CN113230210A - Preparation method of pamidronate disodium injection - Google Patents
Preparation method of pamidronate disodium injection Download PDFInfo
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- CN113230210A CN113230210A CN202110631529.3A CN202110631529A CN113230210A CN 113230210 A CN113230210 A CN 113230210A CN 202110631529 A CN202110631529 A CN 202110631529A CN 113230210 A CN113230210 A CN 113230210A
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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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- 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
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
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- 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
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- 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
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- 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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Abstract
The invention discloses a pamidronate disodium injection, wherein the pH value of the pamidronate disodium injection is 5.5-6.7, and the pamidronate disodium injection comprises pamidronate disodium, glycine and cane sugar in a mass ratio of 1:0.05-0.40: 0.1-0.6. The invention also discloses a preparation method of the pamidronate disodium injection, which comprises the following steps: dissolving glycine and sucrose in water according to a ratio, and stirring to dissolve the glycine and the sucrose to obtain a uniform solution; adding pamidronate disodium, and stirring to dissolve the pamidronate disodium; then, dropwise adding a phosphoric acid-phosphoric acid citric acid buffer solution, and adjusting the pH value of the solution to 5.5-6.7; and finally, filtering and sterilizing by using a microporous filter membrane, and filling to obtain the pamidronate disodium injection. The pamidronate disodium injection provided by the invention has high stability, and solves the problems of poor stability and difficult storage of the existing pamidronate disodium injection.
Description
Technical Field
The invention relates to the technical field of injection preparation, and particularly relates to a pamidronate disodium injection and a preparation method thereof.
Background
Malignant tumor with bone metastasis, such as renal carcinoma, pancreatic cancer, head and neck tumor, esophageal squamous carcinoma, lung cancer and cervical cancer, etc., can secrete osteolytic factor, promote bone absorption, and increase blood calcium. Malignant tumor with osteolytic metastasis, which is often seen in breast cancer, kidney cancer, lung cancer, prostate cancer and the like, osteolytic metastasis, mass bone destruction, and calcium released by the osteolytic metastasis exceeds the calcium clearing capacity of the kidney and intestines. Osteoclast stimulating factor (osteoclast stimulating factor) is secreted by multiple myeloma, leukemia and lymphoma, etc., to promote bone lysis and increase blood calcium.
Disodium Pamidronate (Pamidronate disodium) is a second generation bisphosphonate class of drugs with an action strength of about 100 times that of etidronate sodium. The pharmacological action is as follows: the bone repair liquid is widely distributed on the surface of a trabecular bone to prevent osteoclasts from dissolving the bone; ② inhibiting osteoclast activity; and inhibiting the transformation of osteoclast precursor to osteoclast. Has remarkable inhibitory effect on bone absorption, and has analgesic effect on pain caused by osteolytic bone metastasis of cancer. Animal experiments show that the pamidronate disodium has an analgesic effect on pain caused by osteolytic bone metastasis of cancer, and can be used for treating hypercalcemia caused by cancer.
At present, the administration route of pamidronate disodium is intravenous injection, and the dosage forms in the market mainly comprise injection and freeze-dried powder injection. Because of the poor stability of pamidronate disodium, the injection is not suitable for long-term storage and is extremely inconvenient to transport. The freeze-dried powder injection has relatively high stability, but still has the problems of high content of related substances, poor re-solubility and the like after long-term storage, and the use safety and the effect of the medicine are seriously influenced.
Disclosure of Invention
The invention aims to solve the technical problem of providing the pamidronate disodium injection and the preparation method thereof, the pamidronate disodium injection has high stability, and the problems of poor stability and difficult storage of the existing pamidronate disodium injection are solved.
In order to solve the technical problems, the invention provides the following technical scheme:
the invention provides a pamidronate disodium injection, wherein the pH value of the pamidronate disodium injection is 5.5-6.7, and the pamidronate disodium injection comprises pamidronate disodium, glycine and sucrose in a mass ratio of 1:0.05-0.40: 0.1-0.6.
