CN110339165A - A kind of Dexibuprofen fat emulsion injection and preparation method thereof - Google Patents
A kind of Dexibuprofen fat emulsion injection and preparation method thereof Download PDFInfo
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- CN110339165A CN110339165A CN201910765859.4A CN201910765859A CN110339165A CN 110339165 A CN110339165 A CN 110339165A CN 201910765859 A CN201910765859 A CN 201910765859A CN 110339165 A CN110339165 A CN 110339165A
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- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- 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
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- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
The present invention relates to a kind of preparation methods of Dexibuprofen fat emulsion injection, the following steps are included: heating, stirring form uniform oil-phase solution in long chain fatty acids, medium chain fatty acid and 15-hydroxy polyethylene glycol stearate (KolliphorHS 15)；Emulsifier, osmotic pressure regulator and water are mixed, aqueous phase solution is formed；Water-oil phase is mixed, at a certain temperature stirring and emulsification pretreatment, arrives the Dexibuprofen fat emulsion injection by high-pressure homogeneous, pH adjusting, filtering, sterilizing etc..The present invention uses novel injection solubilizer KolliphorHS15, efficiently solves the problems, such as the compatibility stability and drugloading rate of Dexibuprofen injection in clinical use, while being expected to improve the safety of preparation.
Description
Technical field
The present invention relates to field of pharmaceutical preparations more particularly to a kind of Dexibuprofen fat emulsion injection and preparation method thereof.
Background technique
Brufen is antipyretic-antalgic non-steroid antiphlogistic, is usually used in caused fever of catching a cold, be also used for alleviating it is various it is light,
Moderate pain.Dexibuprofen is the pure space corresponding body of brufen, and it is the 1.6 of raceme that activity, which is 160 times of levo form,
Times.Not only pharmacological activity is good for Dexibuprofen, but also gastrointestinal side effect and liver renal toxicity are small.The country clinically applies at present
Dexibuprofen dosage form mainly has tablet, suppository, capsule and suspension, and dissolubility is poor, drug effect is slow, and there has been no injection listings.
The ibuprofen injection that in June, 2009 Cumberland company develops obtains FDA approval listing, the ibuprofen injection in the U.S.
Use arginine as solubilizer, brufen is easy to be precipitated in clinical application.The right side more safely, effectively, stable is developed thus
Motrin is very necessary.
Indissoluble, Chinese invention patent CN102362857 A disclose a kind of (S)-ibuprofen injection to Dexibuprofen in water
Liquid and preparation method thereof, this method promote Dexibuprofen in water using meglumine, citric acid, trisodium citrate as cosolvent
At salt in solution, to solve the problems, such as solubility.But this formula solution stability is poor, and Dexibuprofen salt solubility can be with
The variation of pH value of solution and change, drugloading rate, safety still have some problems in clinical compatibility use.
Fat Emulsion can increase the solubility of the such insoluble drug of Dexibuprofen as carrier, improve medicine stability and life
Object availability reduces medicine irritation, and drug is made to generate targeting, has good safety.Chinese invention patent
CN104546706 A discloses a kind of (S)-ibuprofen emulsion for injection and preparation method thereof, and oily phase auxiliary material faces only with soybean oil
Often cause injection pain in bed application；In addition, the technique uses poloxamer for emulsifier, had in clinical application molten
The adverse reactions such as blood, vascular stimulation, allergic reaction occur, and there are certain safety problems.
Summary of the invention
In order to solve the above technical problems, the object of the present invention is to provide a kind of Dexibuprofen fat emulsion injection and its preparations
Method, present invention injection solubilizer 15-hydroxy polyethylene glycol stearate (KolliphorHS15) safe to use,
The use for avoiding conventional solubilizer polysorbate, poloxamer, effectively improves safety, avoids all kinds of adverse reactions, prepared
Dexibuprofen fat emulsion injection have both the characteristic that drugloading rate is high, solution-stabilized and safe clinical compatibility simultaneously.
To achieve the goals above, the present invention provides the following technical solutions:
One aspect of the present invention provides a kind of Dexibuprofen fat emulsion injection preparation method, comprising the following steps:
(1) Dexibuprofen is dissolved in the long chain fatty acids, medium chain fatty acid and solubilizer, forms oil-phase solution；Institute
Stating solubilizer is -15 hydroxy stearic acid ester of polyethylene glycol；
The emulsifier, osmotic pressure regulator and water are mixed, aqueous phase solution is formed；The emulsifier is phospholipid chemical combination
Object；
(2) oil-phase solution and aqueous phase solution are mixed, stirring and emulsification pretreatment at 20~75 DEG C DEG C, 500~
PH adjusting agent is added under 900bar pressure after homogeneous and adjusts pH to 4.0~9.0, obtains the Dexibuprofen rouge after filtering, sterilizing
Fat emulsion injection.
