CN115531306B - Left ornidazole derivative emulsion preparation for injection and preparation method thereof - Google Patents
Left ornidazole derivative emulsion preparation for injection and preparation method thereof Download PDFInfo
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- CN115531306B CN115531306B CN202210516223.8A CN202210516223A CN115531306B CN 115531306 B CN115531306 B CN 115531306B CN 202210516223 A CN202210516223 A CN 202210516223A CN 115531306 B CN115531306 B CN 115531306B
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- ornidazole
- injection
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- oil
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- 235000008524 evening primrose extract Nutrition 0.000 description 1
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- 229960004063 propylene glycol Drugs 0.000 description 1
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- 238000010898 silica gel chromatography Methods 0.000 description 1
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- 239000008347 soybean phospholipid Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
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- 230000000007 visual effect Effects 0.000 description 1
Classifications
-
- 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
- A61K9/10—Dispersions; Emulsions
-
- 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
- A61K31/41—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
- A61K31/4164—1,3-Diazoles
-
- 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
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
The invention relates to a levo-ornidazole derivative emulsion preparation and a preparation method thereof. The invention utilizes the left ornidazole derivative to prepare the emulsion injection of the left ornidazole derivative, and is double innovative in terms of compound structure and dosage form, the two technologies are effectively combined to control the drug exposure speed, thereby achieving the purpose of reducing vascular irritation, overcoming the safety and patient compliance problems existing in the clinical application of the existing left ornidazole injection, and the dosage form can provide proper quality attribute for the clinical application with more flexibility.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and in particular relates to a levo-ornidazole derivative emulsion preparation and a preparation method thereof.
Background
Nitroimidazole antibacterial drugs are artificially synthesized antibacterial drugs, have unique killing effect on anaerobic bacteria and protozoa, and are combined with other antibiotics to be applied to various clinical fields. After the first generation nitroimidazole drug metronidazole in the 50 th century of 20 was developed, the second replacement nitroazole and the third generation ornidazole which are sequentially marketed are widely used clinically for various infections caused by anaerobes, amoeba, giardia, trichomonas and the like.
The ornidazole as one kind of third generation nitroimidazole medicine is mainly racemic modification, and has equal amount of levo-isomer and dextro-isomer and the injection as main preparation form. Through experimental researches on the levo-isomer of the ornidazole, the invention patent CN1332662C discovers that the pharmacokinetic properties of the levo-ornidazole are superior to those of the dextro-ornidazole and the racemo-ornidazole, the central toxicity is lower than those of the dextro-ornidazole and the racemo-ornidazole, and the application of the levo-ornidazole in preparing anaerobic infection resisting medicines is more practical.
The sodium chloride injection of the left ornidazole on the market acts on DNA of anaerobe, amoeba, giardia and trichomonas cells, and the nitro group of the molecule is reduced into amino group in an anaerobic environment or the free radical is formed to break the spiral structure of the DNA and block the transcription and the replication of the DNA to die, so that the aims of resisting bacteria and resisting infection are achieved. Compared with nitroimidazole medicines such as tinidazole, metronidazole and the like, the levo-ornidazole has more obvious anti-infection advantage and smaller side effect. Clinical trials prove that on the basis that the clinical curative effect of the anti-anaerobic bacterial infection is equivalent to that of the ornidazole, the incidence rate of the clinical total adverse reaction is obviously reduced, which is only 1/15 of that of the ornidazole, and the method has obvious advantages in the aspect of nerve safety.
In clinical use for many years, the sodium chloride injection of the left ornidazole has obvious curative effect on anaerobic bacteria and reduces neurotoxicity compared with the racemate injection, but has other unresolved problems.
Because the water solubility of the left ornidazole is extremely poor, the pH value of the prepared transfusion preparation is about 3.5, the acidity value is higher than the tolerance pH value of a human body by 4.0-9.0, the strong irritation during injection can interfere the normal metabolism and functions of vascular intima, damage vascular endothelial cells, induce platelet aggregation, secondary thrombotic chain reaction, generate tingling sensation when light, and generate different degrees of venous inflammation when heavy, such as red swelling and vein strip rope change of partial patients, so that the patient compliance is poor, especially for old people and children with hardened vascular walls or thinner vascular walls.
In clinical use, the sodium chloride injection of the left ornidazole can only adopt an infusion administration mode, the infusion time is controlled to be between 0.5 and 1h in order to moderately relieve the irritation of an administration part, intravenous injection cannot be adopted, and the patient has poor compliance and consumes more medical resources at the same time, so that the clinical application is limited.
Therefore, for nitroimidazole anti-anaerobe injection, there is a clinical need for safer, more convenient products that can increase patient compliance.
Disclosure of Invention
The invention aims to provide a levo-ornidazole derivative emulsion preparation for injection and a preparation method thereof. The existing clinical problems are cooperatively solved from two aspects of product dosage forms and compound structures.