In a preferred embodiment of the invention, the pH of the pamidronate disodium injection is adjusted to 5.5-6.7 by a phosphoric acid-phosphoric acid citric acid buffer solution.
In a preferred embodiment of the invention, in the pamidronate disodium injection, the mass ratio of the pamidronate disodium, the glycine and the sucrose is 1:0.12-0.30: 0.3-0.5.
In a preferred embodiment of the invention, in the pamidronate disodium injection, the mass ratio of pamidronate disodium, glycine and sucrose is 1:0.15: 0.3.
In a preferred embodiment of the invention, the pH of the pamidronate disodium injection is adjusted to 5.8-6.5 by a phosphoric acid-phosphoric acid citric acid buffer solution.
In a preferred embodiment of the invention, in the pamidronate disodium injection, the concentration of pamidronate disodium is 0.1mg/mL, the concentration of glycine is 15-25 μ g/mL, and the concentration of sucrose is 30-45 μ g/mL.
The second aspect of the invention provides a preparation method of the pamidronate disodium injection, which comprises the following steps:
dissolving glycine and sucrose in water according to a ratio, and stirring to dissolve the glycine and the sucrose to obtain a uniform solution; adding pamidronate disodium, and stirring to dissolve the pamidronate disodium; then, dropwise adding a phosphoric acid-phosphoric acid citric acid buffer solution, and adjusting the pH value of the solution to 5.5-6.7; and finally, filtering and sterilizing by using a microporous filter membrane, and filling to obtain the pamidronate disodium injection.
In a preferred embodiment of the present invention, the pore size of the microfiltration membrane is 0.22 μm.
Compared with the prior art, the invention has the beneficial effects that:
the pamidronate disodium injection disclosed by the invention can effectively inhibit the degradation of pamidronate disodium in a solution by adding a trace amount of glycine; in addition, compared with the traditional pH regulator, the invention adopts the phosphoric acid-phosphoric acid citric acid buffer solution as the pH regulator, can better control the stability of the pH in the injection and also improves the stability of the injection to a certain extent.
Detailed Description
The present invention is further described below in conjunction with specific examples to enable those skilled in the art to better understand the present invention and to practice it, but the examples are not intended to limit the present invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
The experimental methods used in the following examples are conventional methods unless otherwise specified, and materials, reagents and the like used therein are commercially available without otherwise specified.
Example 1
The embodiment provides a pamidronate disodium injection, the pH of the pamidronate disodium injection is 5.8, and the pamidronate disodium injection comprises pamidronate, glycine and sucrose, the concentration of the pamidronate disodium is 0.1mg/mL, the concentration of the glycine is 16 mug/mL, and the concentration of the sucrose is 41 mug/mL.
The preparation method of the pamidronate disodium injection comprises the following steps: taking 500mL of ultrapure water, weighing glycine and sucrose according to a ratio, dissolving in water, and stirring to dissolve to obtain a uniform solution; adding pamidronate disodium, and stirring to dissolve the pamidronate disodium; then, dropwise adding a phosphoric acid-phosphoric acid citric acid buffer solution, and adjusting the pH value of the solution to 5.8; and finally, filtering and sterilizing by using a 0.22-micron microporous filter membrane, filling into a penicillin bottle, and sterilizing, corking and capping to obtain the pamidronate disodium injection.
Example 2
The embodiment provides a pamidronate disodium injection, the pH of which is 6.2, wherein the pamidronate disodium injection comprises pamidronate disodium, glycine and sucrose, the concentration of the pamidronate disodium is 0.1mg/mL, the concentration of the glycine is 22 mug/mL, and the concentration of the sucrose is 36 mug/mL.
The preparation method of the pamidronate disodium injection comprises the following steps: taking 500mL of ultrapure water, weighing glycine and sucrose according to a ratio, dissolving in water, and stirring to dissolve to obtain a uniform solution; adding pamidronate disodium, and stirring to dissolve the pamidronate disodium; then, dropwise adding a phosphoric acid-phosphoric acid citric acid buffer solution, and adjusting the pH value of the solution to 6.2; and finally, filtering and sterilizing by using a 0.22-micron microporous filter membrane, filling into a penicillin bottle, and sterilizing, corking and capping to obtain the pamidronate disodium injection.
