sterile minocycline hydrochloride (i.e., sterile bulk drug).

[0016] Another object of the present invention is the use of the above-mentioned minocycline hydrochloride as a raw material in the preparation of a minocycline preparation; preferably, the minocycline preparation is a minocycline hydrochloride sterile ointment.

[0017] As one of the specific embodiments of the minocycline hydrochloride sterile ointment described in the present invention, the minocycline hydrochloride sterile ointment is composed of the following components by weight: 0.5% to 10.0% minocycline hydrochloride, 0.5% to 10.0% magnesium chloride, 1.0% to 10.0% aqueous phase skeleton material, 1.0% to 10.0% oil phase skeleton material, 3.0% to 40.0% oily skeleton solvent, and the balance is aqueous skeleton solvent. It is characterized in that the minocycline hydrochloride is the minocycline hydrochloride described above in the present invention.

[0018] As another object of the present invention, a method for preparing the above-mentioned sterile minocycline hydrochloride ointment is also provided, comprising the following steps:

[0019] (1) According to the method described above, a sterile raw material of minocycline hydrochloride is prepared;

[0020] (2) mixing and dissolving magnesium chloride, an aqueous skeleton solvent, and an aqueous phase skeleton material at 120° C.±10° C., and filtering the mixed solution by sterilization to obtain an aqueous phase;

[0021] (3) mixing and dissolving the oil phase skeleton material and the oily skeleton solvent at 100°C ± 10°C, and filtering the mixed solution by sterilization to obtain the oil phase;

[0022] (4) adding the oil phase prepared in step (3) to the aqueous phase prepared in step (2) and mixing them to prepare a sterile matrix;

[0023] (5) Add the sterile raw material of minocycline hydrochloride prepared in step (1) to the sterile matrix prepared in step (4), mix and dissolve thoroughly, and then aseptically fill into a pre-filled sterile syringe.

[0024] The pharmaceutical excipients and preparation methods of the sterile minocycline hydrochloride ointment described above can be, for example, referenced to the minocycline hydrochloride ointment and preparation method disclosed in the applicant's prior patent application CN202010785369.3. The disclosure of the prior patent application CN202010785369.3 is incorporated into this application.

[0025] The present invention surprisingly achieves at least two more beneficial technical effects when crystallizing and purifying minocycline hydrochloride API using anhydrous ethanol as a solvent, compared to crystallizing and purifying minocycline hydrochloride API using 95% ethanol as a solvent. On the one hand, the amount of solvent used is significantly reduced: 1 gram of minocycline hydrochloride API requires approximately 30 ml of anhydrous ethanol when using anhydrous ethanol, while approximately 300 ml of 95% ethanol is required when using 95% ethanol. On the other hand, the impurity content in the minocycline hydrochloride API is reduced, particularly the content of the diastereomer (i.e., diastereomer) impurity. The diastereomer content in the minocycline hydrochloride API obtained by recrystallization from 95% ethanol is significantly higher than that in the minocycline hydrochloride API obtained by recrystallization from anhydrous ethanol.

[0026] The limits for related substances in minocycline hydrochloride APIs are currently stipulated in both the U.S. and Chinese Pharmacopoeias at 1.2% for diastereomers and 2.0% for all other impurities excluding diastereomers. The diastereomers and other impurities in the minocycline hydrochloride API produced by the method of the present invention are significantly lower than the limits specified in the pharmacopoeias and are also significantly lower than those in currently commercially available minocycline hydrochloride APIs. The sterile minocycline hydrochloride ointment produced from the sterile minocycline hydrochloride API of the present invention also contains significantly lower levels of diastereomers and other impurities than the reference preparation, Paileo. Compared to the prior art, the present invention improves the quality and safety of the minocycline hydrochloride API and its preparations. DETAILED DESCRIPTION

[0027] In the following examples or comparative examples, content determination and related substance inspection were carried out according to the methods of "Related Substances" and "Content Determination" in the 2020 edition of the Chinese Pharmacopoeia for Minocycline Hydrochloride; the sterility test method was carried out according to Zhang Guanghua et al., "Establishment of Sterility Inspection Method for Minocycline Hydrochloride Ointment", Capital Food and Medicine, Issue 2, 2019.