The irritation sources of the administration part of the injection mainly comprise: the main components of the solvent, the pH of the solvent and the nature of the compound. Based on the quality condition of commercial products, the invention prepares the injection with the pH value of 4.0-9.0 and even near neutral, and eliminates the unsuitable factor of the pH value; furthermore, the emulsion type is used for wrapping the active ingredient in the oil phase, the drug release time is properly delayed, the irritation caused by the compound is relieved, and furthermore, the structure of the left ornidazole is modified according to the solubility requirement of the dosage form on the compound to prepare the prodrug with a certain metabolic rate, so that the release of the left ornidazole at the drug administration position is thoroughly avoided.
The invention is mainly realized by the following technical scheme:
the present invention provides an emulsion formulation containing a derivative of levo-ornidazole, comprising:
(a) A compound of structural formula (1), racemates, stereoisomers, pharmaceutically acceptable salts or solvates thereof, or solvates of pharmaceutically acceptable salts thereof:
(b) An emulsifying agent;
(c) Oil for injection.
According to an embodiment of the invention, the active ingredient is present in a mass percentage of 0.1-10% (w/v), preferably 1-5% (w/v), based on 100% of the total volume of the emulsion formulation.
The emulsifier suitable for use in the present invention is selected from natural emulsifiers selected from soy lecithin, egg yolk lecithin, hydrogenated lecithin, saturated and unsaturated C 12-18 A combination of one, two or more of fatty acyl phosphatidylcholine;
according to an embodiment of the invention, the emulsifier is selected from natural egg yolk lecithin or/and natural soybean lecithin, in a mass percentage of 0.5-5% (w/v), preferably 1-2% (w/v).
Suitable oils for use in the present invention are injectable oil esters selected from soybean oil, safflower oil, cottonseed oil, olive oil, sesame oil, coconut oil, castor oil, sea buckthorn oil, evening primrose oil, corn oil, brucea javanica oil, perilla oil, grapeseed oil, tea oil, palm oil, peanut oil, medium chain oil (medium chain triglycerides), long chain triglycerides, ethyl oleate, acetylated monoglycerides, propylene glycol diester, glyceryl linoleate or glyceryl polyethylene glycol laurate, or a combination of two or more thereof.
According to an embodiment of the invention, the oil is selected from one or more of medium chain triglycerides, soybean oil, peanut oil, in a mass percentage of 5-30% (w/v), preferably 10-20% (w/v).
According to an embodiment of the present invention, the emulsion formulation further comprises a stabilizer selected from one or more of oleic acid, sodium oleate, kolliphor HS15, polysorbate, docusate sodium, deoxycholic acid, poloxamer.
According to an embodiment of the present invention, the emulsion formulation further comprises an isotonicity adjusting agent selected from one or more of sucrose, dextrose, sorbitol, xylitol, sodium chloride, glycerin.
According to an embodiment of the present invention, the emulsion formulation may further comprise a pH adjuster selected from one or more of citric acid, hydrochloric acid, citric acid, fumaric acid, lysine, tartaric acid, sodium histidine citrate, sodium hydroxide, sodium citrate, sodium dihydrogen phosphate, disodium hydrogen phosphate.
The invention also provides a preparation method of the emulsion preparation containing the left ornidazole derivative, which comprises the following steps:
(1) Preparing an oil phase: adding an emulsifying agent and a fat-soluble stabilizing agent into the oil for injection, shearing at a high speed to dissolve the emulsifying agent and the fat-soluble stabilizing agent, adding the left ornidazole derivative, stirring, dissolving and uniformly mixing to obtain the compound;
(2) Preparing an aqueous phase: adding isotonic regulator and water-soluble stabilizer into injectable water, adding pH regulator if necessary, stirring for dissolving to obtain the final product;
(3) Preparation of colostrum: adding the water phase in the step (2) into the oil phase in the step (1), and shearing and dispersing at a high speed under water bath heat preservation to form colostrum;
(4) Preparing final emulsion: homogenizing the colostrum obtained in the step (3) under high pressure to obtain final milk, and adding a pH regulator to adjust the pH of the final milk if necessary;
(5) Filtering, filling, nitrogen charging, and wet heat sterilizing.
The emulsion formulations prepared in accordance with the present invention are suitable for administration by parenteral administration, including intravenous, intra-arterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration may be in the form of a single bolus dose or may be administered by, for example, a continuous infusion pump. Or intracranial, e.g., intrathecal or intraventricular, administration; the common containers for injection include glass ampoule, penicillin bottle, plastic ampoule, prefilled syringe, etc.