Example 3
The embodiment provides a pamidronate disodium injection, the pH of which is 6.5, wherein the pamidronate disodium injection comprises pamidronate disodium, glycine and sucrose, the concentration of the pamidronate disodium is 0.1mg/mL, the concentration of the glycine is 24 mug/mL, and the concentration of the sucrose is 32 mug/mL.
The preparation method of the pamidronate disodium injection comprises the following steps: taking 500mL of ultrapure water, weighing glycine and sucrose according to a ratio, dissolving in water, and stirring to dissolve to obtain a uniform solution; adding pamidronate disodium, and stirring to dissolve the pamidronate disodium; then, dropwise adding a phosphoric acid-phosphoric acid citric acid buffer solution, and adjusting the pH value of the solution to 6.5; and finally, filtering and sterilizing by using a 0.22-micron microporous filter membrane, filling into a penicillin bottle, and sterilizing, corking and capping to obtain the pamidronate disodium injection.
Example 4
The embodiment provides a pamidronate disodium injection, the pH of the pamidronate disodium injection is 6.0, and the pamidronate disodium injection comprises pamidronate, glycine and sucrose, the concentration of the pamidronate disodium is 0.1mg/mL, the concentration of the glycine is 18 mug/mL, and the concentration of the sucrose is 44 mug/mL.
The preparation method of the pamidronate disodium injection comprises the following steps: taking 500mL of ultrapure water, weighing glycine and sucrose according to a ratio, dissolving in water, and stirring to dissolve to obtain a uniform solution; adding pamidronate disodium, and stirring to dissolve the pamidronate disodium; then, dropwise adding a phosphoric acid-phosphoric acid citric acid buffer solution, and adjusting the pH value of the solution to 6.0; and finally, filtering and sterilizing by using a 0.22-micron microporous filter membrane, filling into a penicillin bottle, and sterilizing, corking and capping to obtain the pamidronate disodium injection.
Comparative example 1
The comparative example provides a disodium pamidronate injection, the pH of the disodium pamidronate injection is 5.8, the disodium pamidronate injection comprises disodium pamidronate and sucrose, the concentration of the disodium pamidronate is 0.1mg/mL, and the concentration of the sucrose is 41 mug/mL.
The preparation method of the pamidronate disodium injection of the comparative example comprises the following steps: taking 500mL of ultrapure water, weighing sucrose according to a ratio, dissolving the sucrose in water, and stirring to dissolve the sucrose to obtain a uniform solution; adding pamidronate disodium, and stirring to dissolve the pamidronate disodium; then, dropwise adding a phosphoric acid-phosphoric acid citric acid buffer solution, and adjusting the pH value of the solution to 5.8; and finally, filtering and sterilizing by using a 0.22-micron microporous filter membrane, filling into a penicillin bottle, and sterilizing, corking and capping to obtain the pamidronate disodium injection.
Comparative example 2
The embodiment provides a pamidronate disodium injection, the pH of the pamidronate disodium injection is 5.8, and the pamidronate disodium injection comprises pamidronate, glycine and sucrose, the concentration of the pamidronate disodium is 0.1mg/mL, the concentration of the glycine is 16 mug/mL, and the concentration of the sucrose is 41 mug/mL.
The preparation method of the pamidronate disodium injection comprises the following steps: taking 500mL of ultrapure water, weighing glycine and sucrose according to a ratio, dissolving in water, and stirring to dissolve to obtain a uniform solution; adding pamidronate disodium, and stirring to dissolve the pamidronate disodium; then, dropwise adding a phosphoric acid solution, and adjusting the pH value of the solution to 5.8; and finally, filtering and sterilizing by using a 0.22-micron microporous filter membrane, filling into a penicillin bottle, and sterilizing, corking and capping to obtain the pamidronate disodium injection.
