CN113952294A - Zoledronic acid injection and preparation method thereof - Google Patents

Zoledronic acid injection and preparation method thereof Download PDF

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Publication number
CN113952294A
CN113952294A CN202011562403.7A CN202011562403A CN113952294A CN 113952294 A CN113952294 A CN 113952294A CN 202011562403 A CN202011562403 A CN 202011562403A CN 113952294 A CN113952294 A CN 113952294A
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zoledronic acid
injection
solution
prescription
regulator
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Chinese (zh)
Inventor
李娟�
狄绍炎
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Changzhou Fangyuan Pharmaceutical Co ltd
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Changzhou Fangyuan Pharmaceutical Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/00—Medicinal preparations characterised by special physical form
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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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • 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
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

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Abstract

The invention discloses a zoledronic acid injection and a preparation method thereof, which consists of zoledronic acid, an osmotic pressure regulator, a pH regulator and water for injection; the injection is prepared according to the following steps: firstly, dissolving a prescription amount of osmotic pressure regulator in water for injection; adding a pH regulator sodium citrate with a prescription amount into the solution obtained in the step I; adding a prescribed amount of zoledronic acid monohydrate into the solution obtained in the step two; adding water for injection to the prescription amount, and filtering with a filter membrane to obtain a zoledronic acid injection prescription solution, wherein the pH value of the solution is 6.0-6.7; fifthly, filling the prescription solution in the step IV, filling nitrogen and sterilizing. The whole preparation process of the zoledronic acid injection only uses one liquid preparation tank, the length of a connecting pipeline is shortened, the possibility of liquid medicine pollution is reduced, active carbon is not needed in the whole production process, and the safety of the medicine is improved.

