WO2024152464A1

WO2024152464A1 - Cyclosporine soft capsule and preparation method therefor

Info

Publication number: WO2024152464A1
Application number: PCT/CN2023/089402
Authority: WO
Inventors: 周平凡; 程林; 张永祥; 李彦朴; 张娴; 张慧明; 赵红星; 梁冉; 谷灵玉; 苗晓革; 董珊红; 李军良; 刘崧
Original assignee: 华北制药股份有限公司
Priority date: 2023-01-19
Filing date: 2023-04-20
Publication date: 2024-07-25
Also published as: CN118356481A

Abstract

Provided are a cyclosporine soft capsule and a preparation method therefor. The cyclosporine soft capsule comprises a capsule shell and a capsule content; the capsule content comprises cyclosporine, absolute ethyl alcohol, polyoxyethylene castor oil, corn oil/olive oil, and oleic acid polyethylene glycol glyceride; the capsule shell comprises gelatin for capsules, titanium dioxide, cyclodextrin, and absolute ethyl alcohol.

Description

Cyclosporine soft capsule and preparation method thereof

Technical Field

The invention relates to the technical field of medicine, in particular to a cyclosporine soft capsule and a preparation method thereof.

Background technique

Organ transplantation is the most ideal means to treat end-stage organ failure. How to improve the long-term survival rate of transplants and recipients is the main topic of transplantation research. The application of immunosuppressants plays an important role in the survival rate of organ transplant recipients, especially in the maintenance period of organ transplantation, which requires long-term use of immunosuppressants.

Cyclosporine, also known as "cyclosporine A", "cyclosporine" or "cyclosporin", is a metabolite of fungi. It is a high-level peptide compound composed of 11 amino acids, with a large relative molecular mass, strong lipid solubility and extremely poor hydrophilicity. Cyclosporine is almost insoluble in water. In 1976, Borel first published a report that cyclosporine A has a strong immunosuppressive effect. In 1978, Calne of Cambridge University began to apply it to kidney transplantation and liver transplantation after animal experiments, with significant therapeutic effects. Cyclosporine soft capsules were first launched in Switzerland in 1983. In July 1995, a new type of microemulsified cyclosporine soft capsule was launched under the trade name of New San Diming, which is now widely used around the world. Microemulsion has very low surface tension and forms small particles of 0.05-0.10 microns in water, which makes cyclosporine have high absorption and permeability properties, and both solubility and dissolution rate are increased. A large number of pharmacological experiments and clinical practices have proven that cyclosporine A is one of the first choice drugs for preventing and treating rejection reactions after allogeneic organ transplantation and some autoimmune diseases (hematological diseases, nephrotic syndrome, skin diseases, etc.).

However, cyclosporine belongs to BCS Class II drugs in the biopharmaceutical classification, that is, low solubility and high permeability drugs. For this type of drug, the dissolution process of the drug may be the rate-limiting step of drug absorption. It has the following disadvantages in clinical application:

1) The raw material is a fermented polypeptide, with as many as 19 impurities reported, most of which are cyclosporine homologues. The purity and stability of the raw material are crucial to the preparation.

2) There are many types of auxiliary materials and the process is complicated. The finished products are prone to cracks, bubbles and irregular shapes, the qualified rate of finished products is low, and the production cost is high.

3) It has significant hydrophobicity and is almost insoluble in water. Therefore, it is rarely absorbed by the human body after oral administration. The bioavailability is very low (30% or less), and there are reports that the absorption varies greatly between human bodies. When administered for a long time, it will show serious side effects such as nephrotoxicity and hepatotoxicity.

4) Cyclosporine is a drug with a narrow therapeutic index. Studies have found that when the blood concentration of cyclosporine fluctuates between 150 and 250 g·mL ^-1 , the risk of adverse reactions increases. In addition, patients whose minimum blood concentration of cyclosporine is lower than 200 ng·mL ^-1 in the third week after surgery are more likely to experience serious adverse reactions.

5) There are more middle-aged and elderly patients, most of whom have underlying diseases and have a higher incidence of adverse reactions.