The beneficial effects are that:
the invention uses the unreported novel compound of the left ornidazole derivative as an active ingredient, and the preparation prescription is further researched by researching the physicochemical property of the active ingredient and comprehensively considering the in-vivo and in-vitro metabolism test, so that a safe and stable emulsion preparation containing the left ornidazole derivative is obtained; and different drug release rates can be realized by controlling the average particle size, so as to meet diversified clinical treatment schemes.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of a left ornidazole derivative.
FIG. 2 shows a high performance liquid chromatogram of the measurement of substances related to the left ornidazole derivative.
FIG. 3 is a typical particle size distribution diagram of an emulsion formulation of a levo-ornidazole derivative of the present invention.
FIG. 4 is a graph of typical Zeta potential measurements of a milky formulation of a levo-ornidazole derivative of the present invention.
Fig. 5 is a graph of blood concentration versus time for a levo-ornidazole sodium chloride injection and a levo-ornidazole derivative emulsion injection.
Detailed Description
The invention will now be further described in detail with reference to the following examples, which are intended to be illustrative only and not limiting in any way, and the raw materials used, unless otherwise specified, may be either commercially available or self-contained.
The main detection method comprises the following steps:
1. and (3) pH measurement:
the pH value is measured according to the pH value measurement method (China pharmacopoeia 2020 edition general rule 0631).
2. Related substance measurement
The sample was diluted with 70% acetonitrile aqueous solution to a concentration of about 0.5mg/ml for the left ornidazole derivative as a test solution. The measurement is carried out according to high performance liquid chromatography (rule 0512 of Chinese pharmacopoeia 2020 edition). Gradient elution was performed using an Agilent Zorbax C18 (250 x 4.6mm,5 μm) column with water as mobile phase a and acetonitrile as mobile phase B, as follows:
flow rate: 1.0ml/min; detection wavelength: 318nm; column temperature: 35 ℃; sample injection amount: 10 μl, record the chromatogram and analyze for impurities.
Typical relevant substance patterns are shown in figure 2.
3. Particle size, zeta potential measurement:
about 50 mu L of the emulsion injection is diluted in 4mL of filtered purified water, and the mixture is uniformly mixed by shaking, so as to obtain a sample mixture. According to the particle size and particle size distribution measurement method (third method of the rule 0982 of the edition 2020 of Chinese pharmacopoeia), a dynamic light scattering optical particle size analyzer PSS Nicomp Z3000 based on Rayleigh scattering theory is adopted, and the following parameters are adopted: the optical intensity is 300KHz; refraction angle 90 °; the time was 5 minutes, and particle size and Zeta potential measurements were performed. Gaussian distribution of particle size was recorded and data such as average particle size, PI, zeta potential, etc. were analyzed. Typical particle size spectra are shown in FIG. 3, and Zeta potential measurements are shown in FIG. 4.
Experimental example 1 synthesis of the left ornidazole derivative:
synthesis of intermediate 1: left ornidazole (5.036 g,22.93 mmol) was weighed into a bottle, DCM 20ml was added and stirred at room temperature for dissolution, py (3.319 g,45.62 mmol) was then weighed into a reaction bottle, DMAP (2.611 g,23.01 mmol) was then added into the bottle in sequence, acetic anhydride (3.514 g,34.42 mmol) was finally weighed into the reaction bottle slowly and stirred for 1h, TLC was monitored until the starting material disappeared. After working up, 50ml of water and 30ml of DCM were added and the organic layer was separated by extraction, and the organic layer was then washed with 50ml of saturated NaHCO, respectively 3 Washing with saturated salt water, anhydrous Na 2 SO 4 Drying and then concentration under reduced pressure gave a white solid (4.367 g,16.69 mmol) in 72.8% yield.
Synthesis of compounds of structural formula (1): weighing intermediate 1 (1.056 g,4.04 mmol) and adding DCM6ml, stirring at room temperature for dissolution, replacing the reaction bottle with Ar gas for 3 times, transferring the reaction bottle to a cold trap, stirring at-78 ℃, slowly dripping diisobutylaluminum hydride (1.162 g,8.17 mmol) into the reaction bottle, keeping stirring for 1h after dripping, weighing Py (0.965 g,12.20 mmol), respectively diluting DMAP (1.04 g,8.22 mmol) with 2ml DCM, slowly dripping acetic anhydride (2.496 g,24.45 mmol) into the reaction bottle after dripping, keeping stirring for 20h, starting the post-treatment, adding DCM 40ml and saturated NH 4 Extracting with 50ml of Cl, separating to obtain organic layers, washing the organic layers with 50ml of water and saturated salt water respectively, and anhydrous Na 2 SO 4 Drying, rotary steaming to obtain oily substance, separating by silica gel column chromatography, and using n-hexane: ethyl acetate 4:1, and concentrating by rotary evaporation to obtain the final product (0.272 g,0.89 mmol) with a yield of 22.0%.1HNMR (400 MHz, CDCl 3) delta 7.97 (d, 1H, J=11.3 Hz), delta 5.82-5.44 (m, 1H), delta 4.73-4.60 (m, 1H), delta 4.38-4.09 (m, 2H)) δ3.76-3.64 (m, 2H), δ2.53 (s, 3H), δ1.90 (d, 3H, j=95.0 Hz), δ1.25 (dd, 3H, j=5.3 Hz, j=69.2 Hz); the nuclear magnetic hydrogen spectrum is shown in figure 1.
