CN108261393B - Zoledronic acid-containing pharmaceutical composition for injection - Google Patents
Zoledronic acid-containing pharmaceutical composition for injection Download PDFInfo
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Abstract
The patent application of the invention provides a pharmaceutical composition for injection containing zoledronic acid, which has the advantages of simple prescription and process, and better stability and repeatability. And the preparation process is provided for preparing the injection. Thereby achieving the purpose of obviously enhancing the storage stability of the zoledronic acid injection. The preparation method of the pharmaceutical composition is simple, has good stability, and is easy for industrial production.
Description
The invention has application number 201510624755.3, application date 2015.09.27 and the name "a zoledronic acid-containing composition for injection" as a divisional application of the patent.
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a zoledronic acid-containing composition for injection, and a preparation method and application thereof.
Background
The malignant tumor bone metastasis is the most common complication of advanced malignant tumor, and is mostly seen in breast cancer, prostate cancer and the like. The main mechanism of malignant tumor bone metastasis is that red bone marrow has rich blood supply, is favorable for tumor cells to reach local parts, generates adhesion molecules, is combined with bone trabeculae and bone matrix, generates bone absorption factors to promote the activation of osteoclasts, causes bone absorption, causes bone-related events such as aggravation of pain, hypercalcemia, pathological fracture of long bones or pelvic fracture, and paralysis is caused by spinal cord compression. Bone metastasis is also one of the common causes of death in cancer patients. Because accelerated osteolysis and inflammatory reaction are key factors for the occurrence and development of bone-related events, bisphosphonates are used as inhibitors of osteoclast activity, play a role in alleviating bone pain and the like by inhibiting bone mineralization or bone resorption, and have a certain anti-inflammatory effect.
Osteoporosis, the most common metabolic bone disease, can embrittle and weaken the bone, thereby increasing the risk of fractures, particularly of the vertebrae, ilium, carpal bones, pelvis, and upper arm. The national institute of health estimates that 1 in every 2 women over the age of 50 will experience at least 1 osteoporotic fracture for the rest of their lives, thereby greatly increasing the rate of injury, disability and even mortality. It is speculated that postmenopausal osteoporosis affects 2 hundred million people worldwide. Not only is osteoporosis a high incidence of disease affecting the health of elderly men, with an estimated approximately fifth of men over the age of 50 experiencing at least 1 osteoporotic fracture and higher mortality rates after fracture than women. Although the osteoporosis has serious consequences, the osteoporosis can be treated by treatment with bisphosphonate medicines and the like, so that the risk of osteoporosis fracture is effectively reduced. Bisphosphonates can prevent osteoporosis by inhibiting bone resorption and increasing bone mineral density by altering osteoclast activity and function.
The bisphosphonate medicine can be applied to treat malignant tumor bone metastasis and osteoporosis. Bisphosphonates have been successfully used in the treatment of bone calcium metabolism diseases and some bone related diseases since the development in the 80's 20 th century, and 3's have been developed so far, and in their clinical application, bisphosphonates were found to cause excessive bone suppression, in addition to gastrointestinal symptoms, and to cause hypocalcemia.
Zoledronic acid is a nitrogen heterocyclic ring bisphosphonate developed by Nuohua, Swiss, is a generation 3 bisphosphonate medicine, and in vitro and in vivo experiments show that zoledronic acid is a bisphosphonate medicine with the strongest pharmacological activity so far. The medicine is firstly marketed in 10 months in 2000, and can be used for treating malignant tumor bone metastasis. In 8 months 2007, the FDA approved a new indication for zoledronic acid for the treatment of osteoporosis in postmenopausal women and men at risk of fracture.
Zoledronic acid (Zoledronic acid), having the chemical name 1-hydroxy-2- (imidazol-1-yl) -ethylene-1, 1-diphosphonic acid, and having the formula:
the formulation is disclosed by Nowa company in the zoledronic acid injection product specification, as follows:
the zoledronic acid injection prepared by the prescription is researched and found that: in the production process, degradation products of imidazole acetic acid and other impurities are easily generated, and the degradation products of imidazole acetic acid are further degraded into imidazole and acetic acid along with the prolonging of storage time. This degradation seriously affects the stability of the drug and should be minimized as much as possible.
