Method for manufacturing lyophilized aminolevulinic acid salts

Abstract

The present invention provides a freeze-dried preparation of aminolevulinate and a method for producing the same, which belong to the technical field of pharmaceutical preparations. The present invention uses the performance shape, moisture, related substances and content of the freeze-dried preparation of aminolevulinate as evaluation indicators, and explores the temperature, rate, time of the pre-freezing and sublimation processes, and the processes related to multiple freezings. By optimizing the freeze-drying process after scale-up, the performance shape, appearance and quality of the product after freeze-drying can all meet the predetermined requirements. By understanding the influence of different concentrations of the drug solution of aminolevulinate and different volumes on freeze-drying, the present invention can prevent the occurrence of bulges on the manufactured drug, improve the quality of the product, and expand the industrial applicability.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and specifically relates to a method for manufacturing freeze-dried aminolevulinate. Agent It relates to a manufacturing method.

Background Art

[0002] 5-ALA or 5-aminolevulinic acid is also called 5-amino-4-oxopentanoic acid. Its molecular formula is C5H9NO3, and its molecular weight is 131.13. Its chemical structural formula is

Chem.

[0003] Aminolevulinic acid hydrochloride is the hydrochloride salt of 5-ALA (5-ALA HCl), with a molecular weight of 167.59. Currently, aminolevulinic acid hydrochloride is the main application form of 5-ALA. Although aminolevulinic acid hydrochloride has good water solubility and strong hygroscopicity, the stability of aminolevulinic acid hydrochloride solution is poor, and impurities are easily formed due to the degradation of aminolevulinic acid hydrochloride. By producing lyophilized formulations with aminolevulinic acid hydrochloride, the stability of the formulation can be increased, and transportation and storage can be facilitated. The advantages of lyophilization are as follows: 1. Drying under low-temperature conditions can reduce the decomposition of heat-sensitive products. 2. By carrying out the process in a liquid state, raw materials can be supplied accurately. 3. The moisture content of the final product can be controlled during the process. 4. Products that have undergone freeze-drying have good physical shape.

[0004] However, because aminolevulinic acid hydrochloride is a hydrochloride, the concentration of the prepared drug solution becomes very high, and since the formulation does not contain auxiliary materials, the crystal nuclei formed during the pre-freezing process may become dense. In addition, because the eutectic point and collapse temperature of the drug solution are low, it does not contribute to the sublimation of water, and lyophilization may easily occur in the freeze-dried sample. This affects the appearance and quality of the product and makes freeze-drying extremely difficult.

[0005] Therefore, it is necessary to provide the present invention. [Overview of the project] [Problems that the invention aims to solve]

[0006] To improve the freeze-drying process of aminolevulinic acid hydrochloride, solve the problem of poor appearance and quality of freeze-dried formulations, and produce products with a predetermined appearance and quality, the present invention provides the following technical matters. [Means for solving the problem]

[0007] In a first example of the present invention, a method for producing a lyophilized aminolevulinate preparation is provided. The method for producing a lyophilized aminolevulinate preparation comprises the steps of: S1 preparing an aminolevulinate solution; S2 filling the solution; and S3 lyophilizing the solution. Step S1 for preparing the aminolevulinate solution specifically includes: injecting water corresponding to 70-90% of the prescribed amount, preferably 80% of the prescribed amount, into a container, starting stirring, then adding the prescribed amount of aminolevulinate; injecting the entire amount of water, starting stirring, stopping stirring once the aminolevulinate is completely dissolved, filtering and sterilizing using a filter with a 0.22 μm or smaller filtration device, or sterilizing using a 22 μm filter sterilizer; and adjusting the final concentration of the aminolevulinate solution to 100-200 mg / ml, preferably 150 mg / ml. Step S2, which involves filling, specifically includes filling a 50 ml vial with the liquid obtained in step S1 at a standard rate of 7.5 to 15 ml / bottle, preferably 10 ml / bottle, and then performing stoppering (in this case, partial stoppering). Step S3, which involves freeze-drying, A pre-freezing step S3.1 is performed in which the temperature is lowered to -45°C or below at a rate of 5.0~15.0°C / h, and once the temperature drops to a predetermined level, it is maintained at that state for 10~20 hours. Vacuuming process S3.2, which creates a vacuum by reducing the pressure to ≤50 Pa, The first sublimation step S3.3 involves raising the temperature at a rate of 0.5~5.0℃ / h to -15℃ or below, and once the temperature reaches a predetermined level, maintaining that state for 100~150h. A second sublimation step S3.4 is performed in which the temperature is raised to 35°C or below 35°C at a rate of 1.0~10.0°C / h, and once the temperature reaches the predetermined temperature, it is maintained at that state for 6~10 hours. The process includes a stopping step S3.5 in which, upon completion of the pressurization test, nitrogen is introduced and the pressure is set to 0.1 to 1.0 BarA to perform stoppering under vacuum conditions, and upon completion of stoppering, the plate layer is lifted and external air is drawn in to restore the pressure to normal, thereby obtaining the freeze-dried product.

