Method for preparing budesonide suspension for inhalation through moist heat sterilization

Abstract

The invention discloses a method for preparing budesonide suspension for inhalation through moist heat sterilization, belongs to the technical field of medicines, and solves the problem of adverse change of budesonide properties caused by thermal sterilization in the prior art. The method comprises the following steps: adding a certain amount of water into budesonide, part of a surfactant, part of a pH regulator, part of a chelating agent and part of an osmotic pressure regulator according to a prescription dosage, uniformly mixing to obtain a concentrated solution, carrying out moist heat sterilization, and cooling to obtain the sterilized concentrated solution; uniformly mixing the auxiliary materials with the remaining prescription dosage and the water for injection, filtering and sterilizing to obtain a sterilized auxiliary material solution; and mixing the sterilized concentrated solution with the sterilized auxiliary material solution, and filling to obtain the budesonide suspension for inhalation. The method is simple and easy to industrialize, not only can ensure that the product meets the sterile requirement, but also the product impurity is controllable, the suspension particle size change amplitude is small, and the particle size of the sterilized product is suitable for lung deposition after medicine inhalation.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceuticals, and particularly relates to a method for preparing budesonide suspension for inhalation by moist heat sterilization. Background Art

[0002] Budesonide, with the molecular formula C 25 H 34 O6 and the chemical name of 16α,17α-22R,S-propylmethylenedioxy-pregna-1,4-diene-11β,21-dihydroxy-3,20-dione, has the following structural formula:

[0003]

[0004] Budesonide is a commonly used anti-inflammatory drug, belonging to the hormonal steroid anti-inflammatory drugs, and has various effects such as inhibiting respiratory inflammatory reactions and reducing airway hyperresponsiveness. Budesonide suspension for inhalation has good administration compliance for children and small systemic adverse reactions, so it is widely used in the treatment of childhood asthma in China.

[0005] As an inhalation preparation, budesonide suspension for inhalation should be a sterile preparation. In the prior art, heating sterilization is generally used to make the inhalation preparation meet the sterile requirements. However, the raw material of budesonide has poor thermal stability, and degradation products will be produced during sterilization under high temperature conditions, and the particle size of the suspension will also increase. In some sterilization processes of the prior art, it will also cause difficulty in dispersing budesonide in water, and it is easy to form a difficult-to-treat paste after dispersion under severe conditions, and the process operability is poor.

[0006] Therefore, providing a method for preparing budesonide suspension for inhalation, which can not only ensure that the budesonide suspension for inhalation meets the sterile requirements, but also ensure that the product impurities are controllable, the change range of the suspension particle size is small, and the particle size of the product after sterilization is suitable for pulmonary deposition after inhalation medication, and the product has good dispersibility, has become an urgent problem to be solved by those skilled in the art. Summary of the Invention

[0007] The purpose of the present invention is to provide a method for preparing budesonide suspension for inhalation by moist heat sterilization, and solve the problem that the properties of budesonide change unfavorably due to thermal sterilization in the prior art.

[0008] To achieve the above purpose, the technical scheme adopted by the present invention is as follows:

[0009] The method for preparing budesonide suspension for inhalation by moist heat sterilization disclosed by the present invention includes the following steps:

[0010] Step 1: Preparation and sterilization of concentrated solution;

[0011] Prepare a concentrated solution by adding the prescribed amount of budesonide, a portion of surfactant, a portion of pH regulator, a portion of chelating agent, a portion of osmotic pressure regulator, and water. Then, subject the concentrated solution to moist heat sterilization and cool it to obtain the sterilized concentrated solution.

[0012] Step 2: Preparation and sterilization of the excipient solution;

[0013] Mix the remaining prescribed amount of excipients and injection water, and filter and sterilize to obtain the sterilized excipient solution.

[0014] Step 3: Mixing and filling:

[0015] Mix the sterilized concentrated solution prepared in Step 1 and the sterilized excipient solution prepared in Step 2, and fill to obtain the budesonide suspension for inhalation.

