How the drug is manufactured

Abstract

To provide a method for producing a drug.SOLUTION: A method for producing a drug comprises the following steps: first, dissolving an effective administration dose of API in a dissolving agent to form a first solution, the API containing triamcinolone acetonide (formula (I) below) or YC-1 compound (formula (II) below); then, filtering the first solution through a filtration membrane at room temperature to obtain a second solution; then, adding a precipitating agent to the second solution to obtain a third solution, and subsequently stirring the third solution continuously to precipitate the crystals; further stirring the third solution at room temperature under low pressure to sequentially remove the dissolving agent and precipitating agent; and finally, quantifying the volume of the crystals in order to primarily package and refill the crystals to obtain the drug.SELECTED DRAWING: Figure 3

Description

[Technical field]

[0001] The present disclosure relates to a method for producing a drug, and in particular to a method for producing an injectable drug. [Background technology]

[0002] Common drug dosage forms can be divided into drops, ointments, injections, gels, etc., and injections are generally used by directly delivering themselves into the blood system until an effective dosage is reached, so as to obtain benefits such as rapid and effective response. However, the product quality of injections as well as their production are both important to the pharmaceutical industry. Firstly, injections are required to be highly stable and low in toxicity, and the weight and particle size of the prepared powder or lyophilized powder are also required to be uniform and microminiaturized at the same time, thereby dramatically reducing the possible irritation of any drug. In addition, the raw materials of injections and the manufacturing process for processing the raw materials (including preparation, secondary packaging, transportation, primary packaging, and filling) are required to be contamination-free to fully avoid any residues, such as residues of impurities below 100 micrometers, which may impair product quality. Therefore, it is urgent to overcome all the limitations and shortcomings of the manufacturing method of injections to meet the practical requirements of the pharmaceutical industry. Summary of the Invention [Problem to be solved by the invention]

[0003] The objective of the present disclosure is to provide a method for the preparation of a drug, in which an active pharmaceutical ingredient (API) is processed by using two solvents for crystal precipitation, so as to effectively avoid possible contamination and dramatically control the particle size of the drug.In this way, the drug thereby obtained in the present disclosure can meet various product requirements, such as less contamination, lower toxicity, and finer particles, thereby achieving better product quality. [Means for solving the problem]

[0004] In order to achieve the above object, one embodiment of the present disclosure provides a method for producing a drug, which includes the following steps. First, an effective dose of an active pharmaceutical ingredient is dissolved in a dissolving agent to form a first solution, where the active pharmaceutical ingredient includes triamcinolone acetonide or YC-1 compound. Then, the first solution is filtered through a filtration membrane at room temperature to obtain a second solution. Then, a precipitating agent is added to the second solution to obtain a third solution, and then the third solution is continuously stirred to precipitate crystals. The third solution is further stirred at room temperature and under low pressure to sequentially remove the dissolving agent and precipitating agent from the third solution. Finally, the volume of the crystals is quantified for primary packaging and refilling, and the crystals are further subjected to a freeze-drying process to obtain a drug, where triamcinolone acetonide is represented by the following structural formula (I):

[0005] [ka] The YC-1 compound is represented by the following structural formula (II):

[0006] [ka] It is represented by:

[0007] Overall, according to the drug manufacturing method of the present disclosure, a special crystal precipitation technique and a freeze-drying process are combined to accurately determine the particle size of precipitated crystals, in which multiple solvents are applied to the active pharmaceutical ingredient for crystal precipitation, and the freeze-drying process is carried out when the crystals are in a semi-solid dosage form, thereby simplifying the drug manufacturing process and effectively preventing any external contamination at the same time.In this way, the drug obtained from the drug manufacturing method of the present disclosure can obtain better product quality.

[0008] These and other objectives of the present invention will no doubt become obvious to those of ordinary skill in the art after reading the following detailed description of the preferred embodiments that are illustrated in the various figures and drawings. [Brief description of the drawings]