Further, in step (1), the long chain fatty acids are soybean oil；Every 1000mL Dexibuprofen Fat Emulsion note
Penetrate addition 50~150g of long chain fatty acids in liquid.
Further, in step (1), the medium chain fatty acid is median chain triglyceride oil；Every 1000mL Dexibuprofen
50~150g of medium chain fatty acid is added in fat emulsion injection.
Further, in step (1), the phospholipids compounds are egg yolk lecithin；Every 1000mL Dexibuprofen rouge
6~18g of emulsifier is added in fat emulsion injection.
Further, in step (1), the osmotic pressure regulator is glycerol；Every 1000mL Dexibuprofen Fat Emulsion note
Penetrate addition osmotic pressure regulator 25g in liquid.
Further, in step (2), the pH adjusting agent is sodium hydroxide or hydrochloric acid.
Further, in step (2), homogenization cycles are 3~8 times.
Further, in step (2), homogenizing temperature is 20~75 DEG C.
Further, in step (2), further include the steps that water, which is added, is settled to target volume before adjusting pH.
In a preferred embodiment, Dexibuprofen fat emulsion injection preparation method the following steps are included:
(1) long chain fatty acids and medium chain fatty acid are weighed, is mixed, is stirred spare；
(2) solubilizer KolliphorHS15 is added in the mixed liquor that step (1) obtains, under the conditions of room temperature~75 degree
Stirring is until all dissolutions；
(3) Dexibuprofen is added in the mixed liquor that step (2) obtains, stirring under the conditions of room temperature~75 degree is until all
Dissolution, it is spare as oily phase；
(4) water for injection is taken, emulsifier and osmotic pressure regulator is added, mills under the conditions of room temperature~75 degree, stirring is straight
It is uniform to solution, it is spare as water phase；
(5) solution obtained step (3) and (4) mixes, emulsification pretreatment, and under the conditions of the degree of room temperature~75 stirring up to
Solution is uniform, forms colostric fluid；
(6) NaOH or hydrochloric acid are used, adjusts colostric fluid pH value to 4.0~9.0, stirring is uniform, and solution temperature maintains room
Temperature~75 degree；
(7) lotion for obtaining step (6) uses high pressure homogenizer homogeneous, 500~900Bar of homogenization pressure, homogenization cycles
3~8 times, before last time homogeneous plus water constant volume is to prescribed volume.The stable right cloth of uniform particle diameter, quality is made after homogeneous
Ibuprofen fat emulsion injection, milk particle average grain diameter therein is in 160~320nm, and the milk particle accounting (pFat5) for being greater than 5 μm is small
In 0.05%；
(8) lotion obtained step (7) filters, encapsulating, 121 degree moist heat sterilization 15 minutes, it is fatty to obtain Dexibuprofen
Emulsion injection finished product.
Further, it is carried out under nitrogen protection in step (1)~(8) preparation process.
On the other hand, the present invention also provides a kind of Dexibuprofen fat emulsion injection using above method preparation is every
It include the component of following quality: 2~100g of Dexibuprofen, 50~150g of long chain fatty acids in 1000mL fat emulsion injection；In
50~150g of chain fatty acid；- 15 0.5~200g of hydroxy stearic acid ester of polyethylene glycol；6~18g of phospholipids compounds；Osmotic pressure tune
Save agent 25g；Surplus is water and pH adjusting agent, and the pH of the Dexibuprofen fat emulsion injection is 4.0~9.0.