MS(ESI-MS)calcd for C 11 H 16 ClN 3 O 5 [M+H]+306.08,found 306.0
Test example 2: compound stability study
The experimental method comprises the following steps: placing a proper amount of a compound with the structural formula (1) in a penicillin bottle, respectively placing the penicillin bottle under the conditions of high temperature (60 ℃, opening), illumination (4500 lx,25 ℃, opening) and high humidity (75 percent RH and 92.5 percent RH, opening), sampling the penicillin bottle respectively for 0, 1, 5 and 8 days, and examining the purity of the compound and the change condition of related substances, wherein the specific results are shown in the following table:
the test results show that after the compound is placed under the conditions of high temperature (60 ℃, open), illumination (4500 lx,25 ℃, open) and high humidity (75 percent RH and 92.5 percent RH, open) for 8 days, the impurities are slightly increased under the conditions of illumination and high temperature, but the content is more than 98 percent, and the impurities are consistent with the impurities before sample retention under the conditions of high humidity, so that the compound has good stability in 8 days under the conditions, and can support the related study of preparing the compound into emulsion injection.
Test example 3: oil phase screening
The common oil auxiliary materials in the field of pharmaceutical preparations mainly comprise peanut oil, medium-chain triglyceride, rice oil, castor oil, sunflower seed oil, sesame oil, tea oil, corn germ oil, soybean oil and the like.
The experimental method comprises the following steps:
about 0.1g of the compound was weighed and added to about 1g of the above oil, and the mixture was stirred at room temperature to observe dissolution. If clear, 0.1g of compound is added until it is not dissolved to a clear state.
| Oil type | Dissolution conditions |
| Sesame oil | The addition of 0.3g of compound starts to be turbid |
| Medium chain triglycerides | The addition of 0.6g of compound started to be turbid |
| Soybean oil | The addition of 0.4g of compound starts to be turbid |
| Castor oil | The addition of 0.2g of compound starts to be turbid |
| Peanut oil | The addition of 0.3g of compound starts to be turbid |
The test results show that: the solubility of the compound in medium chain triglycerides is obviously larger than that in sesame oil, soybean oil, castor oil and peanut oil, and the soybean oil or the medium chain triglycerides are used as oil phases in combination with the widely-used drug-carrying emulsion injection in clinic at present, and the subsequent examples only examine the influence of the medium chain triglycerides as the oil on the stability of the emulsion injection and the like.
The invention will be further illustrated with reference to specific examples.
Example 1
Prescription composition:
the preparation method comprises the following steps:
(1) Preparing an oil phase: under the water bath heat preservation of 60 ℃, adding egg yolk lecithin Lipod E80 and oleic acid into medium chain triglyceride, shearing at high speed to dissolve the mixture, adding a left ornidazole derivative which is a compound shown in a structural formula (1), stirring, dissolving and uniformly mixing to obtain the compound;
(2) Preparing an aqueous phase: adding glycerol into water for injection under the condition of water bath heat preservation at 60 ℃, stirring and dissolving to obtain the compound;
(3) Preparation of colostrum: adding the water phase in the step (2) into the oil phase in the step (1), and shearing and dispersing for 1min at a high speed under the water bath heat preservation of 60 ℃ to form colostrum;
(4) Preparing final emulsion: homogenizing the colostrum obtained in the step (3) under high pressure for 90s under 800-1000bar pressure to obtain final emulsion, and adding 1M NaOH solution to adjust pH to 7.37;
(5) Filtering, packaging into penicillin bottle, adding nitrogen, sealing, and sterilizing at 116 deg.C for 40 min.
Example 2
Prescription composition:
| raw and auxiliary materials | Charge g |
| Left ornidazole derivative | 0.7 |
| Medium chain triglycerides | 10 |
| Yolk lecithin PL-100M | 1.2 |
| Oleic acid | 0.03 |
| Glycerol | 2.2 |
| Water for injection | 85.87 |
The preparation method comprises the following steps:
(1) Preparing an oil phase: under the water bath heat preservation of 60 ℃, adding egg yolk lecithin PL-100M and oleic acid into medium chain triglyceride, shearing at high speed to dissolve the mixture, adding a left ornidazole derivative which is a compound of a structural formula (1), stirring, dissolving and mixing uniformly to obtain the compound;
(2) Preparing an aqueous phase: adding glycerol into water for injection under the condition of water bath heat preservation at 60 ℃, stirring and dissolving to obtain the compound;
(3) Preparation of colostrum: adding the water phase in the step (2) into the oil phase in the step (1), and shearing and dispersing for 1min at a high speed under the water bath heat preservation of 60 ℃ to form colostrum;
(4) Preparing final emulsion: homogenizing the colostrum obtained in the step (3) under high pressure for 90s under 800-1000bar pressure to obtain final emulsion, and adding 1M NaOH solution to adjust pH to 7.46;
(5) Filtering, packaging into penicillin bottle, adding nitrogen, sealing, and sterilizing at 116 deg.C for 40 min.
