CN111544378A - Topiroxostat injection for treating gout and preparation method thereof - Google Patents
Topiroxostat injection for treating gout and preparation method thereof Download PDFInfo
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- CN111544378A CN111544378A CN202010381278.3A CN202010381278A CN111544378A CN 111544378 A CN111544378 A CN 111544378A CN 202010381278 A CN202010381278 A CN 202010381278A CN 111544378 A CN111544378 A CN 111544378A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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Abstract
The invention discloses topiroxostat injection for treating gout, which comprises the following components in parts by weight: 20mg/ml of topiroxostat, 10-100mg/ml of absolute ethyl alcohol, a pH regulator and the balance of water for injection. The pH regulator is used for regulating the pH value of the injection, the pH regulator is a sodium hydroxide solution/hydrochloric acid solution, and the dosage of the pH regulator is based on regulating the pH value of the injection to 6.8-7.6. The preparation method of the topiroxostat injection comprises the following steps: preparing raw material components according to the dosage, adding topiroxostat into absolute ethyl alcohol for dissolving and uniformly stirring, adding the mixed solution of the topiroxostat and the absolute ethyl alcohol into injection water cooled to be below 30 ℃, uniformly stirring, adjusting the pH to 7.2 +/-0.5 by using a pH regulator, fixing the volume by using the injection water, stirring at the stirring speed of 300-350 rpm for 20-40 min, filtering by using a sterilizing filter, filling into an ampoule, sealing, and sterilizing to obtain the topiroxostat injection. The topiroxostat injection has the advantages of single and stable raw and auxiliary materials, definite curative effect and good quality. The preparation method in the method is suitable for expanded production.
Description
Technical Field
The invention relates to topiroxostat injection for treating gout and a preparation method thereof, belonging to the field of medicines.
Background
Gout is a common disease causing abnormal uric acid production due to purine metabolic disorder, is listed as one of the 21 st century and 20 th stubborn diseases by the united nations, and is the second largest metabolic disease next to diabetes. In recent years, the number of gout patients in China is increased rapidly, which is mainly caused by the improvement of living standard of people and the change of dietary structure. The number of gout attack in European and American areas is about 0.13-0.37% of the general population, the annual incidence rate is 0.20-0.35 per mill, the prevalence rate in China is 0.15-0.67%, and is obviously increased compared with the prior art. The narrow therapeutic goal of gout is to suppress urate deposition in body tissues and avoid many symptoms (e.g., gouty arthritis) caused by urate deposition, and the therapeutic goal of serum uric acid level is to reduce the serum uric acid level to below 6.0 mg/dL. The treatment of gout and hyperuricemia is most important to improve the dietary living habits, but the treatment of recurrent gouty arthritis and gout nodules is difficult only by improving the living habits, and the serum uric acid value can be maintained below 6.0mg/mL only by drug treatment.
Topiroxostat is a selective Xanthine Oxidoreductase (XOR) inhibitor without a purine structure, gout is mainly caused by long-term overhigh concentration of uric acid in human body, purine is a main raw material for generating uric acid, and the uric acid is a final product of purine structure metabolism in the human body and is converted from hypoxanthine into xanthine through the effect of XOR. Topiroxostat has competitive inhibition effect (Ki value is 5.1 nmol/L) on XOR, can inhibit the generation of endogenous uric acid, has no inhibition effect on other purine pyrimidine metabolic enzymes, and belongs to a specific inhibitor on XOR.
Topiroxostat has obvious inhibition effect on oxidized and reduced XOR, so that the product has the following advantages compared with allopurinol: allopurinol only has an inhibiting effect on reduced XOR, and topiroxol has a remarkable inhibiting effect on oxidized XOR and reduced XOR, so that the effect of reducing uric acid is more powerful and lasting; ② because allopurinol is purine analogue, inevitably causes influence on other enzyme activities related to purine and pyridine metabolism, therefore, in allopurinol treatment, repeated large dose administration is needed to maintain higher drug level. Therefore, serious and even fatal adverse reactions caused by drug accumulation are caused, and the topiroxostat is a non-purine XOR inhibitor and has better safety.
