Freeze-dried preparation of aminolevulinate and method for producing the same

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 freeze-dried preparation of aminolevulinate and a method for producing the same.

Background Art

[0002] 5-ALA or 5-aminolevulinic acid is also called 5-amino-4-oxopentanoic acid. Its molecular formula is C 5 H 9 NO 3 and its molecular weight is 131.13. Its chemical structural formula is

Chemical

[0003] Aminolevulinic acid hydrochloride is the hydrochloride salt of 5-ALA (5-ALA HCl), and its molecular weight is 167.59. Currently, aminolevulinic acid hydrochloride is the main application form of 5-ALA. Aminolevulinic acid hydrochloride has good water solubility and strong hygroscopicity, but due to the poor stability of the aminolevulinic acid hydrochloride solution, impurities are easily formed by the degradation of aminolevulinic acid hydrochloride. By manufacturing a freeze-dried preparation with aminolevulinic acid hydrochloride, the stability of the preparation can be enhanced, and transportation and storage can be facilitated. The advantages of freeze-drying are as follows. 1. By drying under low-temperature conditions, the decomposition of heat-sensitive products can be reduced. 2. By performing the process in the liquid state, the raw materials can be accurately replenished. 3. The moisture content of the final product can be controlled in the process. 4. The product subjected to lyophilization has a good physical shape.

[0004] However, since aminolevulinic acid hydrochloride belongs to hydrochloride, the concentration of the prepared chemical solution is very high, and since the preparation does not contain auxiliary materials, the crystal nuclei formed in the pre-freezing process may become densified. Also, since the eutectic point and collapse temperature of the drug solution are low, it does not contribute to the sublimation of moisture, and there is a risk that bulges, local re-dissolution, and indentations may easily occur in the sample subjected to lyophilization. Thereby, it affects the appearance and quality of the product, and it becomes very difficult to perform lyophilization.

[0005] Therefore, it is necessary to provide the present invention.

Summary of the Invention

Problems to be Solved by the Invention

[0006] In order to improve the lyophilization process of aminolevulinic acid hydrochloride, solve the problem of poor appearance and quality of the lyophilized preparation, and manufacture a product having a predetermined appearance and quality, the present invention provides the following technical matters.

Means for Solving the Problems

[0007] In a first exemplification of the present invention, a method for manufacturing a lyophilized preparation of aminolevulinic acid is provided. The method for manufacturing a lyophilized preparation of aminolevulinic acid includes a step S1 of preparing an aminolevulinic acid solution, a step S2 of filling, and a step S3 of lyophilizing. Step S1 of preparing the aminolevulinate solution specifically includes injecting injection water corresponding to 70 - 90% of the prescribed amount, preferably injection water corresponding to 80% of the prescribed amount, into a container, starting stirring, and then adding aminolevulinate corresponding to the prescribed amount; injecting the total amount of injection water, starting stirring, stopping the stirring when the aminolevulinate is completely dissolved, and filtering and sterilizing with a filtration device of 0.22 μm or less or sterilizing with a 22 μm filtration sterilization device; and making the final concentration of the aminolevulinate solution 100 - 200 mg / ml, preferably 150 mg / ml. Step S2 of filling specifically includes filling the liquid obtained in Step S1 into 50 ml vials according to the standard of 7.5 - 15 ml / vial, preferably 10 ml / vial, and then performing stoppering (here, partial stoppering). Step S3 of freeze - drying is A pre - freezing step S3.1 of lowering the temperature to - 45°C or below - 45°C at a rate of 5.0 - 15.0°C / h and maintaining that state for 10 - 20 h when the temperature drops to the predetermined temperature; A vacuum - forming step S3.2 of forming a vacuum by setting the pressure to ≤50 Pa; A first sublimation step S3.3 of raising the temperature to - 15°C or below - 15°C at a rate of 0.5 - 5.0°C / h and maintaining that state for 100 - 150 h when the temperature rises to the predetermined temperature; A second sublimation step S3.4 of raising the temperature to 35°C or below 35°C at a rate of 1.0 - 10.0°C / h and maintaining that state for 6 - 10 h when the temperature rises to the predetermined temperature; After the pressure - increasing test is completed, introducing nitrogen, performing stoppering in a vacuum state by setting the pressure to 0.1 - 1.0 BarA, and after the stoppering is completed, lifting the plate layer and inhaling external air to restore to normal pressure to obtain a freeze - dried product, including a stoppering step S3.5.