Example 3
Prescription composition:
| raw and auxiliary materials | Charge g |
| Compounds of formula (1) | 1.4 |
| Medium chain triglycerides | 10 |
| Yolk lecithin PL-100M | 1.2 |
| Oleic acid | 0.03 |
| Glycerol | 2.2 |
| Water for injection | 85.17 |
The preparation method comprises the following steps:
(1) Preparing an oil phase: under the water bath heat preservation of 60 ℃, adding egg yolk lecithin PL-100M and oleic acid into medium chain triglyceride, shearing at high speed to dissolve the mixture, adding a left ornidazole derivative which is a compound of a structural formula (1), stirring, dissolving and mixing uniformly to obtain the compound;
(2) Preparing an aqueous phase: adding glycerol into water for injection under the condition of water bath heat preservation at 60 ℃, stirring and dissolving to obtain the compound;
(3) Preparation of colostrum: adding the water phase in the step (2) into the oil phase in the step (1), and shearing and dispersing for 1min at a high speed under the water bath heat preservation of 60 ℃ to form colostrum;
(4) Preparing final emulsion: homogenizing the colostrum obtained in the step (3) under high pressure for 90s under 800-1000bar pressure to obtain final emulsion, and adding 1M NaOH solution to adjust pH to 7.68;
(5) Filtering, packaging into penicillin bottle, adding nitrogen, sealing, and sterilizing at 116 deg.C for 40 min.
Example 4
Prescription composition:
| raw and auxiliary materials | Charge g |
| Compounds of formula (1) | 1.4 |
| Medium chain triglycerides | 10 |
| Yolk lecithin PL-100M | 2 |
| Oleic acid | 0.03 |
| Glycerol | 2.2 |
| Water for injection | 84.37 |
The preparation method comprises the following steps:
(1) Preparing an oil phase: adding oleic acid into medium-chain triglyceride at 60 ℃ under water bath heat preservation, shearing at high speed to dissolve the medium-chain triglyceride, adding a left ornidazole derivative which is a compound of the structural formula (1), stirring, dissolving and uniformly mixing to obtain the compound;
(2) Preparing an aqueous phase: adding glycerol into injectable water at 60deg.C under water bath, stirring to dissolve, adding egg yolk lecithin PL-100M, and stirring to disperse uniformly;
(3) Preparation of colostrum: adding the water phase in the step (2) into the oil phase in the step (1), and shearing and dispersing for 1min at a high speed under the water bath heat preservation of 60 ℃ to form colostrum;
(4) Preparing final emulsion: homogenizing the colostrum obtained in the step (3) under high pressure for 90s under 800-1000bar pressure to obtain final emulsion, and adding 1M NaOH solution to adjust pH to 7.62;
(5) Filtering, packaging into penicillin bottle, adding nitrogen, sealing, and sterilizing at 116 deg.C for 40 min.
Example 5
Prescription composition:
| raw and auxiliary materials | Charge g |
| Left ornidazole derivative | 5 |
| Medium chain triglycerides | 15 |
| Yolk lecithin PL-100M | 2 |
| Oleic acid sodium salt | 0.5 |
| Glycerol | 2.3 |
| Water for injection | 75.20 |
The preparation method comprises the following steps:
(1) Preparing an oil phase: under the water bath heat preservation of 60 ℃, adding egg yolk lecithin PL-100M into medium chain triglyceride, shearing at high speed to dissolve the mixture, adding a left ornidazole derivative which is a compound of the structural formula (1), stirring, dissolving and mixing uniformly to obtain the compound;
(2) Preparing an aqueous phase: adding glycerol and sodium oleate into water for injection under the condition of water bath heat preservation at 60 ℃, stirring and dissolving to obtain the compound;
(3) Preparation of colostrum: adding the water phase in the step (2) into the oil phase in the step (1), and shearing and dispersing for 1min at a high speed under the water bath heat preservation of 60 ℃ to form colostrum;
(4) Preparing final emulsion: homogenizing the colostrum obtained in the step (3) under high pressure for 120s under 800-1000bar pressure to obtain final emulsion, and adding 1M HCl solution to adjust pH to 6.98;
(5) Filtering, packaging into penicillin bottle, adding nitrogen, sealing, and sterilizing at 116 deg.C for 40 min.