[0008] Preferably, in the filling process, the liquid flowing down from the Grade A layer is filled using a filling machine.

[0009] Preferably, the freeze-dried product is capped and sealed.

[0010] Preferably, the freeze-dried formulation is a freeze-dried powder or a freeze-dried sheet.

[0011] Preferably, the lyophilized preparation includes a sterile lyophilized preparation.

[0012] In a second example of the present invention, a lyophilized aminolevulinate preparation is provided, which is produced by the method for producing a lyophilized aminolevulinate preparation of the first example of the present invention.

[0013] Preferably, the moisture content of the lyophilized aminolevulinate preparation is ≤1.0%, and the related substance content is ≤1.0%.

[0014] The aforementioned related substances contain known and unknown impurities. The content of the known impurities in the lyophilized preparation of the aminolevulinate does not exceed 0.1%, and the known impurities are impurity A and isopropylidene acetone. Impurity A is 3,3'-(pyrazine-2,5-diyl)dipropionic acid, and its structure is [ka] That is the case.

[0015] Preferably, the content of the component with the highest content among the unknown impurities in the lyophilized aminolevulinate formulation does not exceed 0.2%.

[0016] Preferably, the content of the active ingredient in the freeze-dried formulation is 95-105% of the indicated amount, and the active ingredient is an aminolevulinic acid salt.

[0017] Preferably, the pH value of the freeze-dried formulation is 2.0 to 3.0.

[0018] Preferably, the redissolution time for the freeze-dried preparation is ≤2 minutes.

[0019] Preferably, the lyophilized preparation is a lyophilized powder or a lyophilized sheet.

[0020] Preferably, the lyophilized preparation further contains auxiliary materials that can be used in the pharmaceutical field.

Effects of the Invention

[0021] The present invention can achieve the following effects of the invention. As a result of measuring the influence of various concentrations of the drug solution and various filling amounts on the lyophilized preparation of aminolevulinate, it was found that the filling amount is preferably 7.5 to 15 ml and the concentration is preferably 100 to 200 mg / ml.

[0022] The present invention uses the performance shape, moisture, and related substances of the aminolevulinate drug as evaluation indicators (evaluating indicator), and explores the processes related to the temperature, speed, time of the pre-freezing and sublimation processes, and multiple freezings. By optimizing the lyophilization process after expansion, the lyophilization process of the present invention can prevent the occurrence of bulges, redissolution, and indentations on the drug during the lyophilization process, and can meet the requirements regarding the performance shape, appearance, and quality of the product after lyophilization.

Modes for Carrying Out the Invention

[0023] Hereinafter, in order to explain the technical matters of the present invention in more detail, the technical matters of the present invention will be explained in more detail by specific examples of the present invention.

[0024] Example 1 Manufacturing process and quality control of freeze-dried powder of aminolevulinate (Aminolevulinic acid hydrochloride) 1. Freeze-drying process (1) Preparation of aminolevulinic acid hydrochloride solution Inject 80% of the prescription quantity of injection water into the liquid preparation tank and start stirring. Then add the prescribed amount of aminolevulinate (3.3 kg). Inject the remaining 33 L of injection water and start stirring. Stop stirring when the aminolevulinate is completely dissolved. After filtering and sterilizing with a 0.22 μm filter, await filling.

[0025] (2) Filling The liquid flowing down from the Grade A layer is filled into 50 ml vials using a filling machine. The standard filling volume is 15 ml / vial. After stoppering (sealing), in this case partial stoppering, the vials are placed in boxes and freeze-dried.

[0026] (3) Freeze drying Pre-freezing: The temperature is lowered at a rate of 5.0°C / h to -45°C or below, and once the temperature reaches the specified level, it is maintained at that level for 10 hours.

[0027] A vacuum is created by activating a vacuum pump to evacuate the material, and sublimation begins when the vacuum reaches ≤50 Pa.