[0008] Preferably, in the filling step, the liquid flowing down from the Class A layer is filled with a filling machine.

[0009] Preferably, capping and sealing of the lyophilized product are carried out.

[0010] Preferably, the lyophilized preparation is a lyophilized powder or a lyophilized sheet.

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

[0012] In a second exemplification of the present invention, there is provided a lyophilized preparation of aminolevulinate produced by the method for producing a lyophilized preparation of aminolevulinate according to the first exemplification of the present invention.

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

[0014] The related substances include known impurities and unknown impurities. The content of the known impurities in the lyophilized preparation of 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

Chemical formula

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

[0016] Preferably, the content of the active ingredient in the lyophilized preparation is 95 - 105% of the labeled amount, and the active ingredient is aminolevulinate.

[0017] Preferably, the pH value of the lyophilized preparation is 2.0 - 3.0.

[0018] Preferably, the re-dissolution time of the lyophilized 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.

Advantages of the Invention

[0021] The present invention can achieve the following advantages of the invention. As a result of measuring the influence of various concentrations of drug solutions 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 aminolevulinate drugs as evaluating indicators, and explores the processes related to the temperature, rate, time of the pre-freezing and sublimation processes, and multiple freezings. By optimizing the enlarged lyophilization process, 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.

Embodiments 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 aminolevulinic acid hydrochloride 1. Freeze-drying process (1) Preparation of Aminolevulinic Acid Hydrochloride Solution Inject injection water corresponding to 80% of the prescription quantity into the liquid preparation tank. After starting stirring, add the prescription quantity of aminolevulinic acid hydrochloride (3.3 Kg). Inject a total of 33 L of injection water, start stirring, and stop stirring when the aminolevulinic acid hydrochloride is completely dissolved. After filtering and sterilizing with a 0.22 μm filter, wait for filling.

[0025] (2) Filling Fill the liquid flowing down from the Class A layer into 50 ml vials with a filling machine. The standard filling volume is 15 ml / bottle. After stoppering (here, partial stoppering is performed), put it in a box and perform lyophilization.

[0026] (3) Lyophilization Pre-freezing: Lower the temperature to -45 °C or below at a rate of 5.0 °C / h, and hold the state for 10 h when the temperature drops to the predetermined temperature.

[0027] Start the vacuum pump to evacuate and form a vacuum. When the vacuum is ≤ 50 Pa, start sublimation.

[0028] First sublimation process: Raise the temperature to -15 °C or below at a rate of 0.5 °C / h, and hold the state for 100 h when the temperature rises to the predetermined temperature.

[0029] Second sublimation process: Raise the temperature to 35 °C or below at a rate of 1.0 °C / h, and hold the state for 6 h when the temperature rises to the predetermined temperature.

[0030] Stopping, transferring: After the pressure boosting test is completed, nitrogen is introduced and the pressure is set to 0.1 BarA to perform stopping in a vacuum state. After stopping is completed, the plate layer is lifted to inhale external air to restore to normal pressure and transfer the product.

[0031] (4) Capping Perform capping and sealing of the lyophilized product.

[0032] In the appearance of the samples manufactured in this example, there are no bulges, dents, redissolve, etc.

[0033] Example 2 Manufacturing process and quality control of the lyophilized powder of aminolevulinic acid salt 1. Lyophilization process (1) Preparation of aminolevulinic acid salt solution Inject the injection water corresponding to 80% of the prescription amount into the liquid preparation tank. After starting stirring, add the aminolevulinic acid salt (3.3 Kg) of the prescription amount. Inject the injection water with a total volume of (16.5 L), start stirring, and stop stirring when the aminolevulinic acid salt is completely dissolved. After filtering and sterilizing with a 0.22 μm filter, wait for filling.