Chinese patent 201310709854.2 provides a zoledronic acid injection and its preparation method, which is to add one or two of imidazole acetic acid and imidazole, degradation products of zoledronic acid, to the prescription of zoledronic acid injection to stabilize the injection. However, the addition of impurities to the injection solution undoubtedly poses a challenge to the safety of the injection solution.
Disclosure of Invention
In view of the above-mentioned drawbacks of the prior art, the inventors have conducted extensive studies to obtain a zoledronic acid-containing composition for injection having a simple formulation and process, and having improved stability and reproducibility. And the preparation process is provided for preparing the injection. Thereby achieving the purpose of obviously enhancing the storage stability of the zoledronic acid injection.
The preparation method of the pharmaceutical composition is simple, has good stability, and is easy for industrial production.
The composition takes zoledronic acid as a main medicine 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 pH regulator is characterized in that the pH regulator is sodium acetate, and the pH value is 6.0-6.5.
Furthermore, the crushing operation is to crush the raw material medicine into fine powder, namely the obtained powder can completely pass through a 80-mesh sieve and contains not less than 95% of powder which can pass through a 100-mesh sieve.
The osmotic pressure regulator is glycerol, and the glycerol can play a role of a stabilizer, so that disqualification of visible foreign matters caused by precipitation of raw material medicines and other reasons in a long-term storage process is avoided.
The injection prescription of the patent is as follows:
the preparation method comprises the following steps:
1) taking zoledronic acid raw material medicine, and crushing the zoledronic acid raw material medicine into fine powder for later use;
2) sequentially dissolving sodium acetate and glycerol in 80% of total volume of water for injection;
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 the full amount of the drug-containing solution I obtained in the step 3), and adjusting the pH value to 6.0-6.5 by using 0.1M sodium acetate aqueous solution 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 injection of the patent further preferably has the following formula:
the preparation method comprises the following steps:
1) taking zoledronic acid raw material medicine, and crushing the zoledronic acid raw material medicine into fine powder for later use;
2) sequentially dissolving sodium acetate and glycerol in 80% of total volume of water for injection;
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 the full amount of the drug-containing solution I obtained in the step 3), and adjusting the pH value to 6.0-6.5 by using 0.1M sodium acetate aqueous solution 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 invention aims to increase the stability of zoledronic acid injection in the long-term storage process, reduce the degradation of zoledronic acid serving as a raw material drug in the storage process to generate imidazole acetic acid, and further degrade the imidazole acetic acid to generate imidazole and acetic acid. Sodium acetate is added into the injection, and the sodium acetate is dissociated into acetic acid and sodium ions under the acidic pH6.0-6.5 environment, so that free acetic acid effectively inhibits the degradation of imidazole acetic acid and further inhibits the degradation of zoledronic acid.
Meanwhile, after the zoledronic acid is prepared into injection, the raw material medicine is easy to separate out and generate insoluble particles after being stored for a long time, so that visible foreign matters are unqualified. Meanwhile, the glycerol is used as a micromolecule and also plays a role in osmotic pressure regulation.
The obtained zoledronic acid injection is simple in preparation method, can be produced by adopting a conventional preparation method, and has the remarkable advantages of easiness in industrialization, high production efficiency, good stability, controllable quality and the like. The patent application of the present invention is further illustrated by the following experiments.
Experiment one: prescription screening
According to the original design of the present patent application, sodium acetate is added to the zoledronic acid injection to enhance the storage stability of the solution while maintaining the pH of the injection. Adding glycerol to maintain osmotic pressure of the solution and inhibit crystallization of the raw materials to form insoluble particles.
The glycerol concentration was set at 4.95% to provide the majority of the osmotic pressure. Zoledronic acid and sodium acetate are used to provide osmotic pressure to the rest of the solution, maintaining the solution isotonic or hypertonic.
Meanwhile, the water solubility of the zoledronic acid serving as a raw material medicine is general, and the solubility of the zoledronic acid in an aqueous solution needs to be increased in a mode of reducing the particle size.
In order to increase the patient compliance, the stimulation to the injection site is minimized while maintaining the stability of the injection solution, and the pH of the injection solution is set to 6.0-6.5 in consideration of the buffer range of the sodium acetate solution.