[0028] First sublimation step: The temperature is raised at a rate of 0.5°C / h to -15°C or below, and once the temperature reaches the predetermined temperature, it is maintained at that state for 100 hours.

[0029] Second sublimation step: The temperature is raised to 35°C or below 35°C at a rate of 1.0°C / h, and once the temperature reaches the predetermined level, it is maintained at that level for 6 hours.

[0030] Stoppering and Transferring: Once the pressurization test is complete, nitrogen is introduced and the pressure is set to 0.1 BarA to perform stoppering under vacuum. After stoppering is complete, the plate layer is lifted and external air is drawn in to restore normal pressure, and the product is transferred.

[0031] (4) Capping Capping and sealing of freeze-dried products.

[0032] The sample produced in this embodiment showed no signs of bulging, indentation, redissolvement, or other abnormalities in its appearance.

[0033] Example 2 Manufacturing process and quality control of freeze-dried aminolevulinic acid powder 1. Freeze-drying process (1) Preparation of aminolevulinate solution Inject 80% of the prescribed amount of injection water into the liquid preparation tank and start stirring. Then add the prescribed amount of aminolevulinate (3.3 kg). Inject the remaining 16.5 L of injection water and start stirring. Stop stirring when the aminolevulinate is completely dissolved. After filtering and sterilizing with a 0.22 μm filter, await filling.

[0034] (2) Filling The liquid flowing down from the Grade A layer is filled into 50 ml vials using a filling machine. The standard filling volume is 7.5 ml / vial. After stoppering, in this case partial stoppering, the vials are placed in boxes and freeze-dried.

[0035] (3) Freeze drying Pre-freezing: The temperature is lowered at a rate of 5.0°C / h to -45°C or below, and once the temperature reaches the specified level, it is maintained at that level for 20 hours.

[0036] A vacuum is created by activating a vacuum pump to evacuate the material, and sublimation begins when the vacuum reaches ≤50 Pa.

[0037] First sublimation step: The temperature is raised at a rate of 5.0°C / h to -15°C or below, and once the temperature reaches the predetermined temperature, it is maintained at that state for 150 hours.

[0038] Second sublimation step: The temperature is raised to 35°C or below 35°C at a rate of 10.0°C / h, and once the temperature reaches the predetermined level, it is maintained at that level for 10 hours.

[0039] Stoppering and Transfer: Once the pressurization test is complete, nitrogen is introduced and the pressure is set to 1.0 BarA to perform stoppering under vacuum. After stoppering is complete, the plate layer is lifted and external air is drawn in to restore normal pressure, and the product is transferred.

[0040] (4) Capping Cap and seal the freeze-dried products.

[0041] The sample produced in this embodiment showed no signs of bulging, indentation, redissolution, or other abnormalities in its appearance.

[0042] Example 3 Measurement of the lyophilized aminolevulinic acid salts produced in Example 1 and Example 2 The results of measuring the freeze-dried powders of each aminolevulinic acid salt can be found in Table 1 below. As shown in Table 1, all of the indicators for the freeze-dried powders of aminolevulinic acid salts meet the prescribed requirements.

[0043] Table 1: Indices of lyophilized aminolevulinic acid salts [Table 1]

[0044] Example 4 Manufacturing process and quality control of freeze-dried aminolevulinic acid powder 1. Freeze-drying process (1) Preparation of aminolevulinate solution Inject 80% of the prescribed amount of injection water into the liquid preparation tank and start stirring. Then add the prescribed amount of aminolevulinate (3.3 kg). Inject the remaining 22 L of injection water and start stirring. Stop stirring when the aminolevulinate is completely dissolved. After filtering and sterilizing with a 0.22 μm filter, await filling.

[0045] (2) Filling The liquid flowing down from the Grade A layer is filled into 50 ml vials using a filling machine. The standard filling volume is 10 ml / vial. After stoppering, in this case partial stoppering, the vials are placed in boxes and freeze-dried.

[0046] (3) Freeze drying Pre-freezing: The temperature is lowered to -40°C at a rate of 5.0°C / h, and once the temperature reaches the specified level, it is maintained at that level for 20 hours.

[0047] A vacuum is created by activating a vacuum pump to evacuate the material, and sublimation begins when the vacuum reaches 100 Pa.

[0048] First sublimation step: The temperature is raised to -15°C at a rate of 5.0°C / h, and once the temperature reaches the predetermined level, it is maintained at that level for 70 hours.

[0049] Second sublimation process: The temperature is raised to 35°C at a rate of 10.0°C / h, and once the temperature reaches the predetermined level, it is maintained at that level for 4 hours.