[0009] [Figure 1] FIG. 2 is a schematic diagram illustrating the particle size distribution (PSD) of the product obtained in the drug manufacturing method according to the first embodiment of the present disclosure. [Diagram 2] FIG. 2 is a schematic diagram illustrating the particle size distribution of another product obtained in the drug manufacturing method according to the first embodiment of the present disclosure. [Diagram 3] FIG. 2 is a schematic diagram illustrating the particle size distribution of a product obtained in a drug manufacturing method according to a second embodiment of the present disclosure, illustrating the particle size distribution of the product obtained in Example 1. [Figure 4] FIG. 2 is a schematic diagram illustrating the particle size distribution of a product obtained in a drug manufacturing method according to a second embodiment of the present disclosure, illustrating the particle size distribution of the product obtained in Example 2. [Diagram 5] FIG. 1 is a schematic diagram illustrating the particle size distribution of a product obtained in a drug manufacturing method according to a second embodiment of the present disclosure, illustrating the particle size distribution of the product obtained in Example 3. [Figure 6] FIG. 1 is a schematic diagram illustrating the particle size distribution of a product obtained in a drug manufacturing method according to a second embodiment of the present disclosure, illustrating the particle size distribution of the product obtained in Example 4. [Figure 7] FIG. 1 is a schematic diagram illustrating the particle size distribution of a product obtained in a drug manufacturing method according to a second embodiment of the present disclosure, illustrating the particle size distribution of the product obtained in Example 5. [Figure 8] FIG. 1 is a schematic diagram illustrating the particle size distribution of a product obtained in a drug manufacturing method according to a second embodiment of the present disclosure, illustrating the particle size distribution of the product obtained in Example 6. [Figure 9]FIG. 11 is a schematic diagram illustrating the particle size distribution of another product obtained in the drug manufacturing method according to the second embodiment of the present disclosure, illustrating the particle size distribution of the product obtained in Example 7. [Figure 10] FIG. 11 is a schematic diagram illustrating the particle size distribution of another product obtained in the drug manufacturing method according to the second embodiment of the present disclosure, illustrating the particle size distribution of the product obtained in Example 8. [Figure 11] FIG. 11 is a schematic diagram illustrating the particle size distribution of another product obtained in the drug manufacturing method according to the second embodiment of the present disclosure, illustrating the particle size distribution of the product obtained in Example 9. [Figure 12] FIG. 11 is a schematic diagram illustrating the particle size distribution of another product obtained in the drug manufacturing method according to the second embodiment of the present disclosure, illustrating the particle size distribution of the product obtained in Example 10. [Figure 13] FIG. 11 is a schematic diagram illustrating the particle size distribution of another product obtained in the drug manufacturing method according to the second embodiment of the present disclosure, illustrating the particle size distribution of the product obtained in Example 11. [Figure 14] FIG. 11 is a schematic diagram illustrating the particle size distribution of another product obtained in the drug manufacturing method according to the second embodiment of the present disclosure, illustrating the particle size distribution of the product obtained in Example 12. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] In order to make the present disclosure more understandable, preferred embodiments are described in detail. The preferred embodiments of the present disclosure are illustrated in the accompanying drawings with numbered elements. In addition, the technical features in the different embodiments described below can be exchanged, recombined, or mixed together to form another embodiment without departing from the spirit of the present disclosure.

[0011] In this disclosure, the term "about" or "substantially" generally means within 20%, preferably within 10%, more preferably within 5%, 3%, 2%, 1%, or 0.5% of a given value or range. Unless otherwise specified, all numerical ranges, amounts, values, and percentages disclosed herein should be understood as being modified in all instances by the term "about" or "substantially". Thus, unless otherwise indicated, the numerical parameters set forth in this disclosure and the appended claims are approximations that can be varied as necessary.

[0012] The manufacturing method of the drug according to the first embodiment includes, but is not limited to, the following steps: First, an active pharmaceutical ingredient (API) is provided, and an effective dose of the API is processed through dry powder filling technology, and the API is refilled by sterile dry powder, and then its volume or weight is quantified for primary packaging. Thereby, the drug of the first embodiment is then obtained, and the API includes any pharmaceutical raw materials used in the treatment of eye diseases, such as triamcinolone acetonide, YC-1 compound (CAS#:170632-4), analogs or compositions of this pharmaceutical raw materials, or other ingredients that need to be manufactured as injections. Triamcinolone acetonide is represented by the following structural formula (I):

[0013] [ka] The YC-1 compound is represented by the following structural formula (II):

[0014] [ka] It is represented by:

[0015] When the API comprises triamcinolone acetonide, the particle size distribution (PSD) of the crystals within the drug product is approximately 1 micrometer (μm) to 100 μm, with 10% of the crystals having a particle size (D10) less than 4.444 μm, 50% of the crystals having a particle size (D50) less than 11.189 μm, and 90% of the crystals having a particle size (D90) less than 30.504 μm, meeting good manufacturing practice (GMP) standards for the drug product, as shown in FIG. 1. On the other hand, when the API contains the YC-1 compound, the particle size distribution (PSD) of the crystals in the drug is about 0.5 μm to 250 μm, and as shown in FIG. 2, 10% of the crystals have a particle size (D10) less than 0.648 μm, 50% of the crystals have a particle size (D50) less than 14.061 μm, and 90% of the crystals have a particle size (D90) less than 215.136 μm, also meeting the GMP standard for the drug.

[0016] Through these steps, the drug obtained from the manufacturing method of the first embodiment can be used as an injection, particularly as a powder suspension, which generally refers to a drug that can be stored in a sterile container and further dissolved in a suitable liquid to form a suspension, and can meet the GMP standard for drugs. However, those skilled in the art should easily recognize that the manufacturing method of the drug in the present disclosure is not limited to the above-mentioned embodiments, and may further include other examples or variants under practical product requirements. The following description details different embodiments of the manufacturing method of the drug in the present disclosure. In order to simplify the description, the following description details the differences between different embodiments, and the same features are not described redundantly. In order to easily compare the differences between the embodiments, the same components in each of the following embodiments are marked with the same symbols.

