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CN112618486A - Suspension oil agent for injection and preparation method thereof - Google Patents

Suspension oil agent for injection and preparation method thereof Download PDF

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Publication number
CN112618486A
CN112618486A CN202011546314.3A CN202011546314A CN112618486A CN 112618486 A CN112618486 A CN 112618486A CN 202011546314 A CN202011546314 A CN 202011546314A CN 112618486 A CN112618486 A CN 112618486A
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injection
oil
piperacillin
tazobactam
suspension
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CN112618486B (en
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徐成苗
方昌义
邱新
杨金纬
刘美玲
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Beijing Medfron Medicina Technology Co ltd
Zhejiang Anglikang Pharmaceutical Co ltd
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Beijing Wanpeng Langge Medicine Technology Co ltd
Zhejiang Anglikang Pharmaceutical Co ltd
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    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
    • 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
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    • A—HUMAN NECESSITIES
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    • 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
    • A61K47/24—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
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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 application provides a suspension oil agent for injection and a preparation method thereof, belonging to the technical field of medical preparations. Comprises piperacillin and tazobactam, the ratio of the piperacillin to the tazobactam is 8:1 or 4:1, and also comprises a liquid medium, a suspending agent and an antioxidant, wherein the liquid medium is oil for injection, and the ratio of the piperacillin to the tazobactam is as follows: the liquid medium is 1:5-1:20, the suspension oil preparation for injection is used for intramuscular injection, the stability of piperacillin and tazobactam preparations is improved, and compared with salifying and freeze-drying processes, the suspension oil preparation for injection has the advantages of simple process, short production period, low energy consumption and the like.

Description

Suspension oil agent for injection and preparation method thereof
Technical Field
The application relates to a suspension oil agent for injection and a preparation method thereof, belonging to the technical field of medical preparations.
Background
Piperacillin sodium is a semi-synthetic beta-lactam broad-spectrum antibiotic with molecular formula C23H27N5O7S·H2O, molecular weight 535.58, and can be used for treating septicemia due to sensitive Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter, upper urinary tract infection, complicated urinary tract infection, respiratory tract infection, biliary tract infection, abdominal cavity infection, pelvic cavity infection, skin infection, and soft tissue infection. The product can be used together with aminoglycosides for treating infection of patients with granulocytopenia and immunodeficiency.
Tazobactam sodium is a beta-lactamase inhibitor, and has a molecular formula C10H12N4O5S, molecular weight 300.29, its clinical application effect is better, it is more broad to inhibit enzyme spectrum, tissue penetrability is strong, distribute extensively. It has inhibiting effect on chromosome, plasmid mediated enzyme, broad spectrum enzyme and penicillinase.
The combination of piperacillin and tazobactam has better synergistic effect. The currently marketed piperacillin sodium tazobactam sodium for injection is first marketed in france in 1992 on day 7/2 under the trade name "tazociline", and subsequently marketed in the united states, the european union, japan under the trade name "ZOSYN", and in the european union under the trade name "Tazocin". The varieties sold in the market at present have two specifications of piperacillin and tazobactam 8:1 and 4: 1. The medicine is clinically applicable to septicemia, complicated cystitis and pyelonephritis caused by staphylococcus, coliform bacteria, citric acid bacteria, klebsiella, enterobacter, providencia and pseudomonas which are sensitive to the medicine. Piperacillin sodium and tazobactam sodium for injection are prepared by reacting piperacillin and tazobactam with sodium bicarbonate to obtain piperacillin sodium and tazobactam sodium, and freeze-drying to obtain powder for injection; however, the stability of piperacillin sodium and tazobactam sodium is poor, the product impurities are increased due to the high alkalinity of sodium bicarbonate in the salt forming process, and although the stability of the product can be improved to a certain extent by a freeze-dried preparation, the product is degraded at high temperature and is hydrolyzed after being dissolved before clinical use.