[0016] In some embodiments of the present invention, in the concentrated solution, the chelating agent, pH regulator, and osmotic pressure regulator respectively account for 2% - 50% of their prescribed amounts.

[0017] In some embodiments of the present invention, in the concentrated solution, the chelating agent, pH regulator, and osmotic pressure regulator respectively account for 2% of their prescribed amounts.

[0018] In some embodiments of the present invention, in the concentrated solution, the concentration of budesonide is 5 mg / ml - 50 mg / ml.

[0019] In some embodiments of the present invention, in the concentrated solution, the concentration of budesonide is 25 mg / ml.

[0020] In some embodiments of the present invention, in the concentrated solution, the concentration of surfactant is 0.1 mg / ml - 0.6 mg / ml.

[0021] In some embodiments of the present invention, in the concentrated solution, the concentration of surfactant is 0.2 - 0.5 mg / ml.

[0022] In some embodiments of the present invention, in the concentrated solution, the concentration of surfactant is 0.2 mg / ml.

[0023] In some embodiments of the present invention, the dosage of budesonide is 1 mg.

[0024] In some embodiments of the present invention, the surfactant includes Tween 80;

[0025] In some embodiments of the present invention, the dosage of the surfactant is 0.4 mg;

[0026] In some embodiments of the present invention, the pH regulator includes citric acid and sodium citrate;

[0027] In some embodiments of the present invention, the pH regulator comprises 0.56 mg of citric acid and 1 mg of sodium citrate;

[0028] In some embodiments of the present invention, the chelating agent comprises disodium edetate;

[0029] In some embodiments of the present invention, the dosage of the chelating agent is 0.2 mg;

[0030] In some embodiments of the present invention, the osmotic pressure regulator comprises sodium chloride;

[0031] In some embodiments of the present invention, the dosage of the osmotic pressure regulator is 17 mg. Through a large number of experiments, the applicant surprisingly found that in addition to the concentration of budesonide in the concentrated solution for moist heat sterilization, the concentration of the surfactant also plays a key role in stabilizing the physical properties of budesonide after sterilization. The concentration of the surfactant selected in the present invention can fully exert its solubilizing effect on hydrophobic drugs, increasing the dissolution amount of budesonide during the sterilization process, and will not have an adverse effect on the particle size change of the suspension particles after sterilization; resulting in insufficient wetting function, and the suspension particles after sterilization are prone to deposit and aggregate into hard lumps, which are difficult to disperse, and the sedimentation volume ratio property of the final suspension product prepared is poor.

[0032] In some embodiments of the present invention, the moist heat sterilization conditions are sterilization at 121 °C for 12 min to 30 min.

[0033] In some embodiments of the present invention, in step 1, the prescribed amount of budesonide is mixed with part of the surfactant, part of the pH regulator, part of the chelating agent, and part of the osmotic pressure regulator, and a certain amount of water is added, and shearing is carried out at 3000 rpm to 5000 rpm for 5 to 30 min to obtain a concentrated solution.

[0034] In some embodiments of the present invention, in step 1, after the concentrated solution is sterilized by moist heat, it is cooled to below 30 °C by an ice-water bath.

[0035] In some embodiments of the present invention, in step 2, two-stage filtration and sterilization are carried out to obtain a sterilized auxiliary material solution; preferably, sterilization filtration is carried out through a two-stage 0.22 μm filter membrane.

[0036] In some embodiments of the present invention, in step 3, the sterilized auxiliary material solution is mixed with the sterilized concentrated solution, and ultrasonic, stirring, shearing or homogenizing mixing is carried out; a sterile budesonide suspension for inhalation is prepared;

[0037] Preferably, shearing is carried out at 3000 rpm to 5000 rpm for 5 to 30 min to prepare a sterile budesonide suspension for inhalation.

[0038] In the present invention, it is the prior art that the concentrated solution is obtained by shearing at 3000 rpm to 5000 rpm for 5 to 30 minutes in step 1. In step 3, ultrasonic, stirring, shearing or homogenizing mixing is the prior art.