[0017] According to the second embodiment of the present disclosure, another drug manufacturing method is provided to precisely control the particle size of the drug and further improve the shortcomings caused by the above-mentioned dry powder filling technique, such as contamination such as hair, impurities, or other residues during sampling of API, or easy to lead to weight fluctuation during the filling process. In addition, the manufacturing method of the second embodiment can obtain a drug with uniform and fine particles under a more complete and simplified process flow, without any external contamination. According to the drug manufacturing method in the second embodiment of the present disclosure, a special crystal precipitation technique and a freeze-drying process are combined to precisely determine the particle size, and the method includes, but is not limited to, the following steps. See Table 1. First, a preparation step (S1) is carried out by dissolving an effective amount of API in a dissolving agent to form a first solution, where the API includes any pharmaceutical raw material used in the treatment of eye diseases, such as triamcinolone acetonide, antibiotic drugs, YC-1 compound (CAS#:170632-4), analogs or compositions of this pharmaceutical raw material, or other ingredients that need to be manufactured as injections. Triamcinolone acetonide has the following structural formula (I):

[0018] [ka] The YC-1 compound is represented by the following structural formula (II):

[0019] [ka] It is represented by:

[0020] The dissolving agent may be any kind of solvent according to the characteristics of the API, such as suitable low-toxicity organic solvent. In this embodiment, the dissolving agent includes, for example, (C1-C4) alcohol or (C1-C4) ketone, preferably selected from the group including, but not limited to, methanol, ethanol, isopropanol, tert-butanol (TBA), and acetone. In this embodiment, each 10 milligrams (mg) of API is dissolved in, for example, 0.5-0.8 milliliters (ml) of dissolving agent, and the dissolving agent is preferably, but not limited to, 0.65 ml. If the volume of dissolving agent is too small, the API cannot be completely dissolved, thereby resulting in poor yield, while if the volume of dissolving agent is too large, the API will therefore obtain poor crystallization efficiency, thereby resulting in poor particle size uniformity.

[0021] Next, the sterilization step (S2) is performed. In this embodiment, the sterile filtration step is carried out by filtering the first solution through a filtration membrane to obtain a second solution, i.e., a sterile filtrate. The opening of the filtration membrane is about 0.22-0.45 μm, preferably about 0.22 μm, but is not limited thereto. In addition, the sterilization step (S2) is preferably performed at room temperature, for example, room temperature is about 20-30 degrees Celsius, more preferably about 25 degrees Celsius, but is not limited thereto.

[0022] Also, a precipitation step (S3) is performed in which a precipitant is added to the second solution to obtain a third solution, the volume ratio of the precipitant to the second solution being about 2:1, followed by continuously stirring the third solution for a period of time, such as 1 hour, to precipitate crystals from the third solution. In this embodiment, the precipitant includes, but is not limited to, for example, pure water or other suitable liquids with low toxicity. In particular, each 10 milligrams (mg) of API is precipitated by about 0.5-1.5 ml of precipitant, the precipitant being preferably, but not limited to, about 1 ml.

[0023] Then, the first concentration step (S4) and the second concentration step (S5) are carried out sequentially by continuously stirring the third solution while gradually reducing the pressure at room temperature (20-30 degrees Celsius), to respectively remove the dissolving agent and the precipitating agent from the third solution, thereby obtaining the crystals. According to the first concentration step (S4), the third solution is stirred under a low pressure of about -720 to -685 mmHg for 20-24 hours to remove the dissolving agent from the third solution, and according to the second concentration step (S5), the third solution is continuously stirred under another low pressure of about -730 to -710 mmHg for 12-16 hours to remove the precipitating agent from the third solution, where the pressure range of the second concentration step (S5) is preferably lower than that of the first concentration step (S4), so as to precisely control the particle size and uniformity of the crystals. Then, the drug obtained thereafter can achieve a uniform and fine particle size at the same time.

[0024] Then, a primary packaging step (S6) and a drying step (S7) are performed in sequence, in which the third solution is continuously stirred, followed by quantifying the volume of the crystals for primary packaging and refilling. The volume of the crystals is about 2-4 ml, but is not limited thereto. Then, a freeze-drying step and a vacuum concentration step are performed in sequence to further remove residual precipitant from the third solution, thereby obtaining the drug. In this embodiment, the freeze-drying step is performed with gradually increasing temperature under low pressure to remove precipitant from the third solution, for example, but is not limited thereto, with gradually increasing temperature from -35 degrees Celsius to 0 degrees Celsius and then to 35 degrees Celsius (-35°C→0°C→35°C) under a pressure of about 0.5 mmHg for about 22 to 24 hours. Meanwhile, the vacuum concentration step is carried out for about 12 to 16 hours at room temperature (20-30° C.) and pressure ranging from −720 to −685 mmHg to remove residual precipitant from the third solution.