Disclosure of Invention
In view of the above, the present application first provides a piperacillin-tazobactam composition-containing suspension oil for injection
Specifically, the method is realized through the following scheme:
a suspension oil agent for injection comprises piperacillin and tazobactam, wherein the mass ratio of the piperacillin to the tazobactam is 8:1 or 4:1, and the suspension oil agent further comprises a liquid medium and an antioxidant, wherein the liquid medium is oil for injection, and the ratio of the piperacillin to the tazobactam is as follows: the liquid medium is 1:5-1: 20.
In the suspension oil agent, piperacillin and tazobactam are isolated by a liquid medium of oil for injection in a solid form, do not contact with acid, alkali, water, oxygen and the like, are not degraded basically, and have stability superior to that of piperacillin sodium and tazobactam sodium for injection. The compound antioxidant is used for intramuscular injection, and the stability of piperacillin and tazobactam preparations is improved.
Further, as preferable:
the liquid medium is any one of soybean oil for injection, medium-chain oil (namely triglyceride) and castor oil; the main function is also as a suspension medium to isolate water and air, and improve stability.
The piperacillin: the liquid medium is 1:7-1: 9.
The suspending agent is any one of lecithin, polyoxyethylene castor oil and tween 80, so that the suspending effect is met, and the selected suspending agent is an auxiliary material which can be dissolved in oil and is matched with a liquid medium to realize the effect.
The antioxidant is any one of vitamin E, tert-butyl p-hydroxyanisole (BHA) and ditert-butyl hydroxy cresol (BHT). The antioxidant can prevent unsaturated fatty acid in grease, especially vegetable oil from being oxidized, and the antioxidant is oil soluble and has good compatibility with liquid medium.
The analgesic also comprises an analgesic, the local irritation is relieved, and the oily solvent which is a suspension is more irritant than a common injection, so that the analgesic adopts benzyl alcohol.
Meanwhile, the application also provides a preparation method of the suspension oil agent for injection, which comprises the following steps: adding the suspending agent and the antioxidant into a liquid medium, stirring and dissolving, carrying out hot-pressing sterilization or aseptic filtration, crushing the aseptic piperacillin and tazobactam, and adding the piperacillin: the solvent is 1:5-1: 20.
The production environment is an aseptic production environment, the suspending agent, the antioxidant and the local analgesic are added into a liquid medium to be stirred and dissolved, the aseptic guarantee is met through hot-pressing sterilization or aseptic filtration, the piperacillin and the tazobactam are added into a solvent to be stirred and uniformly dispersed, and the mixture is encapsulated after being detected to be qualified.
Further, as preferable:
the particle size of the piperacillin and tazobactam is required to be D90 (equivalent diameter of the largest particle with 90% cumulative distribution in a particle size distribution curve) less than 40 μm, preferably D90 less than 15 μm by mechanical crushing or airflow crushing. The piperacillin and tazobactam with the particle size range are beneficial to reducing the sedimentation of suspension solid, so that particles are easier to suspend and disperse, and the uniformity of the content of the preparation is improved.
The piperacillin: the liquid medium is 1:7-1: 9.
The analgesic is added into a liquid medium, stirred and dissolved, and the analgesic is benzyl alcohol.
In the scheme, the antioxidant, the suspending agent and the analgesic are all in the common dosage range specified by the industry.
Meanwhile, the application also provides a preparation method of the suspension oil agent for injection, which comprises the following steps: adding the sterilized piperacillin and tazobactam into a liquid medium after crushing, wherein the weight ratio of piperacillin: the solvent is 1:5-1:20, and then the suspending agent and the antioxidant are added to form the suspension oil agent.
Further, as preferable:
the particle size of the piperacillin and tazobactam is required to be D90 (equivalent diameter of the largest particle with 90% cumulative distribution in a particle size distribution curve) less than 40 μm, preferably D90 less than 15 μm by mechanical crushing or airflow crushing.
The piperacillin: the solvent is 1:7-1: 9.
The analgesic is a benzyl alcohol suspension.