Topiroxostat is a non-purine selective xanthine oxidoreductase inhibitor which is developed by Fuji chemical Co., Ltd. in Japan, and which selectively and reversibly inhibits xanthine oxidoreductase and lowers serum uric acid level. Its trade name: topiloictables, japanese name: トピロリツワ, generic name: topiroxostat, ロキソスタット; specification: 20mg, is used for treating gout and hyperuricemia, a topiroxostat clinical test is carried out in 2004, and the product is approved by the medical supervision bureau 6 months after 2013 to be put on the market. The topiroxostat injection developed in China adds a new variety to the medicine for treating gout and hyperuricemia, meets the requirement of clinical treatment, and has wide application prospect.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide the topiroxostat injection for treating gout and the preparation method thereof. The preparation method in the method is suitable for expanded production.
1. In order to achieve the technical purpose and achieve the technical effect, the invention is realized by the following technical scheme: the topiroxostat injection comprises the following components in parts by weight: 20mg/mL of topiroxostat, 10-100mg/mL of absolute ethyl alcohol, a pH regulator and the balance of water for injection.
2. The pH regulator is used for regulating the pH value of the injection, the pH regulator is a sodium hydroxide solution/hydrochloric acid solution, and the dosage of the pH regulator is based on regulating the pH value of the injection to 6.8-7.6.
3. Preferably, the topiroxostat injection comprises the following components in percentage by weight: topiroxostat 20mg/mL, absolute ethyl alcohol 10mg/mL, pH regulator, and the balance of water for injection: the pH regulator is used for regulating the pH value of the injection, the pH regulator is a sodium hydroxide solution/hydrochloric acid solution, and the dosage of the pH regulator is based on regulating the pH value of the injection to 6.9-7.4.
4. The invention also provides a preparation method of the topiroxostat injection, which comprises the following steps:
5. preparing raw material components according to dosage, adding topiroxostat into absolute ethyl alcohol for dissolving and uniformly stirring, adding the mixed solution into injection water cooled to be below 30 ℃, uniformly stirring, adjusting the pH to be 7.2 +/-0.5 by using a pH regulator, fixing the volume by using the injection water cooled to be below 30 ℃, stirring at the stirring speed of 300-350 rpm for 20-40 min, filtering by using a sterilizing filter, filling into an ampoule, sealing, and sterilizing to obtain the topiroxostat injection.
6. Wherein the sterilization conditions are as follows: sterilizing at 90-110 ℃ for 20-30 min.
7. Further, the preparation method also comprises an ampoule processing process, which comprises the following steps: the ampoule is cleaned by injection water through an ultrasonic cleaning machine, and then dried and sterilized at the temperature of 310-330 ℃.
8. Preferably, the filter precision of the sterilizing filter is 0.22 um.
Detailed Description
Example 1
The topiroxostat injection comprises the following components in parts by weight: topiroxostat 20mg/mL, absolute ethyl alcohol 10mg/mL, a pH regulator and the balance of water for injection; the pH regulator is used for regulating the pH value, the pH regulator is a sodium hydroxide solution/hydrochloric acid solution, and the dosage of the pH regulator is based on regulating the pH value of the injection to 6.8-7.6.
Example 2
The topiroxostat injection comprises the following components in parts by weight: topiroxostat 20mg/mL, absolute ethyl alcohol 50mg/mL, a pH regulator and the balance of water for injection; the pH regulator is used for regulating the pH value, the pH regulator is a sodium hydroxide solution/hydrochloric acid solution, and the dosage of the pH regulator is based on regulating the pH value of the injection to 6.8-7.6.
Example 3
The topiroxostat injection comprises the following components in parts by weight: topiroxostat 20mg/mL, absolute ethyl alcohol 100mg/mL, a pH regulator and the balance of water for injection; the pH regulator is used for regulating the pH value, the pH regulator is a sodium hydroxide solution/hydrochloric acid solution, and the dosage of the pH regulator is based on regulating the pH value of the injection to 6.8-7.6.