[0025] [Table 1] Through these steps, the drug obtained from the manufacturing method of the second embodiment can also be used as an injection, especially as a powder suspension, which refers to a drug that can be further dissolved in a suitable liquid to form a suspension, and meets the GMP standard for drugs. Thus, the manufacturing method of the present embodiment allows water-insoluble APIs, such as triamcinolone acetonide or YC-1 compound, to be processed to produce an injection that can be quickly absorbed and utilized by humans or animals, especially an injection with high purity, low contamination, and low toxicity. For example, when the API includes triamcinolone acetonide, the drug obtained thereby can be used as an injection for the treatment of vitreous visualization in ocular vitrectomy or diabetic macular edema, and a sufficient amount of saline or ocular irrigation solution is added to a bottle containing an effective amount of the drug, followed by shaking the bottle thoroughly to form a suspension, which is then injected into the target area.

[0026] Based on the drug manufacturing method of this embodiment, a sterile crystal precipitation technique and a freeze-drying process are combined to accurately determine the particle size of the precipitated crystals, and in this method, two solvents (including a dissolving agent and a precipitating agent) are both applied to the API for crystal precipitation. To be precise, the API is first dissolved in a dissolving agent (in preparation step S1), followed by a sterilization process (in sterilization step S2) and a precipitation process (in precipitation step S3) in sequence to precipitate the crystals, and then a multi-stage vacuum concentration process (including a first concentration step S4 and a second concentration step S5) is carried out to sequentially remove the dissolving agent and the precipitating agent, thereby achieving effective dissolution, precipitation and freeze-drying in this embodiment. In this way, instead of being repeatedly transferred between various reaction chambers or contacting with the external environment, the API can be processed in the same reaction chamber during the above steps. In this way, the manufacturing method of this embodiment can effectively improve possible contamination and dramatically reduce the residuals, impurities or organic reagents remaining in the drug, so that the obtained drug can meet the requirements of low toxicity and low contamination.

[0027] Further referring to the method for producing the drug in this embodiment, a freeze-drying process different from the general freeze-drying process (including dissolution, sublimation, and crystallization) is carried out on the crystals of the semi-solid dosage form to precisely control the particle size of the drug. For example, when the API contains triamcinolone acetonide, the PSD of the crystals in the drug is controlled at about 40-50 μm, and 90% of the crystals have a particle size (D90) of less than 45 μm. On the other hand, when the API contains the YC-1 compound, the PSD of the crystals in the drug is controlled at about 60-80 μm, and 10% of the crystals have a particle size (D10) of less than 1 μm, 50% of the crystals have a particle size (D50) of less than 20 μm, and 90% of the crystals have a particle size (D90) of less than 70 μm, meeting the GMP standard for drugs.

[0028] Please refer to Figures 3 to 9 for some examples of drug manufacturing methods in the present disclosure. Relevant data are provided in the following paragraphs to verify its functions and advantages. EXAMPLES

[0029] In Example 1, 40 mg of triamcinolone acetonide is dissolved in 2.5 ml of methanol (if necessary, the methanol may be heated to 32°C for rapid dissolution) in a round-bottom flask to obtain a solution, which is then filtered through a filter membrane and the filtrate is collected in a precipitation bottle. Then, 4 ml of filtered pure water is added to the precipitation bottle at room temperature, and the filtrate in the precipitation bottle is continuously stirred for 1 hour to completely precipitate the crystals. Next, while continuously stirring the filtrate in the precipitation bottle, a first concentration step S4 (stirring for 20-24 hours to remove methanol) and a second concentration step S5 (stirring for 12 to 16 hours to remove pure water) are performed, followed by quantifying the volume of the crystals and primary packaging the crystals while continuously stirring the filtrate in the precipitation bottle. Then, a vacuum concentration step is performed for another 12 to 16 hours to further remove the pure water. The PSD of the crystals in the resulting drug is approximately 10-100 μm, and as shown in FIG. 3, 10% of the crystals have a particle size (D10) less than 25.839 μm, 50% of the crystals have a particle size (D50) less than 50.817 μm, and 90% of the crystals have a particle size (D90) less than 91.933 μm. EXAMPLES

[0030] In Example 2, 40 mg of triamcinolone acetonide is dissolved in 2.5 ml of ethanol (if necessary, the ethanol may be heated to 32°C for rapid dissolution) in a round-bottom flask to obtain a solution, which is then filtered through a filter membrane and the filtrate is collected in a precipitation bottle. Then, 4 ml of filtered pure water is added to the precipitation bottle at room temperature, and the filtrate in the precipitation bottle is continuously stirred for 1 hour to completely precipitate the crystals. Next, while continuously stirring the filtrate in the precipitation bottle, a first concentration step S4 (stirring for 20-24 hours to remove ethanol) and a second concentration step S5 (stirring for 12 to 16 hours to remove pure water) are performed, followed by quantifying the volume of the crystals and primary packaging the crystals while continuously stirring the filtrate in the precipitation bottle. Then, a vacuum concentration step is performed for another 12 to 16 hours to further remove the pure water. The PSD of the crystals in the resulting drug is approximately 1-100 μm, and as shown in FIG. 4, 10% of the crystals have a particle size (D10) less than 4.723 μm, 50% of the crystals have a particle size (D50) less than 12.828 μm, and further, 90% of the crystals have a particle size (D90) less than 31.582 μm. EXAMPLES