Example 6
Prescription composition:
| raw and auxiliary materials | Charge g |
| Left ornidazole derivative | 7 |
| Medium chain triglycerides | 18 |
| Yolk lecithin PL-100M | 3 |
| Oleic acid sodium salt | 0.5 |
| Glycerol | 2.2 |
| Water for injection | 69.30 |
The preparation method comprises the following steps:
(1) Preparing an oil phase: under the water bath heat preservation of 60 ℃, adding egg yolk lecithin PL-100M into medium chain triglyceride, shearing at high speed to dissolve the mixture, adding a left ornidazole derivative which is a compound of the structural formula (1), stirring, dissolving and mixing uniformly to obtain the compound;
(2) Preparing an aqueous phase: adding glycerol and sodium oleate into water for injection under the condition of water bath heat preservation at 60 ℃, stirring and dissolving to obtain the compound;
(3) Preparation of colostrum: adding the water phase in the step (2) into the oil phase in the step (1), and shearing and dispersing for 1min at a high speed under the water bath heat preservation of 60 ℃ to form colostrum;
(4) Preparing final emulsion: homogenizing the colostrum obtained in the step (3) under high pressure for 120s under 800-1000bar pressure to obtain final emulsion, and adding 1M HCl solution to adjust pH to 7.19;
(5) Filtering, packaging into penicillin bottle, adding nitrogen, sealing, and sterilizing at 116 deg.C for 40 min.
Example 7
Prescription composition:
| raw and auxiliary materials | Charge g |
| Left ornidazole derivative | 7 |
| Medium chain triglycerides | 18 |
| Yolk lecithin PL-100M | 1.2 |
| Oleic acid sodium salt | 0.5 |
| Poloxamer 188 | 0.5 |
| Glycerol | 2.2 |
| Water for injection | 70.60 |
The preparation method comprises the following steps:
(1) Preparing an oil phase: under the water bath heat preservation of 60 ℃, adding egg yolk lecithin PL-100M into medium chain triglyceride, shearing at high speed to dissolve the mixture, adding a left ornidazole derivative which is a compound of the structural formula (1), stirring, dissolving and mixing uniformly to obtain the compound;
(2) Preparing an aqueous phase: adding glycerol, sodium oleate and poloxamer 188 into water for injection under the condition of water bath heat preservation at 60 ℃, stirring and dissolving to obtain the compound;
(3) Preparation of colostrum: adding the water phase in the step (2) into the oil phase in the step (1), and shearing and dispersing for 1min at a high speed under the water bath heat preservation of 60 ℃ to form colostrum;
(4) Preparing final emulsion: homogenizing the colostrum obtained in the step (3) under high pressure for 90s under 800-1000bar pressure to obtain final emulsion, and adding 1M HCl solution to adjust pH to 7.19;
(5) Filtering, packaging into penicillin bottle, adding nitrogen, sealing, and sterilizing at 116 deg.C for 40 min.
Example 8
Prescription composition:
| raw and auxiliary materials | Charge g |
| Left ornidazole derivative | 10 |
| Medium chain triglycerides | 30 |
| Yolk lecithin PL-100M | 5 |
| Polysorbate 80 | 0.5 |
| Glycerol | 2.2 |
| Water for injection | 52.30 |
The preparation method comprises the following steps:
(1) Preparing an oil phase: under the water bath heat preservation of 60 ℃, adding egg yolk lecithin PL-100M into medium chain triglyceride, shearing at high speed to dissolve the mixture, adding a left ornidazole derivative which is a compound of the structural formula (1), stirring, dissolving and mixing uniformly to obtain the compound;
(2) Preparing an aqueous phase: adding glycerol and polysorbate 80 into injectable water at 60deg.C under water bath, stirring and dissolving to obtain the final product;
(3) Preparation of colostrum: adding the water phase in the step (2) into the oil phase in the step (1), and shearing and dispersing for 1min at a high speed under the water bath heat preservation of 60 ℃ to form colostrum;
(4) Preparing final emulsion: homogenizing the colostrum obtained in the step (3) under high pressure for 240s under 800-1000bar pressure to obtain final emulsion, and adding 1M HCl solution to adjust pH to 8.17;
(5) Filtering, packaging into penicillin bottle, adding nitrogen, sealing, and sterilizing at 116 deg.C for 40 min.
The standard of the sodium chloride injection of the left ornidazole is 0.5g:100ml, and the sodium chloride injection is a high-capacity injection which can be used for intravenous drip only, and according to the prescription composition of the embodiment, the invention can achieve the drug loading rate of about 0.5g:7ml at most based on the left ornidazole, and completely meets the liquid medicine volume requirement of intravenous injection.