[0039] The budesonide suspension for inhalation prepared by the above method disclosed by the present invention.

[0040] Compared with the prior art, the present invention has the following beneficial effects:

[0041] The present invention is scientifically designed, ingeniously conceived, practical in method and easy to industrialize. For the budesonide suspension for inhalation prepared by the method of the present invention, there is no need to specially control the heating and cooling processes of the sterilization temperature, which can not only ensure meeting the aseptic requirements, but also ensure that the changes in the particle size and impurity content of the suspension are controlled within a very small range before and after sterilization, facilitating the manufacturer to more accurately control the product quality. The sedimentation volume ratio, fine particle dose, delivery rate and total delivery amount of the suspension prepared by the present invention have achieved excellent effects.

[0042] By regulating the prescription of the concentrated solution for moist heat sterilization of the present invention, including the concentration of budesonide, the concentration of surfactant, and the addition and concentration of other excipients, the generation of degradation impurities of budesonide after sterilization and the excessive change of the particle size of the active pharmaceutical ingredient are significantly inhibited, and an excellent sedimentation volume ratio of the suspension is ensured. At the same time, the budesonide suspension for inhalation of the present invention has good stability. There are no obvious changes in the main drug content, particle size, impurities, fine particle dose, delivery rate and total delivery amount of the budesonide suspension for inhalation of the present invention. Detailed implementation manners

[0043] To make the objectives, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Those not specified in the embodiments are carried out according to conventional conditions or conditions recommended by the manufacturer. Those reagents or instruments not specified by the manufacturer can be obtained as conventional products through commercial purchase.

[0044] Embodiment

[0045] The single-dose prescription of the budesonide suspension for inhalation described in the embodiments of the present invention is shown in the following table:

[0046] Table 1 Prescription of budesonide suspension for inhalation

[0047] Function Ingredient Dosage Active Pharmaceutical Ingredient (API) Budesonide 1 mg Surfactant Tween 80 0.4 mg pH Regulator Citric Acid 0.56 mg PH Regulator Sodium Citrate 1 mg Chelating Agent Disodium Edetate 0.2 mg Osmotic Pressure Regulator Sodium Chloride 17 mg Solvent Water for Injection q.s. to 2 ml

[0048] Example 1, Example 2 and Comparative Example 1 of the present invention disclose a method for preparing budesonide suspension for inhalation by moist heat sterilization; the sterilization prescription composition and key process parameters are shown in Table 2. The same batch of raw and auxiliary materials was used in Examples 1 - Comparative Example 1.

[0049] Table 2 Sterilization Prescription Composition and Key Process Parameters of Example 1, Example 2, and Comparative Example 1

[0050]

[0051]

[0052] Example 1

[0053] This example discloses a method for preparing budesonide suspension for inhalation by moist heat sterilization of the present invention, which is carried out by magnifying the prescription in Table 1 by 100 times. The specific steps are as follows:

[0054] Step 1. Preparation of concentrated solution and moist heat sterilization:

[0055] Mix the prescribed amount of budesonide, 2% of the prescribed amount of Tween 80, 2% of the prescribed amount of pH regulator, 2% of the prescribed amount of chelating agent, and 2% of the prescribed amount of sodium chloride with the calculated amount of injection water, and shear at 3000 rpm for 30 min to obtain a concentrated solution; in the concentrated solution, the concentration of budesonide is 25 mg / ml, and the concentration of Tween 80 is 0.2 mg / ml.

[0056] Subject the above concentrated solution to moist heat sterilization at 121 °C for 12 min, and cool it to below 30 °C using an ice - water bath to obtain the sterilized concentrated solution.

[0057] Step 2. Preparation of auxiliary material solution and sterilization:

[0058] Mix the remaining prescribed amount of auxiliary materials and injection water, and filter and sterilize through a 0.22 - μm filter membrane in two - stage to obtain the sterilized auxiliary material solution.

[0059] Step 3. Mixing and filling:

[0060] After homogenously mixing the sterilized concentrated solution prepared in Step 1 and the sterilized auxiliary material solution prepared in Step 2, fill it under aseptic conditions.