[0028] Example 1: Sterile Minocycline Hydrochloride API

[0029] Weigh 1kg of commercially available minocycline hydrochloride raw material (0.40% of epimers, 0.15% of the maximum single impurity other than epimers, and 0.45% of the total amount of other impurities other than epimers), dissolve it in 21kg of anhydrous ethanol, and after sterile filtration, set the circulating cooling system temperature at -25°C. When the temperature in the kettle drops by about 10°C, stop stirring, stop the circulating cooling system, and keep it warm for 1h (at -10°C, a large amount of crystals begin to precipitate). When the temperature in the kettle drops below -20°C, keep it warm for 24h, start stirring (50 rev / min), start nitrogen pressing in a three-in-one sterile filter dryer, filter through 0.45μm and 0.22μm filter membranes, dry, and discharge after drying. After discharging, the sterile raw material is placed in a sterile bag for standby use. The finished product yield is 80%, and the content is based on minocycline (C23 H 27 N3O7) is 92%, diastereomers are 0.12%, the largest single impurity excluding diastereomers is 0.12%, and the total amount of other impurities excluding diastereomers is 0.32%.

[0030] Example 2: Minocycline Hydrochloride Sterile Ointment

[0031]

[0032]

[0033] Preparation method:

[0034] 1. Weigh the prescribed amount of magnesium chloride and disperse it in part of the aqueous skeleton solvent. Stir at 120±10℃ for 5-8h, cool to 100℃, then add the prescribed amount of aqueous phase skeleton matrix, stir evenly, and filter the mixed solution by sterilization to obtain the aqueous phase.

[0035] 2. Weigh the prescribed amount of oil phase skeleton material and disperse it into the oily skeleton solvent. Stir and dissolve it at 100±10℃. Sterilize and filter to obtain the oil phase.

[0036] 3. Add the oil phase to the water phase and stir evenly to prepare a sterile matrix;

[0037] 4. Add the prescribed amount of minocycline hydrochloride sterile API to the sterile matrix prepared in step 3, mix and dissolve thoroughly, and aseptically fill into a pre-filled sterile syringe.

[0038] Example 3: Related substance inspection:

[0039] Comparative Example 1 Ointment: Use the commercially available minocycline hydrochloride in Example 1 as the raw material, and prepare minocycline hydrochloride ointment according to the prescription composition and preparation process of Example 1 of CN202010785369.3.

[0040] Ointment of reference preparation: The commercially available Palio was used as the reference preparation.

[0041] Related substance inspection: The results are shown in Table 1.

[0042] Table 1 Results of relevant substance inspection

[0043]

[0044] Comparative Example 2: Recrystallization from 95% ethanol

[0045] 1 g of the commercially available minocycline hydrochloride raw material in Example 1 was dissolved in 300 ml of 95% ethanol, and sterile filtered and then cooled for recrystallization according to the method of Example 1. The treated raw material was collected by filtration and dried to obtain a finished product with a yield of 75%. The content of minocycline (C 23 H 27 N3O7) is 91%, diastereomers are 0.51%, the largest single impurity excluding diastereomers is 0.22%, and the total amount of other impurities excluding diastereomers is 0.38%.

Claims

1. A method for purifying minocycline hydrochloride, comprising the step of crystallizing minocycline hydrochloride, characterized in that The crystallization uses anhydrous ethanol as the crystallization solvent.

2. The method according to claim 1, characterized in that The solution was sterile filtered before crystallization and passed through a three-in-one sterile filter dryer after crystallization to obtain sterile minocycline hydrochloride.

3. A method for preparing a sterile minocycline hydrochloride ointment, wherein the sterile minocycline hydrochloride ointment is composed of the following components by weight: The method comprises the following steps: 0.5% to 10.0% minocycline hydrochloride, 0.5% to 10.0% magnesium chloride, 1.0% to 10.0% aqueous phase skeleton material, 1.0% to 10.0% oil phase skeleton material, 3.0% to 40.0% oily skeleton solvent, and the balance being aqueous skeleton solvent. (1) According to the method of claim 2, a sterile bulk drug of minocycline hydrochloride is prepared; (2) mixing and dissolving magnesium chloride, an aqueous skeleton solvent, and an aqueous phase skeleton material at 120° C.±10° C., and filtering the mixed solution by sterilization to obtain an aqueous phase; (3) mixing and dissolving the oil phase skeleton material and the oily skeleton solvent at 100°C ± 10°C, and filtering the mixed solution by sterilization to obtain the oil phase; (4) adding the oil phase prepared in step (3) to the aqueous phase prepared in step (2) and mixing them to prepare a sterile matrix; (5) Add the sterile raw material of minocycline hydrochloride prepared in step (1) to the sterile matrix prepared in step (4), mix and dissolve thoroughly, and then aseptically fill into a pre-filled sterile syringe.

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