[0031] In Example 3, 40 mg of triamcinolone acetonide is dissolved in 2.5 ml of acetone (if necessary, the acetone may be heated to 32°C for rapid dissolution) in a round-bottom flask to obtain a solution, which is filtered through a filter membrane and the filtrate is collected in a precipitation bottle. Then, 4 ml of filtered pure water is added to the precipitation bottle at room temperature, and the filtrate in the precipitation bottle is continuously stirred for 1 hour to completely precipitate the crystals. Next, while continuously stirring the filtrate in the precipitation bottle, a first concentration step S4 (stirring for 20-24 hours to remove acetone) and a second concentration step S5 (stirring for 12 to 16 hours to remove pure water) are performed, followed by quantifying the volume of the crystals and primary packaging the crystals while continuously stirring the filtrate in the precipitation bottle. Then, a vacuum concentration step is performed for another 12 to 16 hours to further remove the pure water. The PSD of the crystals in the resulting drug is approximately 10-100 μm, and as shown in FIG. 5, 10% of the crystals have a particle size (D10) less than 34.313 μm, 50% of the crystals have a particle size (D50) less than 64.922 μm, and further, 90% of the crystals have a particle size (D90) less than 115.052 μm. EXAMPLES

[0032] In Example 4, 1200 mg of triamcinolone acetonide is dissolved in 75 ml of ethanol (if necessary, the ethanol may be heated to 32°C for rapid dissolution) in a round-bottom flask to obtain a solution, which is filtered through a filter membrane and the filtrate is collected in a precipitation bottle. Then, 120 ml of filtered pure water is added to the precipitation bottle at room temperature, and the filtrate in the precipitation bottle is continuously stirred for 1 hour to completely precipitate the crystals. Next, while continuously stirring the filtrate in the precipitation bottle, a first concentration step S4 (stirring for 20-24 hours to remove ethanol) and a second concentration step S5 (stirring for 12 to 16 hours to remove pure water) are performed, followed by quantifying the volume of the crystals and primary packaging the crystals while continuously stirring the filtrate in the precipitation bottle. Then, a freeze-drying process is carried out for 22 to 24 hours under a pressure of about 0.5 mmHg with gradually increasing temperature from -35 degrees Celsius to 0 degrees Celsius and then to 35 degrees Celsius (-35°C→0°C→35°C) to further remove the impurities. The PSD of the crystals in the drug thus obtained is about 1-100 μm, and 10% of the crystals have a particle size (D10) less than 5.617 μm, 50% of the crystals have a particle size (D50) less than 15.848 μm, and 90% of the crystals have a particle size (D90) less than 35.262 μm, as shown in FIG. 6. EXAMPLES

[0033] In Example 5, 40 mg of triamcinolone acetonide is dissolved in 2.5 ml of tert-butanol (if necessary, tert-butanol may be heated to 30°C for rapid dissolution) in a round-bottom flask to obtain a solution, which is filtered through a filter membrane and the filtrate is collected in a precipitation bottle. Then, 8 ml of filtered pure water is added to the precipitation bottle at room temperature, and the filtrate in the precipitation bottle is continuously stirred for 1 hour to completely precipitate the crystals. Next, the filtrate in the precipitation bottle is continuously stirred while the first concentration step S4 (stirring for 20 to 24 hours to remove tert-butanol) and the second concentration step S5 (stirring for 12 to 16 hours to remove pure water) are performed, followed by quantifying the volume of the crystals and primary packaging the crystals while continuously stirring the filtrate in the precipitation bottle. Then, a vacuum concentration step is performed for another 12 to 16 hours to further remove pure water. The PSD of the crystals in the resulting drug is then approximately 1-100 μm, and as shown in FIG. 7, 10% of the crystals have a particle size (D10) less than 5.488 μm, 50% of the crystals have a particle size (D50) less than 15.824 μm, and further, 90% of the crystals have a particle size (D90) less than 36.362 μm. EXAMPLES

[0034] In Example 6, 40 mg of triamcinolone acetonide is dissolved in 4 ml of isopropanol (if necessary, the isopropanol may be heated to 30°C for rapid dissolution) in a round-bottom flask to obtain a solution, which is then filtered through a filter membrane to collect the filtrate in a precipitation bottle. Then, 9 ml of filtered pure water is added to the precipitation bottle at room temperature, and the filtrate in the precipitation bottle is continuously stirred for 1 hour to completely precipitate the crystals. Next, while continuously stirring the filtrate in the precipitation bottle, a first concentration step S4 (stirring for 20-24 hours to remove isopropanol) and a second concentration step S5 (stirring for 12 to 16 hours to remove pure water) are performed, followed by quantifying the volume of the crystals and primary packaging the crystals while continuously stirring the filtrate in the precipitation bottle. Then, a vacuum concentration step is performed for another 12 to 16 hours to further remove the pure water. The PSD of the crystals in the resulting drug is approximately 10-100 μm, and as shown in FIG. 8, 10% of the crystals have a particle size (D10) less than 15.709 μm, 50% of the crystals have a particle size (D50) less than 29.590 μm, and further, 90% of the crystals have a particle size (D90) less than 53.806 μm. EXAMPLES