[0061] Example 2

[0062] This example discloses a method for preparing budesonide suspension for inhalation by moist heat sterilization of the present invention, which is carried out by magnifying the prescription in Table 1 by 100 times. Compared with Example 1, the concentration of Tween 80 in the concentrated solution is different, and the other conditions are the same.

[0063] The specific steps of the method in this example are as follows:

[0064] Step 1. Preparation of concentrated solution and moist heat sterilization:

[0065] Mix the prescribed amount of budesonide, 5% of the prescribed amount of Tween 80, 2% of the prescribed amount of pH regulator, 2% of the prescribed amount of chelating agent, and 2% of the prescribed amount of sodium chloride with the calculated amount of injection water, and shear at 3000 rpm for 30 min to obtain a concentrated solution; in the concentrated solution, the concentration of budesonide is 25 mg / ml, and the concentration of Tween 80 is 0.5 mg / ml.

[0066] Sterilize the above concentrated solution by moist heat at 121 °C for 12 min, and cool it to below 30 °C by ice-water bath to obtain the sterilized concentrated solution.

[0067] Step 2. Preparation of auxiliary material solution and sterilization:

[0068] Mix the remaining prescribed amount of auxiliary materials and injection water, and filter and sterilize them through a 0.22-μm filter membrane in two stages to obtain the sterilized auxiliary material solution.

[0069] Step 3. Mixing and filling:

[0070] After homogenously mixing the sterilized concentrated solution prepared in Step 1 and the sterilized auxiliary material solution prepared in Step 2, fill them under aseptic conditions.

[0071] Comparative Example 1

[0072] This comparative example discloses a method for preparing budesonide suspension for inhalation by moist heat sterilization, which is carried out by scaling up 100 times according to the prescription in Table 1. Compared with Example 1, the concentration of Tween 80 in the concentrated solution is different, and the other conditions are the same.

[0073] The specific steps of the method in this comparative example are as follows:

[0074] Step 1. Preparation of concentrated solution and moist heat sterilization:

[0075] Mix the prescribed amount of budesonide, 10% of the prescribed amount of Tween 80, 2% of the prescribed amount of pH regulator, 2% of the prescribed amount of chelating agent, and 2% of the prescribed amount of sodium chloride with the calculated amount of injection water, and shear at 3000 rpm for 30 min to obtain a concentrated solution; in the concentrated solution, the concentration of budesonide is 25 mg / ml, and the concentration of Tween 80 is 1 mg / ml.

[0076] Sterilize the above concentrated solution by moist heat at 121 °C for 12 min, and cool it to below 30 °C by ice-water bath to obtain the sterilized concentrated solution.

[0077] Step 2. Preparation of auxiliary material solution and sterilization:

[0078] Mix the excipients and injection water of the remaining prescription amount, and filter and sterilize them through a secondary 0.22 μm filter membrane to obtain a sterilized excipient solution.

[0079] Step 3. Mixing and filling:

[0080] The sterilized concentrated solution prepared in Step 1 and the sterilized excipient solution prepared in Step 2 are homogenously mixed and then filled under aseptic conditions.

[0081] Test Example 1

[0082] Analyze the particle size of the samples prepared in Example 1, Example 2, and Comparative Example 1 by laser diffraction method; use HPLC analysis method to determine the impurity concentration of budesonide (including known and unknown ones), and the detection method is carried out according to the high performance liquid chromatography method (General Rules 0512, Volume IV of Chinese Pharmacopoeia 2020 Edition), and operate under light protection; refer to the sedimentation volume ratio detection method in General Rules 0123, Volume IV of Chinese Pharmacopoeia 2020 Edition, and determine the sedimentation volume ratio of the samples in Example 1, Example 2, and Comparative Example 1. The 3-hour sedimentation volume ratio of the reference pharmacopoeia standard budesonide suspension for inhalation should not be lower than 0.85, and the results are shown in Table 3.