The injection prescription is screened by the following prescription and process:
TABLE 1 zoledronic acid injection formulation screening
The preparation process comprises the following steps:
1) taking zoledronic acid raw material medicine, respectively crushing to medium powder, fine powder and finest powder for later use;
2) taking water for injection with the total volume of 80 percent, and sequentially dissolving sodium acetate and glycerol with the prescription amount;
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 the full amount of the drug-containing solution I obtained in the step 3), and adjusting the pH value to 6.0-6.5 by using 0.1M sodium acetate aqueous solution 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.
And (3) analyzing an experimental result:
in the screening experiment, the feasibility of the prescription is examined by taking the granularity of the raw material medicines of three levels of medium powder, fine powder and finest powder and the concentration of sodium acetate of 0.001M, 0.002M and 0.004M by taking the granularity of the raw material medicines and the dosage of sodium acetate as variables, and the experiment shows that when the granularity of the raw material medicines is fine powder and finest powder, the dissolution time is obviously shortened at the same stirring speed, about 10 minutes and about 6 minutes and about 4 minutes are required for dissolving the medium powder, and more energy is required for crushing the fine powder into the finest powder. When the concentration of sodium acetate is 0.001M, more 0.1M sodium acetate aqueous solution is needed for adjusting the pH value, and when the concentration of sodium acetate is increased to 0.002M or 0.004M, the 0.1M sodium acetate aqueous solution is needed properly, so from the viewpoint of saving materials, 0.002M sodium acetate is selected as the final concentration. In conclusion, the raw material medicine is ground into fine powder, and the first prescription with the sodium acetate concentration of 0.001M is selected as the optimal prescription.
And (3) popularizing the first prescription, and reducing the concentration of the raw material medicines to 0.8mg/ml and 0.05mg/ml to obtain the other two specifications of injection, wherein the three specifications of injection are as follows:
experiment two low temperature experiment
Taking appropriate amount of injection solution of three specifications, respectively placing at 2-8 ℃ for 2 days, then placing at 40 ℃ for 2 days, repeating the steps for three times, sampling and detecting visible foreign matters, and judging whether the raw material medicine is separated out. Through detection, the injection with the three specifications has no visible foreign body abnormality through three cycles of low-temperature tests.
Experiment three 6 months accelerated stability experiment
Respectively taking 4 ml: 4mg, 5 ml: 4mg, 100 ml: the numbers of six groups of samples A-F of 5mg three specifications of zoledronic acid injection and three specifications of commercially available injection are respectively stored for 6 months under the conditions of 40 +/-2 ℃ and 75% +/-5% RH, and the samples are respectively taken for measuring relevant properties at 0 month, 1 month, 2 months, 3 months and 6 months, so as to obtain corresponding data, which are shown in the following table:
TABLE 6 comparison of accelerated stability of zoledronic acid injection with commercially available injection
As can be seen from the data in the table above, after the zoledronic acid injection with three specifications prepared according to the formula and the process is stored for 6 months under the conditions of 40 ℃ plus or minus 2 ℃ and 75% plus or minus 5% RH acceleration, the content of the related substances is changed, but the content exceeds 99.6%, the content of imidazole acetic acid is less than 0.045%, the content of total impurities is less than 0.1%, and visible foreign matters are qualified; correspondingly, after the commercially available zoledronic acid injection with three specifications is stored for 6 months, the content, the imidazole acetic acid content and the total impurity content of the zoledronic acid injection are changed to a large extent.
Based on the analysis, the data of the zoledronic acid injection with three specifications prepared according to the formula and the process of the invention after being stored for 6 months under the accelerated condition show that the stability of the zoledronic acid injection is superior to that of the injection sold on the market, and particularly, the content of the imidazoleacetic acid is effectively controlled, so that the zoledronic acid injection has outstanding substantive characteristics and remarkable progress and has practicability.
Detailed Description
The advantageous effects of the present invention are further illustrated by the following experiments. It is not limited to the following embodiments, and those skilled in the art may make equivalent substitutions or changes without departing from the spirit of the present invention.