Comparative example 1
Prescription composition:
| raw and auxiliary materials | Charge g |
| Left ornidazole derivative | 15 |
| Medium chain triglycerides | 30 |
| Yolk lecithin PL-100M | 5 |
| Oleic acid | 0.1 |
| Polysorbate 80 | 1 |
| Glycerol | 2.2 |
| Water for injection | 46.70 |
The preparation method comprises the following steps:
(1) Preparing an oil phase: under the water bath heat preservation of 60 ℃, adding egg yolk lecithin PL-100M and oleic acid into medium chain triglyceride, shearing at high speed to dissolve the mixture, adding a left ornidazole derivative which is a compound of a structural formula (1), stirring, dissolving and mixing uniformly to obtain the compound;
(2) Preparing an aqueous phase: adding glycerol and polysorbate 80 into injectable water at 60deg.C under water bath, stirring and dissolving to obtain the final product;
(3) Preparation of colostrum: adding the water phase in the step (2) into the oil phase in the step (1), and shearing and dispersing for 1min at a high speed under the water bath heat preservation of 60 ℃ to form colostrum;
(4) Preparing final emulsion: homogenizing the colostrum obtained in the step (3) under high pressure for 240s under 800-1000bar pressure to obtain final emulsion, and adding 1M HCl solution to adjust pH to 7.51;
(5) Filtering, packaging into penicillin bottle, adding nitrogen, sealing, and sterilizing at 116 deg.C for 40 min.
Comparative example 2
Prescription composition:
the preparation method comprises the following steps:
(1) Preparing an oil phase: under the water bath heat preservation of 60 ℃, adding egg yolk lecithin PL-100M into medium chain triglyceride, shearing at high speed to dissolve the mixture, adding a left ornidazole derivative which is a compound of the structural formula (1), stirring, dissolving and mixing uniformly to obtain the compound;
(2) Preparing an aqueous phase: adding glycerol and poloxamer 188 into water for injection under the condition of 60 ℃ water bath heat preservation, stirring and dissolving to obtain the compound;
(3) Preparation of colostrum: adding the water phase in the step (2) into the oil phase in the step (1), and shearing and dispersing for 1min at a high speed under the water bath heat preservation of 60 ℃ to form colostrum;
(4) Preparing final emulsion: homogenizing the colostrum obtained in the step (3) under high pressure for 120s under 800-1000bar pressure to obtain final emulsion, and adding 1M HCl solution to adjust pH to 6.82;
(5) Filtering, packaging into penicillin bottle, adding nitrogen, sealing, and sterilizing at 116 deg.C for 40 min.
Test example 3: stability investigation
Samples of examples 1 to 8 and comparative examples 1 to 2 were taken and subjected to stability lofting at 4℃and 25℃and allowed to stand for 30 days, and then the changes in particle size and potential were examined. The specific results are shown in the following table:
the particle size and potential samples are light yellow emulsion with good fluidity, wherein the demulsification sample is a visual oil drop attached to the wall of the bottle, and the detection is not performed any more. Wherein, the excessive dosage of the left ornidazole derivative in the comparative example 1 leads to larger particle size of the prepared emulsion and easy demulsification. In contrast, the emulsifier of comparative example 2, egg yolk lecithin, was used in a small amount, and did not provide good emulsification, resulting in demulsification after sterilization of the formulation.
Test example 4: the emulsion injection of the invention is used for in vivo pharmacokinetics research of rats
Rats were given by tail vein injection using the emulsion injection of example 6, example 7 and a commercial sodium chloride injection of left ornidazole of the present invention, 3 rats per group were fasted prior to administration at a dose of 50mg/kg based on left ornidazole, and blood was withdrawn through the fundus veins of the rats and placed in heparin-treated tubes at 5, 10, 15, 30, 60, 120, 240, 360, 480, 720 and 1440min after administration, respectively. The whole blood is centrifuged at 8000rpm for 5min, and the separated plasma sample is stored at-80 ℃ for analysis to determine the concentration of the left ornidazole in the plasma. The time dependence of the changes of the left ornidazole in the rat plasma was examined, and fig. 5 is a graph showing the blood concentration-time curve of the left ornidazole sodium chloride injection and the left ornidazole derivative emulsion injection.
According to the design principle, the samples of the invention in the embodiment 6 and the embodiment 7 have a certain peak delay after injection, and can inhibit the exposure of the left ornidazole to the injection site. For the sample of example 6, the peak time of the blood concentration is slightly backward compared with the left ornidazole sodium chloride injection, and the area under the curve of the medicine is not obviously different from that of the left ornidazole sodium chloride injection, which indicates that the antibacterial effect can be consistent with that of the left ornidazole sodium chloride injection. For the sample of the example 7, the significant increase of the particle size leads to the obvious slowing of the drug release rate, the peak time of the blood concentration is about 2 hours, the highest blood concentration is reduced, but the area under the curve is almost unaffected, so that a safer blood concentration space is provided for patients with liver and kidney dysfunction; providing sufficient administration time for preoperative prophylaxis; a certain space is reserved for the combined use of the medicine with other intravenous drugs, and the highest blood concentration of the medicine and the medicine is avoided to increase the metabolic burden of patients. Patient compliance and physician clinical flexibility are both increased.