The above statement provides two preparation schemes with different adding sequences at normal temperature, and compared with salification and freeze-drying processes, the method has the advantages of simple process, short production period, lower energy consumption and the like.
The two preparation methods can be summarized as follows: material crushing → oil solvent preparation → sterilization, or sterilization → suspension preparation → detection → filling; the raw material medicine cannot resist high temperature and can not be subjected to terminal sterilization, and suspension is not suitable for final sterilization filtration, so that the sterilization and the sterilization are both performed on auxiliary materials such as oil for injection and the like, and the operation can be realized by adopting the two procedures.
Detailed Description
Specific examples of the present application are described in detail below to facilitate a further understanding of the invention.
All experimental procedures used in the following examples are conventional unless otherwise specified. Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1
Table 1 shows the formulation of the oil suspension for injection in this example.
TABLE 1 formulation constitution of suspension for injection of this example
Figure BDA0002855825080000041
The preparation process comprises the following steps:
(1) respectively crushing piperacillin and tazobactam by a high-speed crusher to obtain particles with the particle size D90 smaller than 40 μm for later use;
(2) respectively weighing BHA, BHT and injection medium-chain oil in the prescribed amount, adding BHA and BHT into the injection medium-chain oil, and stirring for dissolving;
(3) filling the oil solution into a sealed pressure-resistant container (such as an infusion bottle), sterilizing at 121 ℃ under hot pressure for 15 minutes, taking out and cooling;
(4) weighing the crushed piperacillin and tazobactam according to the prescription amount, adding the weighed materials into the sterilized oil solution, and stirring for 2 hours;
(5) sampling and detecting the content, filling into an ampoule bottle, filling about 11 ml/bottle, and sealing to obtain the product.
Example 2
Table 2 shows the formulation of the oil suspension for injection in this example.
TABLE 2 formulation constitution of suspension for injection of this example
Figure BDA0002855825080000051
The preparation process comprises the following steps:
(1) respectively crushing piperacillin and tazobactam by a high-speed crusher to obtain particles with the particle size D90 smaller than 40 μm for later use;
(2) respectively weighing BHA, BHT, polyoxyethylene castor oil and middle-chain oil for injection in a prescribed amount, adding the BHA, BHT and polyoxyethylene castor oil into the middle-chain oil for injection, and stirring for dissolving;
(3) filling the oil solution into a sealed pressure-resistant container (such as an infusion bottle), sterilizing at 121 ℃ under hot pressure for 15 minutes, taking out and cooling;
(4) weighing the crushed piperacillin and tazobactam according to the prescription amount, adding the weighed materials into the sterilized oil solution, and stirring for 2 hours;
(5) sampling, detecting content, filling into ampoule bottle, filling 7.7 ml/bottle, and sealing.
Example 3
Table 3 shows the formulation of the oil suspension for injection in this example.
TABLE 3 formulation constitution of suspension for injection of this example
Figure BDA0002855825080000052
Figure BDA0002855825080000061
The preparation process comprises the following steps:
(1) respectively crushing piperacillin and tazobactam by a high-speed crusher to obtain particles with the particle size D90 smaller than 40 μm for later use;
(2) respectively weighing BHA, BHT, polyoxyethylene castor oil, Tween 80 and soybean oil for injection, adding BHA, BHT, Tween 80 and polyoxyethylene castor oil into soybean oil for injection, and stirring for dissolving;
(3) filling the oil solution into a sealed pressure-resistant container (such as an infusion bottle), sterilizing at 121 ℃ under hot pressure for 15 minutes, taking out and cooling;
(4) weighing the crushed piperacillin and tazobactam according to the prescription amount, adding the weighed materials into the sterilized oil solution, and stirring for 2 hours;
(5) sampling, detecting content, filling into ampoule bottle, filling 6.8 ml/bottle, and sealing.
Example 4
Table 4 shows the formulation of the oil suspension for injection in this example.