Description

Zoledronic acid injection and preparation method thereof
Technical Field
The invention relates to a zoledronic acid preparation, in particular to a zoledronic acid injection and a preparation method thereof.
Background
Zoledronic acid (zoledronic acid) is an isocyclic third-generation bisphosphonate drug for treating hypercalcemia, and has the chemical name of 1-hydroxy-2- (1-imidazolyl) ethylene-1, 1-diphosphonic acid. Compared with the first generation of bisphosphonate medicines (clodronate and etidronate sodium) and the second generation of bisphosphonate medicines (tiludronate and ammonia hydroxypropyl bisphosphonate), the compound has better titer intensity, long action time and small administration dosage. Zoledronic acid, a specific bone-acting bisphosphonate, inhibits bone resorption due to increased osteoclastic activity, but has no adverse effect on bone formation, mineralization and mechanical properties, and is mainly used for treating hypercalcemia (TIH or HCM) caused by tumors, inhibiting bone metastasis caused by tumors and osteoporosis in menopausal women.
Regarding the preparation of zoledronic acid injection, chinese patent document CN110812324A provides a production process of zoledronic acid injection, which comprises the following steps: (1) preparing an osmotic pressure regulator solution: dissolving the osmotic pressure regulator in the prescribed amount with water for injection, adding medicinal carbon, and decarburizing to obtain osmotic pressure regulator solution; (2) preparing a zoledronic acid and pH regulator solution: dissolving zoledronic acid and a pH regulator in a prescribed amount by using water for injection to obtain a zoledronic acid and pH regulator solution; (3) preparation of a prescription solution: uniformly mixing the obtained osmotic pressure regulator solution, zoledronic acid and pH regulator solution, fixing the volume to the prescription volume by using water for injection, and filtering to obtain zoledronic acid prescription solution, wherein the pH value is 6.2-6.8; (4) and (3) sterilization and packaging: and (4) filling the zoledronic acid prescription solution obtained in the step (3), sterilizing and packaging to obtain the zoledronic acid.
Chinese patent document CN104721132B discloses a zoledronic acid injection and its preparation method: (1) dissolution of zoledronic acid: dissolving sodium citrate in water for injection, adding zoledronic acid monohydrate in a prescribed amount, and stirring to dissolve the zoledronic acid monohydrate to obtain a zoledronic acid dissolved solution; (2) dissolving the osmotic pressure regulator in the prescription amount in water for injection, adding activated carbon, decarburizing and filtering to obtain an osmotic pressure regulator solution 2; (3) uniformly mixing zoledronic acid solution and osmotic pressure regulator solution, and fixing the volume to the prescribed amount to obtain zoledronic acid injection; filling and sterilizing: and (5) filling and sterilizing after the product is qualified.
Chinese patent document CN 105232451B discloses an injection composition containing zoledronic acid, which takes zoledronic acid as a main drug component and consists of an osmotic pressure regulator, a pH regulator and water for injection. The injection can be further prepared by the following steps: 1) taking zoledronic acid raw material medicine, and crushing for later use; 2) taking water for injection with the total volume of 80%, and sequentially dissolving a pH regulator and an osmotic pressure regulator; 3) adding the zoledronic acid bulk drug powder obtained in the step 1) into the solution obtained in the step 2), and stirring to dissolve the zoledronic acid bulk drug powder to obtain a drug-containing solution I; 4) adding water for injection to full dose to the drug-containing solution I obtained in the step 3), and adjusting the pH value to obtain a drug-containing solution II; 5) taking the medicine-containing solution II obtained in the step 4), adsorbing pyrogen by 0.2% of activated carbon, and filtering to obtain a medicine-containing solution III; 6) filling the drug-containing solution obtained in the step 5) into a medium borosilicate glass injection bottle, plugging, and pricking an aluminum cover to obtain a semi-finished product of the zoledronic acid injection; 7) and (3) sterilizing the semi-finished product of the zoledronic acid injection obtained in the step 6) by a flow steam sterilization method at the temperature of 121 ℃ to ensure that the F0 value is larger than 8.0, thus obtaining the finished product of the zoledronic acid injection.
The above patents all use active carbon in the preparation of injections, and clearly stipulate "technical requirements for evaluating the quality of imitation drugs and the consistency of curative effect of chemical injections issued by CDE" that active carbon is not used in the production of injections ". The invention aims at the defects in the patents and improves the prescription and the production process.
Disclosure of Invention
The invention aims to solve the technical problem of providing a zoledronic acid injection with high safety and a preparation method thereof.
The technical scheme for realizing the first purpose of the invention is a zoledronic acid injection which consists of zoledronic acid, an osmotic pressure regulator, a pH regulator and water for injection; the injection is prepared according to the following steps: firstly, dissolving a prescribed amount of osmotic pressure regulator glucose in water for injection; adding a pH regulator sodium citrate with a prescription amount into the solution obtained in the step I, and stirring until the solution is completely dissolved; adding the zoledronic acid monohydrate with the prescription amount into the solution obtained in the step two, and stirring until the zoledronic acid monohydrate is completely dissolved; adding water for injection to the prescription amount, and filtering through a 0.22 mu m filter membrane to obtain a prescription solution of the zoledronic acid injection, wherein the pH value of the solution is 6.0-6.7; fifthly, filling the prescription solution in the step IV, filling nitrogen and sterilizing.
The osmotic pressure regulator is one of mannitol, sodium chloride and glucose.