[0035] In Example 7, 1800 mg of YC compound is dissolved in 40 ml of ethanol (if necessary, ethanol may be heated to 32°C for rapid dissolution) in a round-bottom flask to obtain a solution, which is filtered through a filter membrane and the filtrate is collected in a precipitation bottle. Then, 50 ml of filtered pure water is added to the precipitation bottle at room temperature, and the filtrate in the precipitation bottle is continuously stirred for 1 hour to completely precipitate the crystals. Next, the first concentration step S4 (stirring for 20 to 24 hours to remove ethanol) and the second concentration step S5 (stirring for 12 to 16 hours to remove pure water) are performed while continuously stirring the filtrate in the precipitation bottle, followed by quantifying the volume of the crystals and primary packaging the crystals while continuously stirring the filtrate in the precipitation bottle. Then, a vacuum concentration step is performed for another 12 to 16 hours to further remove the pure water. The PSD of the crystals in the resulting drug product is approximately 0.1 to 110 μm, and as shown in FIG. 9, 10% of the crystals have a particle size (D10) less than 0.188 μm, 50% of the crystals have a particle size (D50) less than 7.627 μm, and further, 90% of the crystals have a particle size (D90) less than 54.780 μm. EXAMPLES

[0036] In Example 8, 400 mg of YC compound is dissolved in 35 ml of tert-butanol (if necessary, tert-butanol may be heated to 30° C. for rapid dissolution) in a round-bottom flask to obtain a solution, which is filtered through a filter membrane and the filtrate is collected in a precipitation bottle. Then, 90 ml of filtered pure water is added to the precipitation bottle at room temperature, and the filtrate in the precipitation bottle is continuously stirred for 1 hour to completely precipitate the crystals. Next, the first concentration step S4 (stirring for 20 to 24 hours to remove tert-butanol) and the second concentration step S5 (stirring for 12 to 16 hours to remove pure water) are performed while continuously stirring the filtrate in the precipitation bottle, followed by quantifying the volume of the crystals and primary packaging the crystals while continuously stirring the filtrate in the precipitation bottle. Then, a vacuum concentration step is performed for another 12 to 16 hours to further remove the pure water. The PSD of the crystals in the resulting drug is approximately 0.1 to 1000 μm, and as shown in FIG. 10, 10% of the crystals have a particle size (D10) less than 0.294 μm, 50% of the crystals have a particle size (D50) less than 11.950 μm, and further, 90% of the crystals have a particle size (D90) less than 188.035 μm. EXAMPLES

[0037] In Example 9, 400 mg of YC compound is dissolved in 30 ml of isopropanol (if necessary, isopropanol may be heated to 30° C. for rapid dissolution) in a round-bottom flask to obtain a solution, which is filtered through a filter membrane and the filtrate is collected in a precipitation bottle. Then, 65 ml of filtered pure water is added to the precipitation bottle at room temperature, and the filtrate in the precipitation bottle is continuously stirred for 1 hour to completely precipitate the crystals. Next, the first concentration step S4 (stirring for 20 to 24 hours to remove isopropanol) and the second concentration step S5 (stirring for 12 to 16 hours to remove pure water) are performed while continuously stirring the filtrate in the precipitation bottle, followed by quantifying the volume of the crystals and primary packaging the crystals while continuously stirring the filtrate in the precipitation bottle. Then, a vacuum concentration step is performed for another 12 to 16 hours to further remove the pure water. The PSD of the crystals in the resulting drug product is approximately 0.1 to 50 μm, and as shown in FIG. 11, 10% of the crystals have a particle size (D10) less than 0.192 μm, 50% of the crystals have a particle size (D50) less than 2.180 μm, and further, 90% of the crystals have a particle size (D90) less than 10.803 μm. EXAMPLES

[0038] In Example 10, 1600 mg of YC compound is dissolved in 80 ml of ethanol (if necessary, ethanol may be heated to 32°C for rapid dissolution) in a round-bottom flask to obtain a solution, which is filtered through a filter membrane and the filtrate is collected in a precipitation bottle. Then, 100 ml of filtered pure water is added to the precipitation bottle at room temperature, and the filtrate in the precipitation bottle is continuously stirred for 1 hour to completely precipitate the crystals. Next, the first concentration step S4 (stirring for 20 to 24 hours to remove ethanol) and the second concentration step S5 (stirring for 12 to 16 hours to remove pure water) are performed while continuously stirring the filtrate in the precipitation bottle, followed by quantifying the volume of the crystals and primary packaging the crystals while continuously stirring the filtrate in the precipitation bottle. Then, a freeze-drying process is carried out for 22 to 24 hours under a pressure of about 0.5 mmHg with gradually increasing temperature from -20 degrees Celsius to 0 degrees Celsius and then to 35 degrees Celsius (-20°C→0°C→35°C) to further remove the impurities. The PSD of the crystals in the drug thus obtained is about 0.5-100 μm, and 10% of the crystals have a particle size (D10) less than 0.717 μm, 50% of the crystals have a particle size (D50) less than 15.572 μm, and 90% of the crystals have a particle size (D90) less than 66.663 μm, as shown in FIG. 12. EXAMPLES