TABLE 4 formulation constitution of suspension for injection of this example
Figure BDA0002855825080000062
The preparation process comprises the following steps:
(1) respectively crushing piperacillin and tazobactam by using an airflow crusher, wherein the particle size D90 is less than 15 mu m for later use;
(2) respectively weighing BHA, BHT, Tween 80, lecithin and soybean oil for injection in a prescription amount, adding the BHA, BHT, Tween 80 and lecithin into the soybean oil for injection, and stirring for dissolving;
(3) filtering the oil solution with 0.22 μm microporous membrane for sterilization;
(4) weighing the crushed piperacillin and tazobactam according to the prescription amount, adding the weighed materials into the sterilized oil solution, and stirring for 2 hours;
(5) sampling, detecting content, filling into ampoule bottle, filling 9.9 ml/bottle, and sealing.
Example 5
Table 5 shows the formulation of the oil suspension for injection in this example.
TABLE 5 formulation constitution of suspension for injection of this example
Figure BDA0002855825080000071
The preparation process comprises the following steps:
(1) respectively crushing piperacillin and tazobactam by using an airflow crusher, wherein the particle size D90 is less than 15 mu m for later use;
(2) respectively weighing BHA, BHT, polyoxyethylene castor oil, lecithin and soybean oil for injection, adding BHA, BHT, Tween 80 and lecithin into soybean oil for injection, and stirring for dissolving;
(3) filtering the oil solution with 0.22 μm microporous membrane for sterilization;
(4) weighing the crushed piperacillin and tazobactam according to the prescription amount, adding the weighed materials into the sterilized oil solution, and stirring for 2 hours;
(5) sampling and detecting the content, filling into a penicillin bottle, filling 10 ml/bottle, pressing a plug, and tying a cover.
Example 6
Table 6 shows the formulation of the oil suspension for injection in this example.
TABLE 6 formulation constitution of suspension for injection of this example
Figure BDA0002855825080000081
The preparation process comprises the following steps:
(1) respectively crushing piperacillin and tazobactam by using an airflow crusher, wherein the particle size D90 is less than 15 mu m for later use;
(2) respectively weighing vitamin E, lecithin, benzyl alcohol and soybean oil for injection according to the prescription amount, adding the vitamin E, the lecithin and the benzyl alcohol into the soybean oil for injection, and stirring for dissolving;
(3) filtering the oil solution with 0.22 μm microporous membrane for sterilization;
(4) weighing the crushed piperacillin and tazobactam according to the prescription amount, adding the weighed materials into the sterilized oil solution, and stirring for 2 hours;
(5) sampling and detecting the content, filling into a penicillin bottle, filling 10 ml/bottle, pressing a plug, and tying a cover.
Comparative example: salt-forming freeze-drying process
The formulation and preparation of the lyophilization process are shown in table 7.
TABLE 7 formulation constitution of the reagents of the comparative examples
Figure BDA0002855825080000091
The preparation process comprises the following steps:
(1) taking 100ml of water for injection, adding piperacillin and tazobactam with the prescribed amount, and stirring and dispersing;
(2) slowly adding the sodium bicarbonate with the prescription amount, reacting to generate a large amount of bubbles, continuously stirring until the bubbles disappear, and completely dissolving the piperacillin and the tazobactam;
(3) adjusting the pH value to 5.5-6.7 by using 0.1mol/L hydrochloric acid or sodium hydroxide, and adding water for injection to fix the volume to 500 ml;
(4) filtering the solution through a 0.22 μm microporous filter membrane for sterilization;
(5) sampling and detecting the content, filling into a penicillin bottle, filling about 5 ml/bottle, and half-pressing and plugging;
(6) the samples were placed in a freeze dryer for freeze drying:
pre-freezing: the temperature of the plate layer is-50 ℃, and the plate layer is kept for 4 hours;
② sublimation: the temperature of the plate layer is increased to-10 ℃ and kept for 28 hours;
analysis and drying: raising the temperature of the plate layer to 30 ℃, and keeping the temperature for 8 hours;
(7) and (5) after the freeze-drying procedure is finished, performing vacuum corking, discharging out of the box, and bundling a cover to obtain the freeze-dried powder.