Therefore, improving the purity and stability of raw materials, improving the solubility, purity, yield rate and quality stability of cyclosporine soft capsules is of great significance to standardizing clinical medication, improving the safety and effectiveness of clinical medication, and thus improving patient compliance. At the same time, the improvement of the qualified rate of finished products also increases the yield, reduces the production cost, and is conducive to the commercial production of this product.

Summary of the invention

The purpose of the present invention is to provide a cyclosporine soft capsule and a preparation method thereof, so as to overcome the shortcomings of the existing products such as low purity, low solubility and poor stability, so that the quality and stability of the cyclosporine soft capsule are improved.

The invention is realized in this way: a cyclosporine soft capsule comprises a rubber skin and capsule contents; the capsule contents comprise cyclosporine, anhydrous ethanol, polyoxyethylene castor oil, corn oil/olive oil, and oleic acid macrogol glyceride; the mass ratio thereof is 25:30-40:100-103:80-90:40-50.

Preferably, the rubber comprises gelatin for capsules, titanium dioxide, cyclodextrin and anhydrous ethanol; the mass ratio thereof is: 110-140: 2-5: 10-50: 20-30.

The preparation method of the cyclosporine soft capsule comprises the following steps:

a. Prepare glue solution: add water and titanium dioxide into a glue tank, grind them thoroughly with a colloid mill, add cyclodextrin, anhydrous ethanol and gelatin for capsules; after they are completely dissolved, glue is dissolved under vacuum conditions, and the glue solution is obtained after filtering;

b. Prepare the feed liquid: grind cyclosporine with a colloid mill for 5-10 minutes; add the ground cyclosporine, polyoxyethylene castor oil, corn oil/olive oil, and oleic acid macrogol glyceride into anhydrous ethanol; heat to 40° C.-50° C. for 0.5-1.5 h, mix thoroughly, and filter to obtain the feed liquid;

c. Set the temperature of the glue liquid to 55-70℃; put the liquid into the hopper and set the speed of the pill press to 1.4-2.0rpm; send the glue liquid into the glue box through the insulation pipe, and the glue box is evenly coated on the drum and cooled to form a rubber skin; shape the qualified soft capsules for more than 1.5 hours, and then dry them to reduce the moisture content of the rubber skin to below 15%.

Preferably, in step a, the vacuum condition is set to -1.0 Bar to -0.8 Bar.

Preferably, in step a, the mass ratio of gelatin, titanium dioxide, cyclodextrin and anhydrous ethanol for capsule is: 110-140: 2-5: 10-50: 20-30.

Preferably, in step b, the mass ratio of cyclosporine, anhydrous ethanol, polyoxyethylene castor oil, corn oil/olive oil, and oleic acid macrogol glyceride is 25:30-40:100-103:80-90:40-50.

The present invention develops a method for preparing cyclosporine soft capsules by improving the formula and process of cyclosporine soft capsules, solving the problems of low purity, low yield, high cost, high impurity content, and poor stability of existing products. The product prepared by the present invention has light color, high content, low impurities, uniform rubber thickness, neat and plump appearance, no cracks, no bubbles, high yield, and greatly improved stability, thereby improving the safety of clinical medication. At the same time, the preparation method provided by the present invention has a high yield, The method is conducive to industrial production, is advanced, and has important theoretical significance and application value for the production and clinical application of cyclosporine soft capsules.

Detailed ways

The present invention conducts a thorough research on the formulation and process of the contents and rubber of the cyclosporine soft capsule, and screens and improves the formulation and process, thereby improving the solubility, purity, quality stability and yield of the cyclosporine soft capsule, thereby improving the bioavailability of cyclosporine, reducing the bioavailability difference between individuals, and improving the safety and effectiveness of clinical medication. The present invention is described in detail below.

1. The prescription of cyclosporine soft capsules is shown in Table 1 below.

Table 1

2. Preparation of Cyclosporine Soft Capsules

Add appropriate amount of water and titanium dioxide to the gelling tank, grind thoroughly with a colloid mill, add cyclodextrin, anhydrous ethanol and gelatin for capsules. The mass ratio of titanium dioxide, cyclodextrin, anhydrous ethanol and gelatin for capsules is 2-5:10-50:20-30:110-140. After complete dissolution, set the vacuum degree to -1.0Bar—-0.8Bar, gel under vacuum conditions, filter after gelling to obtain gel solution, and store the gel solution in a gel storage tank.