[0034] (2) Filling Fill the liquid flowing down from the Class A area into 50 ml vials with a filling machine. The standard filling volume is 7.5 ml / bottle. After performing stopping, here partial stopping, put it in a box and perform lyophilization.

[0035] (3) Lyophilization Pre-freezing: Lower the temperature to -45 °C or below at a rate of 5.0 °C / h, and hold that state for 20 h when the temperature drops to the predetermined temperature.

[0036] Start the vacuum pump to evacuate to form a vacuum, and start sublimation when the vacuum is ≤ 50 Pa.

[0037] The first sublimation process: The temperature is raised to -15°C or below at a rate of 5.0°C / h. When the temperature reaches the predetermined temperature, the state is maintained for 150 h.

[0038] The second sublimation process: The temperature is raised to 35°C or below at a rate of 10.0°C / h. When the temperature reaches the predetermined temperature, the state is maintained for 10 h.

[0039] Stopping and transferring: After the pressure boosting test is completed, nitrogen is introduced and the pressure is set to 1.0 BarA to perform stopping in a vacuum state. After stopping is completed, the plate layer is lifted to inhale external air to restore to normal pressure, and the product is transferred.

[0040] (4) Capping Capping and sealing of the lyophilized product are carried out.

[0041] In the appearance of the sample manufactured in this example, there are no bulges, depressions, redissolutions, etc.

[0042] Example 3 Measurement of the lyophilized powder of aminolevulinate manufactured in Example 1 and Example 2 The results of measuring the lyophilized powder of each aminolevulinate can be referred to Table 1 below. As shown in Table 1, each index of the lyophilized powder of aminolevulinate meets the predetermined requirements.

[0043] Table 1: Each index of the lyophilized powder of aminolevulinate

Table 1

[0044] Example 4 Manufacturing process and quality control of the lyophilized powder of aminolevulinate 1. Lyophilization process (1) Preparation of aminolevulinate solution Inject the injection water corresponding to 80% of the prescription amount into the liquid preparation tank. After starting the stirring, add the aminolevulinate (3.3 Kg) of the prescription amount. Inject the total amount (22 L) of injection water, start the stirring, and stop the stirring when the aminolevulinate is completely dissolved. After filtering and sterilizing with a 0.22 μm filter, wait for filling.

[0045] (2) Filling Fill the liquid flowing down from the Class A area into 50 ml vials with a filling machine. The standard filling volume is 10 ml / bottle. After stoppering, here partial stoppering was carried out, put it in a box and perform lyophilization.

[0046] (3) Lyophilization Pre-freezing: Lower the temperature to -40 °C at a rate of 5.0 °C / h, and maintain that state for 20 h when the temperature drops to the predetermined temperature.

[0047] Start the vacuum pump to evacuate to form a vacuum. When the vacuum reaches 100 Pa, sublimation starts.

[0048] First sublimation process: Raise the temperature to -15 °C at a rate of 5.0 °C / h, and maintain that state for 70 h when the temperature rises to the predetermined temperature.

[0049] Second sublimation process: Raise the temperature to 35 °C at a rate of 10.0 °C / h, and maintain that state for 4 h when the temperature rises to the predetermined temperature.

[0050] Stoppering, transferring: After the pressure increase test is completed, introduce nitrogen and set the pressure to 1.0 BarA to carry out stoppering in the vacuum state. After stoppering is completed, lift the plate layer and inhale the external air to restore to normal pressure and transfer the product.

[0051] (4) Capping Carry out capping and sealing of the lyophilized product.

[0052] In the sample produced in this example, there are no bulges, indentations, redissolutions, etc. on the appearance.

[0053] The applicant has searched the prior art but has not found a patent related to the freeze-drying technology of the present invention. According to the matters of the present invention, an aseptic freeze-dried preparation can be produced, preventing bulges, redissolutions and indentations from occurring on the drug during freeze-drying, and meeting the requirements regarding the performance shape, appearance and quality of the product after freeze-drying, and improving the stability of the product.