[0083] Table 3 Determination results of particle size and sedimentation volume ratio of Example 1, Example 2, and Comparative Example 1

[0084]

[0085] As can be seen from Table 3, after the budesonide suspension for inhalation prepared in Example 1 and Example 2 of the present invention undergoes moist heat sterilization, the impurities in the budesonide suspension do not increase, and the increase in particle size is relatively small. In particular, the increase in particle size D90 of Example 1 and Example 2 is within 0.5 μm, and the particle size meets the requirements for pulmonary deposition after inhalation. In addition, the sedimentation volume ratios of Example 1 and Example 2 also meet the pharmacopoeia standards. From the data of Comparative Example 1, it can be seen that the particle size changes significantly, and the 3-hour sedimentation volume ratio no longer meets the standard requirements.

[0086] Test Example 2

[0087] In this test example, the budesonide suspension for inhalation was prepared by magnifying the prescription in Table 1 by 100 times, and the same batch of raw and auxiliary materials was used for each number. Compared with Example 1, the preparation method of this test example is the same in other conditions except for the different sterilization prescription composition and sterilization time listed in Table 4.

[0088] Table 4 Sterilization prescription composition and key process parameters of Test Example 2

[0089]

[0090]

[0091] The particle size of the samples prepared in the above test examples was analyzed by laser diffraction method, and the impurity concentration of budesonide was determined by HPLC analysis. The results are shown in Table 5.

[0092] Table 5 Determination results of particle size and related substances of Test Example 2

[0093]

[0094] As can be seen from Table 5, when the concentrated solution only contains budesonide and Tween 80, and the concentrated solution sterilization prescription of only raw material drug plus surfactant is adopted, the impurities in the product after heat sterilization are significantly increased compared with those in the starting raw material drug, and even increasing the sterilization time does not reduce the growth rate of impurities.

[0095] Test Example 3

[0096] In this test example, the budesonide inhalation suspension was prepared by magnifying the prescription in Table 1 by 100 times, and the same batch of raw materials and excipients were used for each number. Compared with Example 1, the preparation method of this test example is the same except for the sterilization prescription composition listed in Table 6.

[0097] The sterilization prescription composition and key process parameters of this test example are shown in Table 6.

[0098] Table 6 Sterilization prescription composition and key process parameters of Test Example 3

[0099]

[0100]

[0101] The particle size of the samples prepared in this test example was analyzed by laser diffraction method, and the impurity concentration (including known and unknown) of budesonide was determined by HPLC analysis. Referring to the sedimentation volume ratio detection method in General Rules 0123 of the Fourth Part of Chinese Pharmacopoeia 2020 Edition, the sedimentation volume ratios of the samples in Examples 1 - 3 were determined. The results are shown in the following table.

[0102] Table 7 Determination results of particle size and related substances of Test Example 3

[0103]

[0104] The results show that when the concentrated solution only contains budesonide and Tween 80, the impurity content in the finished product increases significantly after moist heat sterilization; when the content of budesonide is the same, the change range of the particle size of the suspension after sterilization increases with the increase of the concentration of Tween 80. Among them, after scaling up the prescriptions of Test Examples 3 - 2 and 3 - 3 proportionally to the industrial production scale, the increase amplitude of the particle size after sterilization exceeds 20% compared with the starting raw material drug.

[0105] Examples 3 - 5

[0106] Examples 3 to 5 are 3 batches of budesonide suspension for inhalation prepared from the same batch of raw and auxiliary materials and using the same prescription process. The batch size is 480 L, and the sterilization prescription composition and key process parameters are the same as those in Example 1.

[0107] Test Example 4

[0108] The samples of Examples 3 to 5 were placed under the conditions of (temperature 40°C, humidity 75% RH) for accelerated stability study. Particle size analysis was carried out by laser diffraction method, and the contents of budesonide and impurities were determined by HPLC analysis. The results are shown in the following table.

[0109] Table 8 Results of accelerated stability study

[0110]

[0111]

[0112] The structures of impurity D, impurity L and budesonide 17-carboxylic acid are as follows:

[0113]

[0114] It was found that there were no obvious changes in the main drug content, particle size and related substance content of the budesonide suspension for inhalation prepared by the method of the present invention, indicating that the budesonide suspension prepared by the moist heat sterilization of the present invention has a suitable particle size for inhalation, few related substances and good stability.

