CN111568860B - Ornidazole injection and preparation method thereof - Google Patents
Ornidazole injection and preparation method thereof Download PDFInfo
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- CN111568860B CN111568860B CN202010446779.5A CN202010446779A CN111568860B CN 111568860 B CN111568860 B CN 111568860B CN 202010446779 A CN202010446779 A CN 202010446779A CN 111568860 B CN111568860 B CN 111568860B
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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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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- 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
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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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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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The invention relates to an ornidazole injection and a preparation method thereof. Besides 500g of ornidazole, the injection per 3000ml of the injection also contains poloxamer 188 and sodium glycerophosphate, preferably, poloxamer 188 and sodium glycerophosphate of 7.5g are contained in per 1000ml of the injection, and the preferred specification is 3ml:0.5g or 6ml:1 g.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to an ornidazole injection and a preparation method thereof.
Background
Ornidazole, chemical name: 1- (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole, which is a third generation nitroimidazole medicament. The ornidazole injection is the first choice medicine for treating anaerobic bacteria infection and has certain inhibition effect on partial aerobic bacteria. The ornidazole is difficult to dissolve in water, the solubility of the ornidazole is increased under an acidic condition, injection liquid preparations mostly adopt water for injection as a solvent, but the water solubility of the ornidazole is poor under a neutral condition, the ornidazole is dissolved by adjusting the pH value to 1.8-2.3 by acid in the prior art, meanwhile, in order to ensure the stability of the ornidazole, propylene glycol is usually added in the prior art, but is used as a stabilizer and has large side effects, the side effects which are not tolerated by a human body can be caused by the administration dosage of the propylene glycol which exceeds 25mg/kg per day, and as the solvent for injection, the propylene glycol also has a certain stimulation effect, the safety risk is increased, and a part of the technology adopts a large amount of ethanol as the solvent, the disulfiram reaction of a sensitive patient is easily induced, meanwhile, the use of the ethanol needs explosion prevention measures in a production environment, and the production difficulty and the cost are increased. For example: the Chinese application CN104127373A prescription process is added with propylene glycol and ethanol; the Chinese application CN106176585A prescription process is added with propylene glycol and ethanol; the Chinese application CN106309359A prescription process is added with propylene glycol and ethanol; the Chinese application CN104127410A prescription process is added with propylene glycol and ethanol; chinese application CN103006554A prescription is added with a large amount of ethanol; chinese application CN104127379A prescription is added with a large amount of ethanol; the Chinese application CN 107041868A prescription technology adds propylene glycol and ethanol; chinese application CN104013571A prescription is added with a large amount of ethanol; the Chinese application CN103040740A prescription adds a large amount of propylene glycol; the Chinese application CN102552127A prescription process adds propylene glycol and ethanol, and the technologies can not avoid the use of propylene glycol or ethanol. Some technical common senses avoid the use of propylene glycol and ethanol, for example, the chinese application CN103505411A utilizes the thickening effect and the suspending effect of long-chain polyethylene glycol 4000 to increase the physical stability of a small-volume ornidazole injection water system, but the preparation process is performed by high-temperature sterilization and pH adjustment (2.5-4.5), and meanwhile, long-chain polyethylene glycol 4000 is often used as an excipient of a solid preparation, and the long-chain polyethylene glycol 4000 is used as an auxiliary material for injection, which brings potential safety risk to the preparation. The solvent system for dissolving ornidazole in the Chinese application CN110917135A is an organic solvent mixed by short-chain polyethylene glycol and ethanol, and although the amount of the ethanol is reduced by using propylene glycol, the ethanol is still used, so that the occurrence of disulfiram reaction cannot be completely avoided.
Disclosure of Invention
The invention aims to provide an ornidazole injection and a preparation method thereof, the ornidazole injection does not contain organic solvents such as propylene glycol, ethanol and the like, and simultaneously has stable quality indexes, low impurity content and no change of impurities before and after sterilization compared with the prior art, and is obviously superior to the prior art.