Claims

1. A method for manufacturing a freeze-dried preparation of aminolevulinate, comprising step S1 of preparing an aminolevulinate solution, step S2 of filling, and step S3 of freeze-drying, Step S1 of preparing an aminolevulinate solution specifically includes injecting injection water corresponding to 70-90% of the prescription amount into a container, starting stirring, and then adding the aminolevulinate of the prescription amount, injecting all the injection water, starting stirring, stopping the stirring when the aminolevulinate is completely dissolved, sterilizing and filtering with a filtering device of 0.22 μm or less, and making the final concentration of the aminolevulinate solution 100-200 mg / ml. Step S2 of filling specifically includes filling the liquid obtained in step S1 into a 50 ml vial according to the standard of 7.5-15 ml / bottle, and then performing partial stoppering. Step S3 of freeze-drying is A pre-freezing step S3.1 of lowering the temperature of the product obtained in step S2 to -45°C or lower at a rate of 5.0-15.0°C / h, and maintaining that state for 10-20 h when the temperature drops to a predetermined temperature; A vacuumizing step S3.2 of putting the product obtained in the pre-freezing step S3.1 into a vacuum state and making the pressure in the vacuum state 50 Pa or less; A first sublimation step S3.3 of raising the temperature of the product obtained in the vacuumizing step S3.2 to -15°C or lower at a rate of 0.5-5.0°C / h, and maintaining that state for 100-150 h when the temperature rises to a predetermined temperature; A second sublimation step S3.4 of raising the temperature of the product obtained in the first sublimation step S3.3 to 35°C or lower at a rate of 1.0-10.0°C / h, and maintaining that state for 6-10 h when the temperature rises to a predetermined temperature; After the pressure increase test is completed, nitrogen is introduced, and stoppering is performed in the vacuum state by setting the pressure to 0.1-1.0 BarA. After the stoppering is completed, the plate layer is lifted and external air is inhaled to restore to normal pressure, and a stoppering step S3.5 of obtaining a freeze-dried product is included. A method for manufacturing a freeze-dried preparation of aminolevulinate, characterized in that.

2. The method for manufacturing a freeze-dried preparation of aminolevulinate according to claim 1, characterized in that step S1 further includes adding auxiliary materials that can be used in the pharmaceutical field.

3. A method for manufacturing a lyophilized preparation of aminolevulinic acid salt according to claim 1 or 2, characterized by manufacturing a lyophilized preparation of aminolevulinic acid salt.

4. The water content of the lyophilized preparation of aminolevulinic acid salt is 1.0% or less, and the content of related substances is 1.0% or less, and both of the above contents are mass contents (Mass Content). The lyophilized preparation of aminolevulinic acid salt according to claim 3, characterized in that.

5. The related substances include known impurities and unknown impurities. The content of the known impurities in the lyophilized preparation of aminolevulinic acid salt is 0.1% or less, and the known impurities are 3,3'-(pyrazine-2,5-diyl)dipropionic acid and isopropylidene acetone. The lyophilized preparation of aminolevulinic acid salt according to claim 3, characterized in that.

6. The content of the maximum component in the unknown impurities in the lyophilized preparation of aminolevulinic acid salt is 0.2% or less. The lyophilized preparation of aminolevulinic acid salt according to claim 5, characterized in that.

7. The content of the active ingredient in the lyophilized preparation is 95 to 105% of the labeled amount. The lyophilized preparation of aminolevulinic acid salt according to claim 3, characterized in that.

8. The pH value of the lyophilized preparation is 2.0 to 3.

0. The lyophilized preparation of aminolevulinic acid salt according to claim 3, characterized in that.

9. The redissolution time of the lyophilized preparation is 2 minutes or less. The lyophilized preparation of aminolevulinic acid salt according to claim 3, characterized in that.

10. The lyophilized preparation is a lyophilized powder or a lyophilized sheet. The lyophilized preparation of aminolevulinic acid salt according to claim 3, characterized in that.

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