Grind cyclosporine with a colloid mill for 5-10 minutes, and the ground raw material is evenly dispersed, and the particle size distribution is even, and the fluidity of the raw material is good. Add the ground cyclosporine, polyoxyethylene castor oil, corn oil/olive oil and oleic acid macrogol glyceride and other materials into a sufficient amount of anhydrous ethanol, heat to 40°C-50°C, heat for 0.5-1.5h, fully mix, and filter to obtain a liquid.

Set the temperature of the glue liquid to 55-70℃; put the liquid into the hopper, and the speed of the pill press is 1.4-2.0rpm. The glue liquid is sent to the glue box through the insulation pipe, and the glue box is evenly coated on the drum and cooled to form a rubber skin with uniform thickness; the soft capsules that have been pressed and qualified are shaped for more than 1.5 hours, and then dried to reduce the moisture content of the rubber skin to less than 15%.

Example 1

The prescription is shown in Table 2 below.

Table 2

The preparation method is as follows:

Add appropriate amount of water and 2g titanium dioxide to the gelling tank, grind thoroughly with a colloid mill, add 10g cyclodextrin, 20g anhydrous ethanol, and 110g gelatin for capsules. After complete dissolution, set the vacuum degree to -0.8Bar, gelling is complete, filter and place in a gel storage tank.

25g of cyclosporine was ground with a colloid mill for 10 minutes. The ground raw material was evenly dispersed, the particle size distribution was even, and the fluidity of the raw material was good. The ground cyclosporine, 100g of polyoxyethylene castor oil, 80g of corn oil, 40g of oleic acid polyethylene glycol glyceride and other materials were added to 30g of anhydrous ethanol, heated to 40°C, heated for 1.5h, and the liquid was fully mixed and filtered.

Set the temperature of the glue liquid to 55℃; put the liquid into the hopper, and the speed of the pill press is 1.4rpm. The glue liquid is sent to the glue box through the insulation pipe, and the glue box is evenly coated on the drum and cooled to form a rubber skin with uniform thickness. The soft capsules that have passed the pressing are shaped for more than 1.5 hours, and then dried to reduce the moisture content of the rubber skin to less than 15%.

Example 2

The prescription in this example is the same as that in Table 2 of Example 1, and the preparation process parameters are slightly different, as follows:

Add appropriate amount of water and titanium dioxide to the gelling tank, grind them thoroughly with a colloid mill, and then add cyclodextrin, anhydrous ethanol, gelatin for capsules and other materials. After they are completely dissolved, set the vacuum degree to -0.9Bar, the gelling is completed, and the gelling is filtered and placed in a gel storage tank.

Cyclosporine was ground with a colloid mill for 8 minutes. The ground raw material was evenly dispersed and the particle size distribution was uniform. Add the ground cyclosporine, polyoxyethylene castor oil, corn oil, oleic acid macrogol glyceride and other materials to a sufficient amount of anhydrous ethanol, heat to 45°C for 1 hour, mix the liquid thoroughly and filter.

Set the temperature of the glue liquid to 60℃; put the glue liquid into the hopper, and the speed of the pill press is 1.7rpm. The glue liquid is sent to the glue box through the insulation pipe, and the glue box is evenly coated on the drum and cooled to form a rubber skin with uniform thickness. The soft capsules that have been pressed and qualified are shaped for more than 1.5 hours, and then dried to reduce the moisture content of the rubber skin to less than 15%.

Example 3

Add appropriate amount of water and titanium dioxide to the gelling tank, grind them thoroughly with a colloid mill, and then add cyclodextrin, anhydrous ethanol, gelatin for capsules and other materials. After they are completely dissolved, set the vacuum degree to -1.0Bar, the gelling is finished, and filter and put them into the gel storage tank.

Grind cyclosporine with a colloid mill for 5 minutes. The ground raw material is evenly dispersed, the particle size is evenly distributed, and the fluidity of the raw material is good. Add the ground cyclosporine, polyoxyethylene castor oil, corn oil, oleic acid macrogol glyceride and other materials to a sufficient amount of anhydrous ethanol, heat to 50°C, heat for 0.5h, fully mix the liquid, and filter.