The scheme adopted by the invention for solving the technical problems is as follows:
the ornidazole injection contains 500g of ornidazole, poloxamer 188 and sodium glycerophosphate in each 3000ml of injection.
Preferably, the amount of poloxamer 188 is 7.5g and the amount of sodium glycerophosphate is 10.5g per 3000ml injection.
Preferably, the specification of the ornidazole injection is 3ml:0.5g or 6ml: 1.0 g.
The invention also provides a preparation method of the ornidazole injection, which comprises the following steps:
(1) dissolving poloxamer 188 with the prescription amount in 2500ml of water for injection at the temperature of 45-52 ℃, and adjusting the pH value to 2.3-2.5 by hydrochloric acid;
(2) keeping the temperature at 45-52 ℃, sequentially adding the sodium glycerophosphate and the ornidazole according to the prescription amount, stirring and dissolving, and adding water for injection to 3000 ml;
(3) and (3) measuring the pH value and the content of the solution, filtering the solution by using a 0.22 mu m filter membrane, filling the solution into an ampoule according to the specification, and then sterilizing the solution at 121 ℃ for 30 minutes to obtain the ornidazole injection.
The invention adopts sodium glycerophosphate and poloxamer 188 as the auxiliary materials of the ornidazole injection, the combined use of the 2 auxiliary materials is beneficial to increasing the stability of the ornidazole injection, can replace organic solvents such as propylene glycol, ethanol and the like, and has unexpected effects, and especially, the effect of adding 7.5g of poloxamer 188 and 10.5g of sodium glycerophosphate into each 3000ml of the ornidazole injection is optimal.
Detailed Description
The following examples are provided to further illustrate the present invention for better understanding, but the present invention is not limited to the following examples.
Example 1
Injections were prepared according to the following prescription of table 1:
(1) dissolving poloxamer 188 with the prescription amount in 2500ml of water for injection at 45 ℃, and adjusting the pH value to 2.3 by hydrochloric acid;
(2) keeping the temperature at 45 ℃, sequentially adding the sodium glycerophosphate and the ornidazole according to the prescription amount, stirring and dissolving, and adding water for injection to 3000 ml;
(3) measuring the pH value and the content of the solution, filtering the solution by using a 0.22 mu m filter membrane, and mixing the solution according to the volume ratio of 3ml: filling 0.5g of the ornidazole injection into an ampoule, and then sterilizing at 121 ℃ for 30 minutes to obtain the ornidazole injection.
TABLE 1 sodium glycerophosphate and poloxamer 188 injection solutions with different prescription dose
The above 8 prescription samples were subjected to influence factor tests, and were placed at 60 ℃ under strong light (4500 lx ± 500 lx) for 10 days, respectively, and sampled and examined on the 10 th day, and the results were compared with 0 day to examine the stability of the samples, and the results are shown in tables 2 to 3:
TABLE 260 ℃ stability test results
TABLE 3 Strong light (4500 LX) stability test results
The test results in tables 2-3 show that poloxamer 188 and sodium glycerophosphate are used together, which is beneficial to increasing the stability of ornidazole injection, and especially, the specific proportion of 7.5g of poloxamer 188 and 10.5g of sodium glycerophosphate in each 3000ml of ornidazole injection has the best effect, and even if the amount is slightly changed, the ornidazole injection can produce different technical effects.
The ornidazole injection prepared by the prescription 1 is sterilized at 121 ℃ for 30 minutes before and after sterilization, and the results are shown in a table 4:
TABLE 4 quality test results before and after sterilization
| Before sterilization | After sterilization | |
| Content (%) | 100.13 | 100.14 |
| Related substances (Total miscellaneous%) | 0.01 | 0.01 |
The test results in table 4 show that the ornidazole injection prepared by combining poloxamer 188 and sodium glycerophosphate has almost no change in quality before and after sterilization, and the product quality is stable.