Compared with the dissolution of the above examples, topiroxostat can be effectively dissolved in absolute ethyl alcohol with a corresponding proportion, adverse reaction caused by excessive absolute ethyl alcohol in the injection process is considered, and the dosage of the absolute ethyl alcohol is determined to be 10 mg/mL.
Example 4
After the ampoule is taken off the outer packing bottle, the ampoule is sent into a bottle washing room, the ampoule is washed by injection water through an ultrasonic washing machine and then enters a tunnel sterilization dryer with the heating section temperature of 310 ℃ through a conveying belt with the running speed of 50Hz for drying and sterilization.
Example 5
After the ampoule is taken off the outer packing bottle, the ampoule is sent into a bottle washing room, the ampoule is washed by injection water through an ultrasonic washing machine and then enters a tunnel sterilization dryer with the heating section temperature of 320 ℃ through a conveying belt with the running speed of 50Hz for drying and sterilization.
Example 6
After the ampoule is taken off the outer packing bottle, the ampoule is sent into a bottle washing room, the ampoule is washed by injection water through an ultrasonic washing machine and then enters a tunnel sterilization dryer with the heating section temperature of 330 ℃ for drying and sterilization through a conveying belt with the running speed of 50 Hz.
The ampoule after sterilization in the above embodiment is tested and dried and sterilized by a tunnel sterilization dryer at 320 ℃ under the optimal process conditions, no microorganism is detected, and the ampoule bottle treatment process in the preparation method is determined as follows: the ampoule is cleaned by water for injection through an ultrasonic cleaning machine and then dried and sterilized at the temperature of 320 ℃.
Example 7
The raw material components are prepared according to the components and contents in the example 1, and the ampoule is cleaned by the water for injection through an ultrasonic cleaning machine and then dried and sterilized at the temperature of 320 ℃. Adding topiroxostat into absolute ethyl alcohol, dissolving and stirring uniformly, adding a mixed solution of topiroxostat and absolute ethyl alcohol into injection water cooled to be below 30 ℃, stirring uniformly, adjusting the pH to be 6.9 by using a pH regulator, fixing the volume by using the injection water cooled to be below 30 ℃, stirring for 30min at the stirring speed of 350rpm by using a stirring device, filtering by using a 0.22um sterilizing filter, filling into an ampoule, and sealing.
Example 8
The raw material components are prepared according to the components and contents in the example 1, and the ampoule is cleaned by the water for injection through an ultrasonic cleaning machine and then dried and sterilized at the temperature of 320 ℃. Adding topiroxostat into absolute ethyl alcohol, dissolving and stirring uniformly, adding a mixed solution of topiroxostat and absolute ethyl alcohol into injection water cooled to be below 30 ℃, stirring uniformly, adjusting the pH to 7.2 by using a pH regulator, fixing the volume by using the injection water cooled to be below 30 ℃, stirring for 30min at the stirring speed of 350rpm by using a stirring device, filtering by using a 0.22um sterilizing filter, filling into an ampoule, and sealing.
Example 9
The raw material components are prepared according to the components and contents in the example 1, and the ampoule is cleaned by the water for injection through an ultrasonic cleaning machine and then dried and sterilized at the temperature of 320 ℃. Adding topiroxostat into absolute ethyl alcohol, dissolving and stirring uniformly, adding a mixed solution of topiroxostat and absolute ethyl alcohol into injection water cooled to be below 30 ℃, stirring uniformly, adjusting the pH to be 7.6 by using a pH regulator, fixing the volume by using the injection water cooled to be below 30 ℃, stirring for 30min at the stirring speed of 350rpm by using a stirring device, filtering by using a 0.22um sterilizing filter, filling into an ampoule, and sealing.
TABLE 1 results of comparing the contents of topiroxostat injections prepared in examples 7 to 9
Example 10
An ampoule of topiroxostat injection prepared in example 8 was taken, and subjected to sterilization treatment under the following conditions: sterilizing at 110 deg.C for 20 min.
Example 11
An ampoule of topiroxostat injection prepared in example 8 was taken, and subjected to sterilization treatment under the following conditions: sterilizing at 110 deg.C for 30 min.
Example 12
An ampoule of topiroxostat injection prepared in example 8 was taken, and subjected to sterilization treatment under the following conditions: sterilizing at 110 deg.C for 40 min.