Example 14 ml: preparation of 4mg Zoledronic acid injection (unit: g)
Prescription:
the preparation method comprises the following steps:
1) taking zoledronic acid raw material medicine, and crushing the zoledronic acid raw material medicine into fine powder for later use;
2) sequentially dissolving sodium acetate and glycerol in 80% of total volume of water for injection;
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 the full amount of the drug-containing solution I obtained in the step 3), and adjusting the pH value to 6.0-6.5 by using 0.1M sodium acetate aqueous solution 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.
Example 25 ml: preparation of 4mg Zoledronic acid injection (unit: g)
Prescription:
the preparation method comprises the following steps:
1) taking zoledronic acid raw material medicine, and crushing the zoledronic acid raw material medicine into fine powder for later use;
2) sequentially dissolving sodium acetate and glycerol in 80% of total volume of water for injection;
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 the full amount of the drug-containing solution I obtained in the step 3), and adjusting the pH value to 6.0-6.5 by using 0.1M sodium acetate aqueous solution 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.
Example 3100 ml: preparation of 5mg Zoledronic acid injection (unit: g)
Prescription:
the preparation method comprises the following steps:
1) taking zoledronic acid raw material medicine, and crushing the zoledronic acid raw material medicine into fine powder for later use;
2) sequentially dissolving sodium acetate and glycerol in 80% of total volume of water for injection;
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 the full amount of the drug-containing solution I obtained in the step 3), and adjusting the pH value to 6.0-6.5 by using 0.1M sodium acetate aqueous solution 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.
Claims (2)
1. The pharmaceutical composition for injection containing zoledronic acid is characterized by comprising the following components in parts by weight:
2. the pharmaceutical composition for injection containing zoledronic acid as claimed in claim 1, wherein said composition is formulated as an injection by the steps of:
1) taking zoledronic acid raw material medicine, and crushing the zoledronic acid raw material medicine into fine powder for later use;
2) sequentially dissolving sodium acetate and glycerol in 80% of total volume of water for injection;
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 the full amount of the drug-containing solution I obtained in the step 3), and adjusting the pH value to 6.0-6.5 by using 0.1M sodium acetate aqueous solution 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.
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| CN106924269A (en) * | 2016-04-19 | 2017-07-07 | 南京大学 | The purposes of zoledronic acid |
| CN109431990A (en) * | 2018-12-21 | 2019-03-08 | 江西润泽药业有限公司 | Zoledronic acid injection and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1396830A (en) * | 2000-01-20 | 2003-02-12 | 弗·哈夫曼-拉罗切有限公司 | Pharmaceutical parenteral composition containing biphosphonate |
| CN1852739A (en) * | 2003-09-18 | 2006-10-25 | 诺瓦提斯公司 | Pharmaceutical products comprising bisphosphonates |
| CN101198316A (en) * | 2005-03-17 | 2008-06-11 | 伊兰制药国际有限公司 | Nanoparticulate bisphosphonate compositions |
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| AR075721A1 (en) * | 2010-03-05 | 2011-04-20 | Eriochem Sa | PHARMACEUTICAL COMPOSITION THAT INCLUDES A ZOLEDRONIC ACID SOLUTION. |
| CN102000094B (en) * | 2010-09-27 | 2013-03-27 | 天津南开允公医药科技有限公司 | Ibandronic acid-containing medicinal composition and preparation process thereof |
| CN104721132B (en) * | 2013-12-21 | 2018-05-18 | 石药集团恩必普药业有限公司 | A kind of zoledronic acid injection and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1396830A (en) * | 2000-01-20 | 2003-02-12 | 弗·哈夫曼-拉罗切有限公司 | Pharmaceutical parenteral composition containing biphosphonate |
| CN1852739A (en) * | 2003-09-18 | 2006-10-25 | 诺瓦提斯公司 | Pharmaceutical products comprising bisphosphonates |
| CN101198316A (en) * | 2005-03-17 | 2008-06-11 | 伊兰制药国际有限公司 | Nanoparticulate bisphosphonate compositions |
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Effective date of registration: 20200927 Address after: Room 2216, main building, Biomedical Park Research Center, No.1 Lutai Avenue, hi tech Zone, Zibo City, Shandong Province Applicant after: SHANDONG HI-QUAL PHARMATECH Co.,Ltd. Address before: 300000 Jingjiang Road, Hebei District, Tianjin. Applicant before: Dong Guiyu |
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