Set the temperature of the glue liquid to 70℃; put the material liquid into the hopper, and the speed of the pill press is 2.0rpm. The glue liquid is sent to the glue box through the insulation pipe, and the glue box is evenly coated on the drum and cooled to form a rubber skin with uniform thickness. The soft capsules that have passed the pressing are shaped for more than 1.5 hours, and then dried to reduce the moisture content of the rubber skin to less than 15%.

Example 4

The prescription is shown in Table 3 below.

table 3

The preparation method is as follows:

Add appropriate amount of water and 5g titanium dioxide to the gelling tank, grind it thoroughly with a colloid mill, add 50g cyclodextrin, 30g anhydrous ethanol, 140g gelatin for capsules and other materials. After complete dissolution, set the vacuum degree to -0.8Bar, gelling is complete, filter and place in Glue storage tank.

25g of cyclosporine was ground with a colloid mill for 10 minutes. The ground raw material was evenly dispersed, and the particle size distribution was even, and the fluidity of the raw material was good. The ground cyclosporine, 103g of polyoxyethylene castor oil, 90g of corn oil, 50g of oleic acid polyethylene glycol glyceride and other materials were added to 40g of anhydrous ethanol, heated to 40°C, heated for 1.5h, and the liquid was fully mixed and filtered.

Example 5

The prescription in this example is the same as that in Table 3 of Example 4, and the preparation process parameters are slightly different, as follows:

Cyclosporine was ground with a colloid mill for 8 minutes. The ground raw material was evenly dispersed, the particle size was evenly distributed, and the fluidity of the raw material was good. The ground cyclosporine, polyoxyethylene castor oil, corn oil, oleic acid macrogol glyceride and other materials were added to a sufficient amount of anhydrous ethanol, heated to 45°C for 1 hour, and the liquid was fully mixed and filtered.

Set the temperature of the glue liquid to 60℃; put the liquid into the hopper, and the speed of the pill press is 1.7rpm. The glue liquid is sent to the glue box through the insulation pipe, and the glue box is evenly coated on the drum and cooled to form a rubber skin with uniform thickness. The soft capsules that have passed the pressing are shaped for more than 1.5 hours, and then dried to reduce the moisture content of the rubber skin to less than 15%.

Example 6

Comparative Example

The cyclosporine soft capsule is prepared by adopting the existing technology.

The prescription is shown in Table 4.

Table 4

The preparation method is as follows:

Add sufficient purified water to the gel tank, heat it, add the prescribed amount of glycerin and gelatin for capsules and other materials, emulsify, stir, and filter into the gel storage tank.

In a sufficient amount of anhydrous ethanol, add the prescribed amount of cyclosporine, polyoxyethylene castor oil, caprylic and capric triglyceride and other materials in sequence, mix the liquid thoroughly, and filter.

Set the temperature of the glue liquid to 60℃, put the liquid into the hopper, and start pressing the pills. The pressed capsules are shaped in the rotating cage for more than 1.5 hours to remove the moisture in the rubber. The shaped pills are placed on the drying tray and sent to the drying tunnel for drying for more than 48 hours. During the drying process, the pills are turned over at least once to reduce the moisture content of the rubber to less than 20%.

Comparison of Examples and Comparative Examples

(1) Properties, dissolution, content uniformity and content testing

The properties, dissolution, content uniformity and content (labeled amount) of cyclosporine soft capsules are important quality indicators of the product. 100 finished products were taken from each of Examples 1-6 and the comparative example for testing to examine the drug properties, dissolution, content uniformity and content (labeled amount), as shown in Table 5.

Table 5 Test results of properties, dissolution, content uniformity and content (labeled amount)

It can be seen from Table 5 that, compared with the comparative example, the dissolution rate and content (labeled amount) of each embodiment are higher.

(2) Product quality testing

The relevant material test data of Examples 1-6 and Comparative Examples are shown in Table 6

Table 6 Test data of Examples 1-6 and Comparative Examples

It can be seen from Table 6 that the relevant substances in each embodiment and comparative example meet the standards, but compared with the comparative example, the relevant substances in each embodiment are lower.