It preferably, include the component of following quality: 20~60g of Dexibuprofen, long-chain in every 1000mL fat emulsion injection
50~100g of fatty acid；50~100g of medium chain fatty acid；- 15 2~50g of hydroxy stearic acid ester of polyethylene glycol；Phospholipids compounds 8
~16g；Osmotic pressure regulator 25g；Surplus is water and pH adjusting agent, the pH of the Dexibuprofen fat emulsion injection is 4.0~
9.0。
According to the above aspect of the present invention, the present invention at least has the following characteristics that
(1) the present invention provides a kind of Dexibuprofen fat emulsion injection, clinical compatibility quality is stablized, milk particle average grain diameter
In 160~320nm, the milk particle (pFat5) greater than 5 μm meets USP41 requirement less than 0.05%；
(2) the present invention provides a kind of Dexibuprofen fat emulsion injection, drugloading rate reaches 2~100mg/mL；
(3) the present invention provides a kind of Dexibuprofen fat emulsion injections, injection high using new type of safe for the first time
Solubilizer KolliphorHS15 avoids effectively improving safety using traditional solubilizer polysorbate, poloxamer etc., thus
Reduce related reactions；
(4) the present invention provides a kind of Dexibuprofen fat emulsion injections, use equal proportion long chain fatty acids and middle chain rouge
Fat acid is to carry medicine oil phase, increases Dexibuprofen drugloading rate, while also effectively mitigating drug injection pain；
(5) it is high, solution-stabilized to have both drugloading rate simultaneously for Dexibuprofen fat emulsion injection prepared by method of the invention
And the characteristic of clinical compatibility safety.
The above description is only an overview of the technical scheme of the present invention, in order to better understand the technical means of the present invention,
And can be implemented in accordance with the contents of the specification, the following is a detailed description of the preferred embodiments of the present invention and the accompanying drawings.
Detailed description of the invention
Fig. 1 is Dexibuprofen fat emulsion injection homogenization pressure-change of size curve prepared by embodiment 2~6；
Fig. 2 is Dexibuprofen fat emulsion injection homogenization cycles-change of size curve prepared by embodiment 7~10；
Fig. 3 is Dexibuprofen fat emulsion injection KolliphorHS15 different proportion-grain prepared by embodiment 9,11~13
Diameter change curve；
Fig. 4 is the lotion homogeneous photo of the different proportion containing KolliphorHS15 prepared by embodiment 13~14；
Fig. 5 is the finished product photo of Dexibuprofen fat emulsion injection prepared by embodiment 9；
Specific embodiment
With reference to the accompanying drawings and examples, specific embodiments of the present invention will be described in further detail.Implement below
Example is not intended to limit the scope of the invention for illustrating the present invention.
The embodiment that Dexibuprofen fat emulsion injection is prepared below the present invention carries out under the conditions of nitrogen protection.
Embodiment 1
Soybean oil, median chain triglyceride oil, glycerol, appropriate amount of water are taken respectively, excessive Dexibuprofen is added, and rocked at room temperature 24 is small
When, make to form saturated solution, boiled oil layer is taken after centrifugation, measures Dexibuprofen solubility.
Embodiment 2
Soybean oil and each 20.0g of median chain triglyceride oil are weighed, is mixed, stirring；Solubilizer KolliphorHS15 is added
1.0g is heated to 50 degree, and stirring is until all dissolutions；Dexibuprofen 10.0g is added, stirring is until all dissolve, as oily phase；
Water for injection 100mL is taken, glycerol 5.0g, purification egg yolk lecithin 2.4g is added, is heated to 50 degree, mills, stirring is until solution
It is uniform, as water phase；Oily phase and water phase are mixed, shearing, stirring is uniform up to solution, forms colostric fluid.Using high-pressure homogeneous
Machine homogeneous, homogenization pressure 500Bar, homogenization cycles 6 times, after the 5th homogeneous plus water is settled to 200mL.Solution after homogeneous
121 degree moist heat sterilization 15 minutes, obtain Dexibuprofen fat emulsion injection.
Embodiment 3
Soybean oil and each 20.0g of median chain triglyceride oil are weighed, is mixed, stirring；Solubilizer KolliphorHS15 is added
1.0g is heated to 50 degree, and stirring is until all dissolutions；Dexibuprofen 10.0g is added, stirring is until all dissolve, as oily phase；
Water for injection 100mL is taken, glycerol 5.0g, purification egg yolk lecithin 2.4g is added, is heated to 50 degree, mills, stirring is until solution
It is uniform, as water phase；Oily phase and water phase are mixed, shearing, stirring is uniform up to solution, forms colostric fluid.Using high-pressure homogeneous
Machine homogeneous, homogenization pressure 600Bar, homogenization cycles 6 times, after the 5th homogeneous plus water is settled to 200mL.Solution after homogeneous
121 degree moist heat sterilization 15 minutes, obtain Dexibuprofen fat emulsion injection.