The pH regulator is sodium citrate.
The preparation method comprises the following steps of dissolving the osmotic pressure regulator glucose with the prescription amount into 80% of water for injection.
The technical scheme for realizing the second purpose of the invention is a preparation method of zoledronic acid injection, which comprises the following steps:
firstly, glucose as an osmotic pressure regulator is dissolved in the water for injection according to the prescription amount.
And secondly, adding a pH regulator sodium citrate with the prescription amount into the solution obtained in the step I, and stirring until the solution is completely dissolved.
And thirdly, adding the zoledronic acid monohydrate with the prescription amount into the solution obtained in the second step, and stirring until the zoledronic acid monohydrate is completely dissolved.
And fourthly, adding water for injection to the prescription amount, and filtering the mixture through a 0.22 mu m filter membrane to obtain the prescription solution of the zoledronic acid injection, wherein the pH value of the solution is 6.0-6.7.
Fifthly, filling the prescription solution in the step IV, filling nitrogen and sterilizing.
The osmotic pressure regulator is one of mannitol, sodium chloride and glucose.
The pH regulator is sodium citrate.
In the fifth step, sterilization is carried out at 121 ℃/15min under hot pressure.
The invention has the positive effects that: the whole preparation process of the zoledronic acid injection only uses one liquid preparation tank, the length of a connecting pipeline is shortened, the possibility of liquid medicine pollution is reduced, active carbon is not needed in the whole production process, and the safety of the medicine is improved.
Detailed Description
(example 1)
This example prepares zoledronic acid injection (5 mg: 100 mL) 10 as follows:
zoledronic acid 50mg
Glucose 50g
Sodium citrate 300mg
The volume of the water for injection is up to 1000 mL.
The preparation method comprises the following steps:
firstly, glucose as an osmotic pressure regulator is dissolved in 80 percent of water for injection according to the prescription amount.
And secondly, adding a pH regulator sodium citrate with the prescription amount into the solution obtained in the step I, and stirring until the solution is completely dissolved.
And thirdly, adding the zoledronic acid monohydrate with the prescription amount into the solution obtained in the second step, and stirring until the zoledronic acid monohydrate is completely dissolved.
And fourthly, adding water for injection to the prescription amount, and filtering the mixture through a 0.22 mu m filter membrane to obtain the prescription solution of the zoledronic acid injection, wherein the pH value of the solution is 6.0-6.7.
Fifthly, filling the prescription solution in the step IV according to 100mL per bottle, filling nitrogen, sterilizing under high pressure (121 ℃/15 min), and finally packaging.
(example 2)
This example prepares zoledronic acid injection (5 mg: 100 mL) 10 as follows:
zoledronic acid 50mg
Sodium chloride 9g
Sodium citrate 300mg
The volume of the water for injection is up to 1000 mL.
The preparation process is referred to example 1.
(example 3)
This example prepares zoledronic acid injection (5 mg: 100 mL) 10 as follows:
zoledronic acid 50mg
Mannitol 49.5g
Sodium citrate 300mg
The volume of the water for injection is up to 1000 mL.
The preparation process is referred to example 1.
(example 4)
This example prepares zoledronic acid injection (4 mg: 5 mL) 200 as follows:
zoledronic acid 800mg
Mannitol 44g
Sodium citrate 4.8g
The volume of the water for injection is up to 1000 mL.
Preparation method referring to example 1, the bottles were filled with 5mL of each bottle.
(example 5)
This example prepares zoledronic acid injection (4 mg: 5 mL) 200 as follows:
zoledronic acid 800mg
Sodium chloride 9g
Sodium citrate 4.8g
The volume of the water for injection is up to 1000 mL.
Preparation method referring to example 1, the bottles were filled with 5mL of each bottle.
(example 6)
This example prepares zoledronic acid injection (4 mg: 5 mL) 200 as follows:
zoledronic acid 800mg
Glucose 50g
Sodium citrate 4.8g
The volume of the water for injection is up to 1000 mL.
Preparation method referring to example 1, the bottles were filled with 5mL of each bottle.
Comparative example 1
This example prepares zoledronic acid injection (5 mg: 100 mL) 10 as follows:
zoledronic acid 50mg
Glucose 50g
Sodium citrate 300mg
The volume of the water for injection is up to 1000 mL.
The preparation method comprises the following steps:
firstly, dissolving the prescribed amount of glucose serving as an osmotic pressure regulator in 80% of water for injection, adding medicinal charcoal, and decarburizing to obtain an osmotic pressure regulator solution.
② the zoledronic acid and pH regulator solution is obtained by dissolving the prescribed amount of zoledronic acid and pH regulator with water for injection.
Mixing the obtained osmotic pressure regulator solution, zoledronic acid and pH regulator solution uniformly, fixing the volume to the prescription volume by using water for injection, and filtering to obtain zoledronic acid prescription solution, wherein the pH of the solution is 6.0-6.7.
And fourthly, filling 100mL of the solution in the formula in the third step into each bottle, filling nitrogen, sterilizing (15 min at 121 ℃), and finally packaging.
The samples of examples 1-6 and comparative example 1 were subjected to the influence factor test: stability under accelerated conditions of 12 days of illumination, 60 ℃ for one month at high temperature and 40 ℃ for three months, the results are shown in the following table 1:
TABLE 1
Figure 948361DEST_PATH_IMAGE001
As can be seen from Table 1, the zoledronic acid injection prepared by the method of the present invention has good stability.
In addition, only one liquid preparation tank is used in the whole preparation process of the zoledronic acid injection, the length of a connecting pipeline is shortened, the possibility of pollution of liquid medicine is reduced, active carbon is not needed in the whole production process, and the safety of the medicine is improved.