[0050] Stoppering and Transfer: Once the pressurization test is complete, nitrogen is introduced and the pressure is set to 1.0 BarA to perform stoppering under vacuum. After stoppering is complete, the plate layer is lifted and external air is drawn in to restore normal pressure, and the product is transferred.

[0051] (4) Capping Cap and seal the freeze-dried products.

[0052] The sample produced in this embodiment showed no signs of bulging, indentation, redissolution, or other abnormalities in its appearance.

[0053] The applicant has searched for prior art but has not found any patents relating to the freeze-drying technology of the present invention. The present invention makes it possible to manufacture aseptic freeze-dried preparations, prevent bulging, redissolution, and depressions from occurring on the drug surface during freeze-drying, and meet requirements regarding the performance, shape, appearance, and quality of the freeze-dried product, thereby improving product stability.

Claims

1. A method for producing a lyophilized preparation of an aminolevulinate, comprising the steps of: S1 preparing an aminolevulinate solution; S2 filling the preparation; and S3 lyophilizing the preparation. Step S1 for preparing the aminolevulinate solution specifically includes: injecting water corresponding to 70-90% of the prescribed amount into a container, starting stirring, then adding the prescribed amount of aminolevulinate; injecting the entire amount of water, starting stirring, stopping stirring once the aminolevulinate is completely dissolved, sterilizing and filtering using a filtration device of 0.22 μm or less; and adjusting the final concentration of the aminolevulinate solution to 100-200 mg / ml. Step S2, which involves filling the liquid obtained in step S1 into a 50 ml vial at a standard rate of 7.5 to 15 ml / bottle, and then performing partial stoppering. Step S3, which involves freeze-drying, Step S2 involves a pre-freezing step S3.1 in which the temperature of the product obtained is lowered to -45°C or below at a rate of 5.0 to 15.0°C / h, and once the temperature drops to a predetermined level, that state is maintained for 10 to 20 hours. In the pre-freezing step S3.1, the product obtained is brought into a vacuum state, and the vacuum pressure is set to 50 Pa or less in the vacuum step S3.

2. In the first sublimation step S3.3, the temperature of the product obtained in the vacuum step S3.2 is raised to -15°C or below at a rate of 0.5 to 5.0°C / h, and once the temperature has risen to a predetermined temperature, that state is maintained for 100 to 150 hours. In the second sublimation step S3.4, the temperature of the product obtained in the first sublimation step S3.3 is raised to 35°C or below at a rate of 1.0 to 10.0°C / h, and once the temperature reaches a predetermined temperature, it is maintained at that state for 6 to 10 hours. A method for producing a lyophilized aminolevulinate preparation, comprising: a stopping step S3.5, in which nitrogen is introduced upon completion of the pressurization test, the pressure is set to 0.1 to 1.0 BarA to perform stoppering in a vacuum state, and upon completion of stoppering, the plate layer is lifted and external air is drawn in to restore the pressure to normal, thereby obtaining a lyophilized product.

2. The method for producing a lyophilized aminolevulinate preparation according to claim 1, characterized in that step S1 further comprises adding an auxiliary material that can be used in the pharmaceutical field.

3. A method for producing a lyophilized preparation of an aminolevulinate according to claim 1 or 2, characterized in that the moisture content of the lyophilized preparation of the aminolevulinate is 1.0% or less, the related substance content is 1.0% or less, and all of the above contents are mass contents.

4. The method for producing a lyophilized preparation of an aminolevulinate salt according to claim 3, characterized in that the related substance includes known and unknown impurities, the content of the known impurities in the lyophilized preparation of the aminolevulinate salt is 0.1% or less, and the known impurities are 3,3'-(pyrazine-2,5-diyl)dipropionic acid and isopropylideneacetone.

5. The method for producing a lyophilized aminolevulinate preparation according to claim 4, characterized in that the content of the largest component among the unknown impurities in the lyophilized aminolevulinate preparation is 0.2% or less.

6. A method for producing a lyophilized aminolevulinate preparation according to claim 1 or 2, characterized in that the content of the active ingredient in the lyophilized preparation is 95 to 105% of the indicated amount.

7. A method for producing a lyophilized aminolevulinate preparation according to claim 1 or 2, characterized in that the pH value of the lyophilized preparation is 2.0 to 3.

0.

8. The method for producing a lyophilized aminolevulinate preparation according to claim 1 or 2, characterized in that the lyophilized preparation is a lyophilized powder or a lyophilized sheet.

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