TABLE 2 comparison of Topiroxostat injection contents and sterilization effects after sterilization in examples 10-12
Comparing the content and the sterilization effect of the topiroxostat injection in the ampoule after the sterilization of the examples 10-12, the sterilization effect can not be achieved when the sterilization is carried out at the temperature of 90 ℃, and the sterilization is carried out at the temperature of 110 ℃, so that the sterilization temperature is high, the content percentage of the topiroxostat injection is obviously reduced, and the content of related impurities is increased.
For comprehensive comparison, the preparation method of the topiroxostat injection comprises the following steps: preparing raw material components according to the dosage, adding topiroxostat into absolute ethyl alcohol for dissolving and uniformly stirring, adding the mixed solution of the topiroxostat and the absolute ethyl alcohol into injection water cooled to be below 30 ℃, uniformly stirring, adjusting the pH to 7.2 +/-0.5 by using a pH regulator, fixing the volume by using the injection water, stirring for 30min at the stirring speed of 300-350 rpm, filtering by using a sterilizing filter, filling into an ampoule, sealing, and sterilizing to obtain the topiroxostat injection.
The topiroxostat injection has the advantages of single and stable raw and auxiliary materials, definite curative effect and good quality. The preparation method in the method is suitable for expanded production.
Claims (6)
1. The topiroxostat injection for treating gout is characterized by comprising the following components of 20mg/mL of topiroxostat, 10-100mg/mL of absolute ethyl alcohol, a pH regulator and the balance of water for injection; the pH regulator is used for regulating the pH value of the injection, the pH regulator is a sodium hydroxide solution/hydrochloric acid solution, and the dosage of the pH regulator is based on regulating the pH value of the injection to 6.8-7.6.
2. The topiroxostat injection according to claim 1, wherein the topiroxostat injection comprises the following components in percentage by weight: topiroxostat 20mg/mL, absolute ethyl alcohol 10mg/mL, a pH regulator and the balance of water for injection; the pH regulator is used for regulating the pH value of the injection, the pH regulator is a sodium hydroxide solution/hydrochloric acid solution, and the dosage of the pH regulator is based on regulating the pH value of the injection to 6.8-7.6.
3. A method for preparing topiroxostat injection according to claim 1 or 2, comprising the steps of: preparing raw material components according to dosage, adding topiroxostat into absolute ethyl alcohol for dissolving and uniformly stirring, adding the mixed solution into injection water cooled to be below 30 ℃, uniformly stirring, adjusting the pH to be 7.2 +/-0.5 by using a pH regulator, fixing the volume by using the injection water cooled to be below 30 ℃, stirring at the stirring speed of 300-350 rpm for 20-40 min, filtering by using a sterilizing filter, filling into an ampoule, sealing, and sterilizing to obtain the topiroxostat injection.
4. The preparation method of topiroxostat injection according to claim 3, wherein the sterilization condition is that the sterilization is carried out at 90-110 ℃ for 20-30 min.
5. The method for preparing topiroxostat injection according to claim 3, further comprising an ampoule treatment process, wherein the process comprises: the ampoule is cleaned by injection water through an ultrasonic cleaning machine, and then dried and sterilized at the temperature of 310-330 ℃.
6. The method for producing topiroxostat injection according to claim 3, wherein the filtration precision of the sterilizing filter is 0.22 um.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010381278.3A CN111544378A (en) | 2020-05-08 | 2020-05-08 | Topiroxostat injection for treating gout and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010381278.3A CN111544378A (en) | 2020-05-08 | 2020-05-08 | Topiroxostat injection for treating gout and preparation method thereof |
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| Publication Number | Publication Date |
|---|---|
| CN111544378A true CN111544378A (en) | 2020-08-18 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010381278.3A Withdrawn CN111544378A (en) | 2020-05-08 | 2020-05-08 | Topiroxostat injection for treating gout and preparation method thereof |
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| CN (1) | CN111544378A (en) |
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2020
- 2020-05-08 CN CN202010381278.3A patent/CN111544378A/en not_active Withdrawn
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Application publication date: 20200818 |
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