The foregoing description is not intended to limit the scope of the invention, which is defined broadly in the claims, and any person skilled in the art will recognize that the invention is also within the scope of the claims, if exactly the same or equivalent as the claims define.
Claims (6)
1. An emulsion formulation comprising a derivative of levo-ornidazole, comprising:
(a) A compound represented by structural formula (1) as an active ingredient:
(b) An emulsifying agent;
(c) Injection oil;
the emulsifier is egg yolk lecithin, and the mass percentage is 1-2%;
the injection oil is medium chain triglyceride with the mass percentage of 10-20%;
the mass percentage of the active ingredients is 0.1-10% based on 100% of the total volume of the emulsion preparation;
the composition further comprises a stabilizer, wherein the stabilizer is one or more selected from oleic acid, sodium oleate, kolliphor HS15, polysorbate, docusate sodium, deoxycholic acid and poloxamer;
the composition also comprises an isotonic regulator, wherein the isotonic regulator is one or more selected from sucrose, glucose, sorbitol, xylitol, sodium chloride and glycerol;
the pH regulator is one or more selected from citric acid, hydrochloric acid, fumaric acid, lysine, tartaric acid, histidine, sodium citrate, sodium hydroxide, sodium dihydrogen phosphate and disodium hydrogen phosphate;
the dosage form is injection suitable for clinical intravenous injection, intravenous drip or intramuscular injection.
2. The emulsion formulation containing a levo-ornidazole derivative according to claim 1, wherein the mass percentage of the active ingredient is 1-5% based on 100% of the total volume of the emulsion formulation.
3. An emulsion formulation comprising a derivative of levo-ornidazole according to any one of claims 1 to 2, wherein the emulsion formulation has an average particle size in the range of 100 to 1000 nm.
4. A milky formulation containing a levo-ornidazole derivative according to claim 3, wherein the average particle size of the milky formulation is in the range of 100-500 nm.
5. The emulsion formulation comprising a derivative of levo-ornidazole according to claim 4, wherein the emulsion formulation has an average particle size in the range of 150-250 nm.
6. A process for the preparation of an emulsion formulation comprising a derivative of levo-ornidazole according to any one of claims 1 to 5, comprising the steps of:
(1) Preparing an oil phase: adding emulsifier and liposoluble stabilizer into the injectable oil, shearing at high speed to dissolve, adding the left ornidazole derivative, stirring to dissolve, and mixing uniformly to obtain the final product;
(2) Preparing an aqueous phase: adding an isotonic regulator and a water-soluble stabilizer into water for injection, adding a pH regulator, and stirring for dissolution to obtain the injection;
(3) Preparation of colostrum: adding the water phase in the step (2) into the oil phase in the step (1), and shearing and dispersing at a high speed under water bath heat preservation to form colostrum;
(4) Preparing final emulsion: homogenizing the colostrum obtained in the step (3) under high pressure to obtain final milk, and adding a pH regulator to regulate the pH of the final milk;
(5) Filtering, filling, nitrogen charging, and wet heat sterilizing.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1686117A (en) * | 2005-04-28 | 2005-10-26 | 南京圣和药业有限公司 | Application of levoornidazole in preparation of anti anaerobic bacteria infection medicine |
| CN101723969A (en) * | 2009-12-08 | 2010-06-09 | 陕西合成药业有限公司 | Nitro imidazole derivate used for treatment |
| CN102485210A (en) * | 2010-12-03 | 2012-06-06 | 齐鲁制药有限公司 | Voriconazole intravenous injection submicron emulsion and its preparation method |
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| US20070104778A1 (en) * | 2005-11-07 | 2007-05-10 | Hongxia Zeng | Controlled-release emulsion compositions |
| SI2200588T1 (en) * | 2007-09-25 | 2019-08-30 | Solubest Ltd. | Compositions comprising lipophilic active compounds and method for their preparation |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1686117A (en) * | 2005-04-28 | 2005-10-26 | 南京圣和药业有限公司 | Application of levoornidazole in preparation of anti anaerobic bacteria infection medicine |
| CN101723969A (en) * | 2009-12-08 | 2010-06-09 | 陕西合成药业有限公司 | Nitro imidazole derivate used for treatment |
| CN102485210A (en) * | 2010-12-03 | 2012-06-06 | 齐鲁制药有限公司 | Voriconazole intravenous injection submicron emulsion and its preparation method |
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