Embodiment 4
Soybean oil and each 20.0g of median chain triglyceride oil are weighed, is mixed, stirring；Solubilizer KolliphorHS15 is added
1.0g is heated to 50 degree, and stirring is until all dissolutions；Dexibuprofen 10.0g is added, stirring is until all dissolve, as oily phase；
Water for injection 100mL is taken, glycerol 5.0g, purification egg yolk lecithin 2.4g is added, is heated to 50 degree, mills, stirring is until solution
It is uniform, as water phase；Oily phase and water phase are mixed, shearing, stirring is uniform up to solution, forms colostric fluid.Using high-pressure homogeneous
Machine homogeneous, homogenization pressure 700Bar, homogenization cycles 6 times, after the 5th homogeneous plus water is settled to 200mL.Solution after homogeneous
121 degree moist heat sterilization 15 minutes, obtain Dexibuprofen fat emulsion injection.
Embodiment 5
Soybean oil and each 20.0g of median chain triglyceride oil are weighed, is mixed, stirring；Solubilizer KolliphorHS15 is added
1.0g is heated to 50 degree, and stirring is until all dissolutions；Dexibuprofen 10.0g is added, stirring is until all dissolve, as oily phase；
Water for injection 100mL is taken, glycerol 5.0g, purification egg yolk lecithin 2.4g is added, is heated to 50 degree, mills, stirring is until solution
It is uniform, as water phase；Oily phase and water phase are mixed, shearing, stirring is uniform up to solution, forms colostric fluid.Using high-pressure homogeneous
Machine homogeneous, homogenization pressure 800Bar, homogenization cycles 6 times, after the 5th homogeneous plus water is settled to 200mL.Solution after homogeneous
121 degree moist heat sterilization 15 minutes, obtain Dexibuprofen fat emulsion injection.
Embodiment 6
Soybean oil and each 20.0g of median chain triglyceride oil are weighed, is mixed, stirring；Solubilizer KolliphorHS15 is added
1.0g is heated to 50 degree, and stirring is until all dissolutions；Dexibuprofen 10.0g is added, stirring is until all dissolve, as oily phase；
Water for injection 100mL is taken, glycerol 5.0g, purification egg yolk lecithin 2.4g is added, is heated to 50 degree, mills, stirring is until solution
It is uniform, as water phase；Oily phase and water phase are mixed, shearing, stirring is uniform up to solution, forms colostric fluid.Using high-pressure homogeneous
Machine homogeneous, homogenization pressure 900Bar, homogenization cycles 6 times, after the 5th homogeneous plus water is settled to 200mL.Solution after homogeneous
121 degree moist heat sterilization 15 minutes, obtain Dexibuprofen fat emulsion injection.
Embodiment 7
Soybean oil and each 20.0g of median chain triglyceride oil are weighed, is mixed, stirring；Solubilizer KolliphorHS15 is added
1.0g is heated to 50 degree, and stirring is until all dissolutions；Dexibuprofen 10.0g is added, stirring is until all dissolve, as oily phase；
Water for injection 100mL is taken, glycerol 5.0g, purification egg yolk lecithin 2.4g is added, is heated to 50 degree, mills, stirring is until solution
It is uniform, as water phase；Oily phase and water phase are mixed, shearing, stirring is uniform up to solution, forms colostric fluid.Using high-pressure homogeneous
Machine homogeneous, homogenization pressure 700Bar, homogenization cycles 2 times, after the 1st homogeneous plus water is settled to 200mL.Solution after homogeneous
121 degree moist heat sterilization 15 minutes, obtain Dexibuprofen fat emulsion injection.
Embodiment 8
Soybean oil and each 20.0g of median chain triglyceride oil are weighed, is mixed, stirring；Solubilizer KolliphorHS15 is added
1.0g is heated to 50 degree, and stirring is until all dissolutions；Dexibuprofen 10.0g is added, stirring is until all dissolve, as oily phase；
Water for injection 100mL is taken, glycerol 5.0g, purification egg yolk lecithin 2.4g is added, is heated to 50 degree, mills, stirring is until solution
It is uniform, as water phase；Oily phase and water phase are mixed, shearing, stirring is uniform up to solution, forms colostric fluid.Using high-pressure homogeneous
Machine homogeneous, homogenization pressure 700Bar, homogenization cycles 4 times, after the 3rd homogeneous plus water is settled to 200mL.Solution after homogeneous
121 degree moist heat sterilization 15 minutes, obtain Dexibuprofen fat emulsion injection.