Stability test
The pamidronate injection solutions of examples 1 to 4 and comparative examples 1 to 2 were placed in a cool and dry place for 6 months, and the contents of the phosphite and the beta-alanine in the injection solutions were measured, and the results are shown in the following table.
From the results in the table, it can be seen that the contents of phosphite and beta-alanine in the pamidronate disodium injection of examples 1-4 of the invention are significantly lower than those in comparative examples 1-2 after standing for 6 months, which indicates that glycine added to the pamidronate disodium injection of the invention and the phosphoric acid-citric acid buffer used can effectively inhibit the degradation of pamidronate disodium and improve the long-term storage stability of the pamidronate disodium injection.
The above-mentioned embodiments are merely preferred embodiments for fully illustrating the present invention, and the scope of the present invention is not limited thereto. The equivalent substitution or change made by the technical personnel in the technical field on the basis of the invention is all within the protection scope of the invention. The protection scope of the invention is subject to the claims.
Claims (8)
1. The disodium pamidronate injection is characterized in that the pH of the disodium pamidronate injection is 5.5-6.7, wherein the disodium pamidronate injection comprises disodium pamidronate, glycine and sucrose in a mass ratio of 1:0.05-0.40: 0.1-0.6.
2. The disodium pamidronate injection of claim 1, wherein the pH of the disodium pamidronate injection is adjusted to 5.5-6.7 by a phospho-citric acid buffer.
3. The disodium pamidronate injection as claimed in claim 1, wherein the mass ratio of disodium pamidronate, glycine and sucrose in the disodium pamidronate injection is 1:0.12-0.30: 0.3-0.5.
4. The disodium pamidronate injection as claimed in claim 1, wherein the mass ratio of disodium pamidronate, glycine and sucrose in the disodium pamidronate injection is 1:0.15: 0.3.
5. The disodium pamidronate injection of claim 1, wherein the pH of the disodium pamidronate injection is adjusted to 5.8-6.5 by a phospho-citric acid buffer.
6. The disodium pamidronate injection of claim 1, wherein the disodium pamidronate injection has a concentration of 0.1mg/mL, the concentration of glycine is 15-25 μ g/mL, and the concentration of sucrose is 30-45 μ g/mL.
7. The preparation method of the pamidronate injection according to claim 1, comprising the following steps:
dissolving glycine and sucrose in water according to a ratio, and stirring to dissolve the glycine and the sucrose to obtain a uniform solution; adding pamidronate disodium, and stirring to dissolve the pamidronate disodium; then, dropwise adding a phosphoric acid-phosphoric acid citric acid buffer solution, and adjusting the pH value of the solution to 5.5-6.7; and finally, filtering and sterilizing by using a microporous filter membrane, and filling to obtain the pamidronate disodium injection.
8. The method for preparing disodium pamidronate injection according to claim 7, wherein the pore size of the microporous filter membrane is 0.22 μm.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202110631529.3A CN113230210B (en) | 2021-06-07 | 2021-06-07 | Preparation method of pamidronate disodium injection |
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| CN202110631529.3A CN113230210B (en) | 2021-06-07 | 2021-06-07 | Preparation method of pamidronate disodium injection |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103040766A (en) * | 2013-01-10 | 2013-04-17 | 罗诚 | Drug composition containing pamidronate disodium compound |
| CN105147707A (en) * | 2015-08-20 | 2015-12-16 | 南京正大天晴制药有限公司 | Disodium pamidronate and glucose injection and preparation method thereof |
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- 2021-06-07 CN CN202110631529.3A patent/CN113230210B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103040766A (en) * | 2013-01-10 | 2013-04-17 | 罗诚 | Drug composition containing pamidronate disodium compound |
| CN105147707A (en) * | 2015-08-20 | 2015-12-16 | 南京正大天晴制药有限公司 | Disodium pamidronate and glucose injection and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 杨红梅: "《药剂学》", 31 July 2020, 天津科学技术出版社 * |
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