(3) Product stability testing:

Accelerated testing:

The test conditions are temperature 40°C ± 2°C and relative humidity 75 ± 5%. Accelerated stability tests were conducted on Examples 1-6 and the comparative example, and the results of the accelerated tests for 6 months are shown in Tables 7 and 8.

Table 7 Test results of properties, dissolution, content uniformity and content (labeled amount)

Table 8 Stability performance of accelerated test

Long-term trials:

The long-term test was carried out under the conditions of 25°C ± 2°C and 60% ± 10% relative humidity. The long-term stability of Examples 1-6 and the comparative example was investigated, and the long-term 12-month test results are shown in Tables 9 and 10.

Table 9 Test results of properties, dissolution, content uniformity and content (labeled amount)

Table 10 Stability performance of long-term test

From the accelerated and long-term test studies in Tables 7-10, it can be seen that after 6 months of acceleration, the content of the comparative example does not meet the standard; compared with the comparative example, the content of each embodiment is lighter in color, and the relevant substances and various indicators are better than the comparative example.

Combined with the 2020 edition of the Pharmacopoeia, it can be seen that the cyclosporine soft capsules prepared by the present invention have light color, high content, low impurities, and small changes in color, content, and impurities after long-term and accelerated use, and good stability, indicating that the prescription process of the present invention is reasonable, stable, quality controllable, reproducible, and safe for clinical use. By comparison, it can be seen that the products produced under the new preparation method are far superior to the currently produced products in terms of purity, color, content, related substances, stability, etc.

The above describes the specific embodiments of the present invention. It should be understood that the present invention is not limited to the above specific embodiments. For those of ordinary skill in the art, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. In the absence of conflict, the embodiments of the present application and the features in the embodiments can be combined with each other arbitrarily.

Claims

A cyclosporine soft capsule comprises a rubber skin and capsule contents; the characteristics are that the capsule contents comprise cyclosporine, anhydrous ethanol, polyoxyethylene castor oil, corn oil/olive oil, and oleic acid macrogol glyceride; the mass ratios thereof are 25:30-40:100-103:80-90:40-50.
The cyclosporine soft capsule according to claim 1 is characterized in that the rubber skin comprises gelatin for capsule, titanium dioxide, cyclodextrin and anhydrous ethanol; the mass ratio thereof is: 110-140: 2-5: 10-50: 20-30.
A method for preparing cyclosporine soft capsules, characterized in that it comprises the following steps:

a. Prepare glue solution: add water and titanium dioxide into a glue tank, grind them thoroughly with a colloid mill, add cyclodextrin, anhydrous ethanol and gelatin for capsules; after they are completely dissolved, glue is dissolved under vacuum conditions, and the glue solution is obtained after filtering;

b. Prepare the feed liquid: grind cyclosporine with a colloid mill for 5-10 minutes; add the ground cyclosporine, polyoxyethylene castor oil, corn oil/olive oil, and oleic acid macrogol glyceride into anhydrous ethanol; heat to 40° C.-50° C. for 0.5-1.5 h, mix thoroughly, and filter to obtain the feed liquid;

c. Set the temperature of the glue liquid to 55-70℃; put the liquid into the hopper and set the speed of the pill press to 1.4-2.0rpm; send the glue liquid into the glue box through the insulation pipe, and the glue box is evenly coated on the drum and cooled to form a rubber skin; shape the qualified soft capsules for more than 1.5 hours, and then dry them to reduce the moisture content of the rubber skin to below 15%.
The method for preparing cyclosporine soft capsules according to claim 3 is characterized in that, in step a, the vacuum condition is set to -1.0 Bar to -0.8 Bar.
The method for preparing cyclosporine soft capsules according to claim 3 is characterized in that, in step a, the mass ratio of gelatin, titanium dioxide, cyclodextrin and anhydrous ethanol for capsules is: 110-140: 2-5: 10-50: 20-30.
The method for preparing cyclosporine soft capsules according to claim 3, characterized in that, in step b, the mass ratio of cyclosporine, anhydrous ethanol, polyoxyethylene castor oil, corn oil/olive oil, and oleic acid macrogol glyceride is: 25:30-40:100-103:80-90:40-50.