Embodiment 9
Soybean oil and each 20.0g of median chain triglyceride oil are weighed, is mixed, stirring；Solubilizer KolliphorHS15 is added
1.0g is heated to 50 degree, and stirring is until all dissolutions；Dexibuprofen 10.0g is added, stirring is until all dissolve, as oily phase；
Water for injection 100mL is taken, glycerol 5.0g, purification egg yolk lecithin 2.4g is added, is heated to 50 degree, mills, stirring is until solution
It is uniform, as water phase；Oily phase and water phase are mixed, shearing, stirring is uniform up to solution, forms colostric fluid.Using high-pressure homogeneous
Machine homogeneous, homogenization pressure 700Bar, homogenization cycles 6 times, after the 5th homogeneous plus water is settled to 200mL.Solution after homogeneous
121 degree moist heat sterilization 15 minutes, obtain Dexibuprofen fat emulsion injection.
Embodiment 10
Soybean oil and each 20.0g of median chain triglyceride oil are weighed, is mixed, stirring；Solubilizer KolliphorHS15 is added
1.0g is heated to 50 degree, and stirring is until all dissolutions；Dexibuprofen 10.0g is added, stirring is until all dissolve, as oily phase；
Water for injection 100mL is taken, glycerol 5.0g, purification egg yolk lecithin 2.4g is added, is heated to 50 degree, mills, stirring is until solution
It is uniform, as water phase；Oily phase and water phase are mixed, shearing, stirring is uniform up to solution, forms colostric fluid.Using high-pressure homogeneous
Machine homogeneous, homogenization pressure 700Bar, homogenization cycles 8 times, after the 7th homogeneous plus water is settled to 200mL.Solution after homogeneous
121 degree moist heat sterilization 15 minutes, obtain Dexibuprofen fat emulsion injection.
Embodiment 11
Soybean oil and each 20.0g of median chain triglyceride oil are weighed, is mixed, stirring；Solubilizer KolliphorHS15 is added
0.1g is heated to 50 degree, and stirring is until all dissolutions；Dexibuprofen 10.0g is added, stirring is until all dissolve, as oily phase；
Water for injection 100mL is taken, glycerol 5.0g, purification egg yolk lecithin 2.4g is added, is heated to 50 degree, mills, stirring is until solution
It is uniform, as water phase；Oily phase and water phase are mixed, shearing, stirring is uniform up to solution, forms colostric fluid.Using high-pressure homogeneous
Machine homogeneous, homogenization pressure 700Bar, homogenization cycles 6 times, after the 5th homogeneous plus water is settled to 200mL.Solution after homogeneous
121 degree moist heat sterilization 15 minutes, obtain Dexibuprofen fat emulsion injection.
Embodiment 12
Soybean oil and each 20.0g of median chain triglyceride oil are weighed, is mixed, stirring；Solubilizer KolliphorHS15 is added
0.2g is heated to 50 degree, and stirring is until all dissolutions；Dexibuprofen 10.0g is added, stirring is until all dissolve, as oily phase；
Water for injection 100mL is taken, glycerol 5.0g, purification egg yolk lecithin 2.4g is added, is heated to 50 degree, mills, stirring is until solution
It is uniform, as water phase；Oily phase and water phase are mixed, shearing, stirring is uniform up to solution, forms colostric fluid.Using high-pressure homogeneous
Machine homogeneous, homogenization pressure 700Bar, homogenization cycles 6 times, after the 5th homogeneous plus water is settled to 200mL.Solution after homogeneous
121 degree moist heat sterilization 15 minutes, obtain Dexibuprofen fat emulsion injection.
Embodiment 13
Soybean oil and each 20.0g of median chain triglyceride oil are weighed, is mixed, stirring；Solubilizer KolliphorHS15 is added
2.0g is heated to 50 degree, and stirring is until all dissolutions；Dexibuprofen 10.0g is added, stirring is until all dissolve, as oily phase；
Water for injection 100mL is taken, glycerol 5.0g, purification egg yolk lecithin 2.4g is added, is heated to 50 degree, mills, stirring is until solution
It is uniform, as water phase；Oily phase and water phase are mixed, shearing, stirring is uniform up to solution, forms colostric fluid.Using high-pressure homogeneous
Machine homogeneous, homogenization pressure 700Bar, homogenization cycles 6 times, after the 5th homogeneous plus water is settled to 200mL.Solution after homogeneous
121 degree moist heat sterilization 15 minutes, obtain Dexibuprofen fat emulsion injection.