The agents prepared in the above examples and comparative examples were subjected to stability lofting and analysis, as shown in table 8.
TABLE 8 comparison of test results of various examples
Figure BDA0002855825080000092
Figure BDA0002855825080000101
The results show that:
(1) and (3) stability: the samples of the compositions containing piperacillin and tazobactam in each embodiment of the invention are placed at 40 ℃ for 30 days, the related substances slightly rise, and the content is basically unchanged; the comparative example is placed at 40 ℃ for 30 days, the related substances obviously rise, and the content is reduced; therefore, the injection suspension oil agent containing the piperacillin and tazobactam composition in the embodiment has obvious advantage in stability.
(2) The process aspect is as follows: the salt-forming freeze-drying process of the comparative example not only relates to dispersion and dissolution, but also needs to carry out salt forming and freeze drying, needs to be switched among different reaction vessels, is complex to operate, needs to consume a large amount of heat energy to realize state change, can only produce one to twenty thousand bottles in one batch, and has a production period of more than 3 days per batch. The preparation process of the suspension oil for injection only relates to the processes of crushing, mixing, sterilizing or degerming, and is simple; the production cycle is short and the batch is large, the time consumption of one production process is generally not more than 12 hours, and the batch can reach hundreds of thousands of bottles; the preparation process only needs to provide mechanical energy for crushing and mixing, and the energy consumption of the sterilization process or the filter membrane treatment necessary for sterilization is low.

Claims (10)

1. A suspension oil for injection comprises piperacillin and tazobactam, wherein the mass ratio of the piperacillin to the tazobactam is 8:1 or 4:1, and the injection is characterized in that: the injection also comprises a liquid medium and an antioxidant, wherein the liquid medium is oil for injection, and the mass ratio of the piperacillin to the solvent is 1:5-1: 20.
2. An injectable oil suspension according to claim 1, which is characterized in that: the liquid medium is any one of soybean oil for injection, medium-chain oil and castor oil.
3. An injectable oil suspension according to claim 1, which is characterized in that: the suspending agent is one or a combination of more of lecithin, polyoxyethylene castor oil and tween 80.
4. An injectable oil suspension according to claim 1, which is characterized in that: the antioxidant is any one or combination of more of vitamin E, tert-butyl p-hydroxyanisole and di-tert-butyl hydroxytoluene.
5. An injectable oil suspension according to claim 1, wherein the piperacillin: the liquid medium is 1:7-1: 9.
6. An injectable oil suspension according to any one of claims 1 to 5, wherein: also comprises an analgesic, wherein the analgesic adopts benzyl alcohol.
7. A preparation method of a suspension oil agent for injection is characterized by comprising the following steps: adding the suspending agent and the antioxidant into a liquid medium, stirring and dissolving, carrying out hot-pressing sterile or sterile filtration, crushing sterile piperacillin and tazobactam, and adding the obtained product, wherein the weight ratio of piperacillin: the liquid medium is 1:5-1:20, and the injection suspension oil agent is formed according to claim 1.
8. A method for preparing a suspension-oil agent for injection according to claim 7, characterized in that: the piperacillin and tazobactam are mechanically or pneumatically crushed, and the particle size D90 is required to be less than 40 μm.
9. A preparation method of a suspension oil agent for injection is characterized by comprising the following steps: adding the sterilized piperacillin and tazobactam into a liquid medium after crushing, wherein the weight ratio of piperacillin: the solvent is 1:5-1:20, and the suspending agent and the antioxidant are added to form the injection oil suspension agent of claim 1.
10. A method for preparing a suspension-oil agent for injection according to claim 9, characterized in that: the piperacillin and tazobactam are mechanically or pneumatically crushed, and the particle size D90 is required to be less than 40 μm.
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