Example 2
Preparation of Ornidazole injection (Specification: 3ml:0.5 g)
Prescription:
ornidazole: 500g
Poloxamer 188: 7.5g
Sodium glycerophosphate: 10.5g
Adding water for injection to 3000ml
Make 1000 pieces
The process comprises the following steps:
(1) dissolving poloxamer 188 with the prescription amount in 2500ml of water for injection at 45 ℃, and adjusting the pH value to 2.3 by hydrochloric acid;
(2) keeping the temperature at 45 ℃, sequentially adding the sodium glycerophosphate and the ornidazole according to the prescription amount, stirring and dissolving, and adding water for injection to 3000 ml;
(3) and (3) measuring the pH value and the content of the solution, filtering the solution by using a 0.22 mu m filter membrane, filling the solution into an ampoule according to the specification, and then sterilizing the solution at 121 ℃ for 30 minutes to obtain the ornidazole injection.
Example 3
Preparation of Ornidazole injection (Specification: 3ml:0.5 g)
Prescription:
ornidazole: 500g
Poloxamer 188: 7.5g
Sodium glycerophosphate: 10.5g
Adding water for injection to 3000ml
Make 1000 pieces
The process comprises the following steps:
(1) dissolving poloxamer 188 with the prescription amount in 2500ml of water for injection at 52 ℃, and adjusting the pH value to 2.5 by hydrochloric acid;
(2) keeping the temperature at 52 ℃, sequentially adding the sodium glycerophosphate and the ornidazole according to the prescription amount, stirring and dissolving, and adding water for injection to 3000 ml;
(3) and (3) measuring the pH value and the content of the solution, filtering the solution by using a 0.22 mu m filter membrane, filling the solution into an ampoule according to the specification, and then sterilizing the solution at 121 ℃ for 30 minutes to obtain the ornidazole injection.
Example 4
Preparation of Ornidazole injection (Specification: 3ml:0.5 g)
Prescription:
ornidazole: 500g
Poloxamer 188: 7.5g
Sodium glycerophosphate: 10.5g
Adding water for injection to 3000ml
Make 1000 pieces
The process comprises the following steps:
(1) dissolving poloxamer 188 with the prescription amount in 2500ml of water for injection at 48 ℃, and adjusting the pH value to 2.4 by hydrochloric acid;
(2) keeping the temperature at 48 ℃, sequentially adding the sodium glycerophosphate and the ornidazole according to the prescription amount, stirring and dissolving, and adding water for injection to 3000 ml;
(3) and (3) measuring the pH value and the content of the solution, filtering the solution by using a 0.22 mu m filter membrane, filling the solution into an ampoule according to the specification, and then sterilizing the solution at 121 ℃ for 30 minutes to obtain the ornidazole injection.
Example 5
Preparation of Ornidazole injection (Specification: 6ml: 1.0 g)
Prescription:
ornidazole: 500g
Poloxamer 188: 7.5g
Sodium glycerophosphate: 10.5g
Adding water for injection to 3000ml
500 pieces are made
The process comprises the following steps:
(1) dissolving poloxamer 188 with the prescription amount in 2500ml of water for injection at 45 ℃, and adjusting the pH value to 2.3 by hydrochloric acid;
(2) keeping the temperature at 45 ℃, sequentially adding the sodium glycerophosphate and the ornidazole according to the prescription amount, stirring and dissolving, and adding water for injection to 3000 ml;
(3) and (3) measuring the pH value and the content of the solution, filtering the solution by using a 0.22 mu m filter membrane, filling the solution into an ampoule according to the specification, and then sterilizing the solution at 121 ℃ for 30 minutes to obtain the ornidazole injection.