[0115] The above embodiments are only one of the preferred embodiments of the present invention and should not be used to limit the protection scope of the present invention. Any modification or polishing made without substantial significance in the main design concept and spirit of the present invention, as long as the technical problems solved are still the same as those of the present invention, should be included in the protection scope of the present invention.

Claims

1. A method for preparing budesonide suspension for inhalation by moist heat sterilization, characterized in that, It includes the following steps: Step 1: Preparation and sterilization of concentrated solution; Dissolve the prescribed amount of budesonide, part of the surfactant, part of the pH regulator, part of the chelating agent, and part of the osmotic pressure regulator in water to prepare a concentrated solution. Then, sterilize the concentrated solution by moist heat, cool it, and obtain the sterilized concentrated solution; Step 2: Preparation and sterilization of auxiliary material solution; Mix the remaining prescribed amount of auxiliary materials and injection water, filter and sterilize them to obtain the sterilized auxiliary material solution; Step 3: Mixing and filling: Mix the sterilized concentrated solution prepared in Step 1 and the sterilized auxiliary material solution prepared in Step 2, and fill them to obtain the budesonide suspension for inhalation.

2. The method for preparing budesonide suspension for inhalation by moist heat sterilization according to claim 1, characterized in that, The surfactant includes Tween 80; The pH regulator includes citric acid and sodium citrate; The chelating agent includes disodium edetate; The osmotic pressure regulator includes sodium chloride.

3. The method for preparing budesonide suspension for inhalation by moist heat sterilization according to claim 1 or 2, characterized in that, In the concentrated solution, the concentration of budesonide is 5 mg / ml to 50 mg / ml, preferably 25 mg / ml.

4. The method for preparing budesonide suspension for inhalation by moist heat sterilization according to claim 1 or 2, characterized in that, In the concentrated solution, the chelating agent, pH regulator, and osmotic pressure regulator respectively account for 2% to 50% of their prescribed amounts, preferably 2%.

5. The method for preparing budesonide suspension for inhalation by moist heat sterilization according to claim 1 or 2, characterized in that, In the concentrated solution, the concentration of the surfactant is 0.1 mg / ml to 0.6 mg / ml, preferably 0.2 - 0.5 mg / ml, more preferably 0.2 mg / ml.

6. The method for preparing budesonide suspension for inhalation by moist heat sterilization according to claim 1 or 2, wherein The moist heat sterilization conditions are sterilization at 121°C for 12 min to 30 min.

7. The method for preparing budesonide suspension for inhalation by moist heat sterilization according to claim 1 or 2, characterized in that, In Step 1, dissolve the prescribed amount of budesonide, part of the surfactant, part of the pH regulator, part of the chelating agent, and part of the osmotic pressure regulator in a certain amount of water, and shear it at 3000 rpm to 5000 rpm for 5 to 30 min to obtain a concentrated solution.

8. The method for preparing budesonide suspension for inhalation by moist heat sterilization according to claim 1 or 2, characterized in that, In Step 1, after moist heat sterilization of the concentrated solution, cool it to below 30°C by ice-water bath.

9. The method for preparing budesonide suspension for inhalation by moist heat sterilization according to claim 1 or 2, wherein In Step 2, perform two-stage filtration and sterilization to obtain the sterilized auxiliary material solution; preferably, sterilize and filter it through a 0.22 μm filter membrane in two stages.

10. The method for preparing budesonide suspension for inhalation by moist heat sterilization according to claim 1 or 2, characterized in that, In Step 3, mix the sterilized auxiliary material solution and the sterilized concentrated solution, and mix them by ultrasonic, stirring, shearing or homogenization; obtain the sterile budesonide suspension for inhalation; Preferably, shear it at 3000 rpm to 5000 rpm for 5 to 30 min to obtain the sterile budesonide suspension for inhalation.

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