Claims (8)

1. The zoledronic acid injection is characterized by consisting of zoledronic acid, an osmotic pressure regulator, a pH regulator and water for injection; the injection is prepared according to the following steps: firstly, dissolving a prescription amount of osmotic pressure regulator in water for injection; adding a pH regulator sodium citrate with a prescription amount into the solution obtained in the step I, and stirring until the solution is completely dissolved; adding the zoledronic acid monohydrate with the prescription amount into the solution obtained in the step two, and stirring until the zoledronic acid monohydrate is completely dissolved; adding water for injection to the prescription amount, and filtering with a filter membrane to obtain a zoledronic acid injection prescription solution, wherein the pH value of the solution is 6.0-6.7; fifthly, filling the prescription solution in the step IV, filling nitrogen and sterilizing.
2. The zoledronic acid injection of claim 1, wherein: the osmotic pressure regulator is one of mannitol, sodium chloride and glucose.
3. The zoledronic acid injection of claim 1, wherein: the pH regulator is sodium citrate.
4. The zoledronic acid injection of claim 1, wherein: firstly, dissolving the osmotic pressure regulator glucose with the prescription amount in 80 percent of water for injection.
5. The preparation method of the zoledronic acid injection is characterized by comprising the following steps:
firstly, dissolving a prescribed amount of osmotic pressure regulator glucose in water for injection;
adding a pH regulator sodium citrate with a prescription amount into the solution obtained in the step I, and stirring until the solution is completely dissolved;
adding the zoledronic acid monohydrate with the prescription amount into the solution obtained in the step two, and stirring until the zoledronic acid monohydrate is completely dissolved;
adding water for injection to the prescription amount, and filtering through a 0.22 mu m filter membrane to obtain a prescription solution of the zoledronic acid injection, wherein the pH value of the solution is 6.0-6.7;
fifthly, filling the prescription solution in the step IV, filling nitrogen and sterilizing.
6. The method for preparing zoledronic acid injection as claimed in claim 5, wherein: the osmotic pressure regulator is one of mannitol, sodium chloride and glucose.
7. The method for preparing zoledronic acid injection as claimed in claim 5, wherein: the pH regulator is sodium citrate.
8. The method for preparing zoledronic acid injection as claimed in claim 5, wherein: in the fifth step, sterilization is carried out at 121 ℃/15min under hot pressure.
CN202011562403.7A 2020-12-25 2020-12-25 Zoledronic acid injection and preparation method thereof Pending CN113952294A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202011562403.7A CN113952294A (en) 2020-12-25 2020-12-25 Zoledronic acid injection and preparation method thereof

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Application Number Priority Date Filing Date Title
CN202011562403.7A CN113952294A (en) 2020-12-25 2020-12-25 Zoledronic acid injection and preparation method thereof

Publications (1)

Publication Number Publication Date
CN113952294A true CN113952294A (en) 2022-01-21

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Country Status (1)

Country Link
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