Example 6
Preparation of Ornidazole injection (Specification: 6ml: 1.0 g)
Prescription:
ornidazole: 500g
Poloxamer 188: 7.5g
Sodium glycerophosphate: 10.5g
Adding water for injection to 3000ml
500 pieces are made
The process comprises the following steps:
(1) dissolving poloxamer 188 with the prescription amount in 2500ml of water for injection at 52 ℃, and adjusting the pH value to 2.5 by hydrochloric acid;
(2) keeping the temperature at 52 ℃, sequentially adding the sodium glycerophosphate and the ornidazole according to the prescription amount, stirring and dissolving, and adding water for injection to 3000 ml;
(3) and (3) measuring the pH value and the content of the solution, filtering the solution by using a 0.22 mu m filter membrane, filling the solution into an ampoule according to the specification, and then sterilizing the solution at 121 ℃ for 30 minutes to obtain the ornidazole injection.
Example 7
Preparation of Ornidazole injection (Specification: 6ml: 1.0 g)
Prescription:
ornidazole: 500g
Poloxamer 188: 7.5g
Sodium glycerophosphate: 10.5g
Adding water for injection to 3000ml
500 pieces are made
The process comprises the following steps:
(1) dissolving poloxamer 188 with the prescription amount in 2500ml of water for injection at 48 ℃, and adjusting the pH value to 2.4 by hydrochloric acid;
(2) keeping the temperature at 48 ℃, sequentially adding the sodium glycerophosphate and the ornidazole according to the prescription amount, stirring and dissolving, and adding water for injection to 3000 ml;
(3) and (3) measuring the pH value and the content of the solution, filtering the solution by using a 0.22 mu m filter membrane, filling the solution into an ampoule according to the specification, and then sterilizing the solution at 121 ℃ for 30 minutes to obtain the ornidazole injection.
The present invention provides the following test and comparative results:
1. sample 1 (ornidazole injection prepared in inventive example 2, 3ml:0.5 g);
2. sample 2 (commercially available ornidazole injection, 3ml:0.5 g);
samples 1-2 were subjected to accelerated stability studies (40 ℃ ± 2 ℃, RH 75% ± 5%) for 6 months with results shown in table 5:
TABLE 5 stability results of accelerated testing
Long term stability studies (25 ℃. + -. 2 ℃ C., RH 60%. + -. 10%) were performed on samples 1-2, with the results shown in Table 6:
TABLE 6 Long term test stability results
As can be seen from the results in tables 5 to 6, the ornidazole injection prepared by the formula and the process of the present invention maintains extremely high stability, and has significant advantages compared with the ornidazole injection on the market, and similar results are obtained by performing the same tests on the ornidazole injections prepared by other embodiments of the present invention.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (3)
1. The ornidazole injection is characterized in that: each 3000ml of injection contains 500g of ornidazole, poloxamer 188 and sodium glycerophosphate, wherein the dosage of the poloxamer 188 is 7.5g, and the dosage of the sodium glycerophosphate is 10.5 g.
2. The ornidazole injection as claimed in claim 1, characterised in that: the specification of the ornidazole injection is 3ml to 0.5g or 6ml to 1 g.
3. The method for preparing the ornidazole injection as claimed in any one of claims 1 to 2, characterized in that the ornidazole injection is prepared by the following method:
(1) dissolving poloxamer 188 with the prescription amount in 2500ml of water for injection at the temperature of 45-52 ℃, and adjusting the pH value to 2.3-2.5 by hydrochloric acid;
(2) keeping the temperature at 45-52 ℃, sequentially adding the sodium glycerophosphate and the ornidazole according to the prescription amount, stirring and dissolving, and adding water for injection to 3000 ml;
(3) and (3) measuring the pH value and the content of the solution, filtering the solution by using a 0.22 mu m filter membrane, filling the solution into an ampoule according to the specification, and then sterilizing the solution at 121 ℃ for 30 minutes to obtain the ornidazole injection.
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| CN103751131A (en) * | 2011-10-17 | 2014-04-30 | 上海天龙药业有限公司 | Ornidazole dripping pill |
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| CN103751131A (en) * | 2011-10-17 | 2014-04-30 | 上海天龙药业有限公司 | Ornidazole dripping pill |
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| 奥硝唑温敏微乳凝胶的制备与性质考察;王莉 等，;《中国医院用药评价与分析》;20180830;第18卷(第8期);第1078-1081页 * |
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