[0039] In Example 11, 800 mg of YC compound is dissolved in 20 ml of acetone in a round-bottom flask (if necessary, the acetone may be heated to 30° C. for rapid dissolution) to obtain a solution, which is filtered through a filter membrane and the filtrate is collected in a precipitation bottle. Then, 30 ml of filtered pure water is added to the precipitation bottle at room temperature, and the filtrate in the precipitation bottle is continuously stirred for 1 hour to completely precipitate the crystals. Next, the first concentration step S4 (stirring for 20 to 24 hours to remove acetone) and the second concentration step S5 (stirring for 12 to 16 hours to remove pure water) are performed while continuously stirring the filtrate in the precipitation bottle, followed by quantifying the volume of the crystals and primary packaging the crystals while continuously stirring the filtrate in the precipitation bottle. Then, a vacuum concentration step is performed for another 12 to 16 hours to further remove the pure water. The PSD of the crystals in the resulting drug is approximately 0.1 to 120 μm, and as shown in FIG. 13, 10% of the crystals have a particle size (D10) less than 0.548 μm, 50% of the crystals have a particle size (D50) less than 10.168 μm, and further, 90% of the crystals have a particle size (D90) less than 120.467 μm. EXAMPLES

[0040] In Example 12, 600 mg of YC compound is dissolved in 20 ml of ethanol (if necessary, ethanol may be heated to 32°C for rapid dissolution) in a round-bottom flask to obtain a solution, which is filtered through a filter membrane and the filtrate is collected in a precipitation bottle. Then, 120 ml of filtered pure water is added to the precipitation bottle at room temperature, and the filtrate in the precipitation bottle is continuously stirred for 1 hour to completely precipitate the crystals. Next, the first concentration step S4 (stirring for 20 to 24 hours to remove ethanol) and the second concentration step S5 (stirring for 12 to 16 hours to remove pure water) are performed while continuously stirring the filtrate in the precipitation bottle, followed by quantifying the volume of the crystals and primary packaging the crystals while continuously stirring the filtrate in the precipitation bottle. Then, a freeze-drying process is carried out for 22 to 24 hours under a pressure of about 0.5 mmHg with gradually increasing temperature from -20 degrees Celsius to 0 degrees Celsius and then to 35 degrees Celsius (-20°C→0°C→35°C) to further remove the impurities. The PSD of the crystals in the drug thus obtained is about 0.1-100 μm, and 10% of the crystals have a particle size (D10) less than 0.193 μm, 50% of the crystals have a particle size (D50) less than 9.802 μm, and 90% of the crystals have a particle size (D90) less than 58.439 μm, as shown in FIG. 14.

[0041] In addition, please refer to Tables 2 to 6 below, in which the weights of the drugs obtained from the manufacturing method of the first embodiment and the manufacturing method of the second embodiment are further compared. Firstly, as shown in Table 2, in the manufacturing method of the first embodiment, an effective dose of API (such as including triamcinolone acetonide) is processed through dry powder filling technology, the API is filled with sterile dry powder, and then its volume or weight is quantified for primary packaging, thereby obtaining the drug by the manufacturing method of the first embodiment. With these steps, five drug groups (including numbers 1-1 to 1-5 shown in Table 3) are obtained accordingly, and further, the weights (in grams, g) of the five drug groups at various processing steps of the manufacturing method of the drug are measured and listed in the following Table 3, to obtain the coefficient of variation (i.e., reference value / average value, CV) of weight or volume between drugs within the five drug groups, which is about 3.57%.

[0042] Further, please refer to Table 2. The API (including triamcinolone acetonide, etc.) is firstly dissolved in a dissolving agent (preparation step S1), followed by a sterilization step (sterilization step S2) and a precipitation step (precipitation step S3) in sequence to obtain crystals, and then a multi-step vacuum concentration step (including a first concentration step S4 and a second concentration step S5) is carried out to sequentially remove the dissolving agent and the precipitating agent, thereby achieving effective dissolution, precipitation, and freeze-drying in the manufacturing method of the second embodiment. Then, firstly, the volume of the crystals is quantified for primary packaging and refilling, and then the primary packaging step S6 and the drying step S7 are carried out in sequence by removing the residual precipitating agent through a freeze-drying step and a vacuum concentration step, thereby obtaining the drug by the manufacturing method of the second embodiment. With these steps, several drug groups (including Nos. 2-1 to 2-10 as shown in Table 4, Nos. 3-1 to 3-19 as shown in Table 5, and Nos. 4-1 to 4-12 as shown in Table 6) are obtained accordingly, and further, the weights (in grams) of these drug groups at various processing steps of the drug manufacturing process are measured and listed in the following Tables 4, 5, and 6 to obtain the coefficient of variation (i.e., baseline / average, CV) of weight or volume among drugs within these drug groups, which is about 0.29-1.12%.

[0043] [Table 2] In other words, the drug according to the manufacturing method of the second embodiment can be dried when the crystals are incompletely dried or completely dried, and the minute volume or weight of the crystals can be accurately quantified for primary packaging and filling, and the CV of weight or volume between drugs obtained in the second embodiment (e.g., about 0.29-1.12%) is dramatically lower than the CV of weight or volume between drugs obtained in the first embodiment (e.g., about 3.57%). Thus, the drug according to the second embodiment makes it possible to meet the demand for finer particles so as to achieve better product quality.

[0044] [Table 3]

[0045] [Table 4]

[0046] [Table 5]

[0047] [Table 6] Overall, according to the drug manufacturing method of the present disclosure, a special crystal precipitation technique and a freeze-drying process are combined to accurately determine the particle size of the precipitated crystals, in which multiple solvents are applied to the active pharmaceutical ingredient for crystal precipitation, and a freeze-drying process is carried out on the semi-solid dosage form, thereby simplifying the drug manufacturing process and effectively preventing any external contamination at the same time.In this way, the manufacturing method of the present disclosure allows water-insoluble APIs such as triamcinolone acetonide or YC-1 compound or antibiotics to be processed to produce injections that can be absorbed and utilized by humans or animals, especially injections with high purity, low contamination, and low toxicity, such as eye injections for the treatment of vitreous visualization in eye vitrectomy or diabetic macular edema.Through these steps, the drug obtained from the drug manufacturing method of the present disclosure can obtain better product quality.

[0048] Those skilled in the art will readily observe that numerous modifications and variations of the apparatus and method may be made while retaining the teachings of this invention. Accordingly, the above disclosure should be construed as limited only by the metes and bounds of the appended claims.

Claims

1. A method for producing a drug, comprising: dissolving an effective dose of an active pharmaceutical ingredient in a dissolution agent to form a first solution, the active pharmaceutical ingredient comprising triamcinolone acetonide or a YC-1 compound; filtering the first solution through a membrane filter at room temperature to obtain a second solution; adding a precipitating agent to the second solution to obtain a third solution, and continuously stirring the third solution to precipitate crystals; further stirring the third solution at room temperature and low pressure to sequentially remove the dissolving agent and the precipitating agent from the third solution, wherein the pressure for removing the precipitating agent from the third solution is lower than the pressure for removing the dissolving agent from the third solution; subjecting the crystals to a freeze-drying process to obtain a drug product; Including, The triamcinolone acetonide has the following structural formula (I): 【Chemistry 7】 is represented by The YC-1 compound has the following structural formula (II): 【Chemistry 8】 is represented by A method for producing a drug, wherein all of said steps are carried out in the same reaction chamber.

2. The method for producing a drug according to claim 1, wherein the room temperature is 20 to 30 degrees Celsius.

3. The method of claim 1, wherein the openings of the filtration membrane are between 0.22 and 0.45 micrometers.

4. The method for producing a medicament according to claim 1, wherein the dissolving agent is selected from the group consisting of (C1-C4) alcohols and (C3-C4) ketones.

5. The method for producing the medicament according to claim 4, wherein the dissolving agent is selected from the group including methanol, ethanol, isopropanol, tert-butanol, and acetone.

6. The method of claim 1 , wherein the precipitating agent comprises pure water.

7. 7. The method of claim 6, wherein the volume ratio of the precipitant to the second solution is 2:

1.

8. The method for producing a medicament according to claim 1, wherein the ratio of the weight of the active pharmaceutical ingredient to the volume of the dissolution agent is 10 mg:0.5 to 0.8 ml.

9. 2. The method of claim 1, wherein the ratio of the weight of the active pharmaceutical ingredient to the volume of the dissolution agent is 10 mg:0.65 ml.

10. 2. The method of claim 1, wherein the ratio of the weight of the active pharmaceutical ingredient to the volume of the precipitating agent is 10 mg:0.5 to 1.5 ml.

11. 11. The method of claim 10, wherein the ratio of the weight of the active pharmaceutical ingredient to the volume of the precipitating agent is 10 mg:1 ml.

12. performing a first concentration step by stirring the third solution at room temperature under a pressure of -720 to -685 mmHg to remove the lysis agent; performing a second concentration step by stirring the third solution at room temperature under a pressure of -730 to -710 mmHg to remove the precipitant; The method for producing the drug of claim 1 further comprising:

13. The method for producing a drug according to claim 12, wherein the operation time of the first concentration stage is 22 to 24 hours.

14. The method for producing a drug according to claim 12, wherein the operation time of the second concentration stage is between 12 and 16 hours.

15. 2. The method of claim 1, wherein the active pharmaceutical ingredient comprises triamcinolone acetonide, the particle size distribution of the crystals is between 40 and 50 micrometers, and 90% of the crystals have a particle size (D90) of less than 45 micrometers.

16. 2. The method of claim 1, wherein the active pharmaceutical ingredient comprises YC-1 compound, the particle size distribution of the crystals is between 60 and 80 micrometers, and 90% of the crystals have a particle size (D90) of less than 70 micrometers.

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