Embodiment 14
Soybean oil and each 20.0g of median chain triglyceride oil are weighed, is mixed, stirring；Dexibuprofen 10.0g is added, is heated to
50 degree, stirring is until all dissolve, as oily phase；Water for injection 100mL is taken, glycerol 5.0g, purification egg yolk lecithin is added
2.4g is heated to 50 degree, mills, and stirring is until solution is uniform, as water phase；Mutually mixed oily with water phase, shearing, stirring until
Solution is uniform, forms colostric fluid.Using high pressure homogenizer homogeneous, homogenization pressure 700Bar, homogenization cycles 6 times, the 5th homogeneous
Afterwards plus water is settled to 200mL.121 degree of solution moist heat sterilization 15 minutes, obtains Dexibuprofen fat emulsion injection after homogeneous.
1 Dexibuprofen solubility test of test case
Each Dexibuprofen saturated solution prepared by Example 1 weighs in right amount, three parts of test solution is prepared, with efficient liquid
Chromatography measures content, the results are shown in Table 1.As a result surface, Dexibuprofen solubility in soybean oil and median chain triglyceride oil
It is very big, also there is certain solubility in glycerol, but solubility very little in water.
Solubility in 1 different solvents of table
| Solvent | Average solubility, mg/g |
| Soybean oil | 237.50 |
| Median chain triglyceride oil | 397.96 |
| Glycerol | 134.65 |
| Water | 2.39 |
The test of 2 homogenization pressure of test case
The Dexibuprofen fat emulsion injection prepared under the different homogenization pressures of Example 2~6 is appropriate, uses laser particle analyzer
Average grain diameter and the ratio (pFat5) greater than 5 μm of milk particles are measured, the results are shown in Table 2.The result shows that Dexibuprofen Fat Emulsion is injected
Liquid can achieve more satisfactory partial size using 700bar pressure homogeneous.
The partial size of the different homogenization pressures of table 2
| Homogenization pressure | Average grain diameter, nm | PFat5, % |
| Embodiment 2 (500bar) | 291 | 0.0004 |
| Embodiment 3 (600bar) | 222 | 0.0077 |
| Embodiment 4 (700bar) | 204 | 0.0051 |
| Embodiment 5 (800bar) | 204 | 0.0056 |
| Embodiment 6 (900bar) | 206 | 0.0095 |
The test of 3 homogenization cycles of test case
The Dexibuprofen fat emulsion injection prepared under the different homogenization cycles of Example 7~10 is appropriate, uses laser particle size
Instrument measures average grain diameter and the ratio (pFat5) greater than 5 μm of milk particles, the results are shown in Table 3.The result shows that Dexibuprofen Fat Emulsion is infused
Penetrating liquid homogeneous 6 times can achieve more satisfactory partial size.
The partial size of the different homogenization cycles of table 3
| Homogenization cycles | Average grain diameter, nm | PFat5, % |
| Embodiment 7 (2 times) | 477 | 0.2633 |
| Embodiment 8 (4 times) | 262 | 0.0029 |
| Embodiment 9 (6 times) | 186 | 0.0023 |
| Embodiment 10 (8 times) | 307 | 0.0028 |
The test of test case 4KolliphorHS15 ratio
The Dexibuprofen fat emulsion injection that respectively prepared by Example 9,11~13 is appropriate, and is measured with laser particle analyzer
Average grain diameter and ratio (pFat5) greater than 5 μm of milk particles, the results are shown in Table 4.The result shows that when KolliphorHS15 ratio exists
When 0.1% or less, Dexibuprofen fat emulsion injection average grain diameter and pFat5 are bigger；When ratio is up to 0.5% or more,
PFat5 is smaller, Dexibuprofen fat emulsion injection stable homogeneous, and can achieve more satisfactory partial size.
The partial size of 4 difference KolliphorHS15 ratio of table
| KolliphorHS15 ratio | Average grain diameter, nm | PFat5, % |
| Embodiment 11 (0.05%) | 294 | 0.0453 |
| Embodiment 12 (0.1%) | 260 | 0.0294 |
| Embodiment 9 (0.5%) | 197 | 0.0072 |
| Embodiment 13 (1.0%) | 200 | 0.0062 |
Test case 5 is free of the test of KolliphorHS15
Dexibuprofen fat emulsion injection prepared by Example 13~14 is appropriate, checks solution appearance, as a result sees Fig. 4.
Fig. 4 a, b are respectively Dexibuprofen fat emulsion injection prepared by embodiment 13 and embodiment 14, the results showed that, it is free of
Occur exception in the Dexibuprofen fat emulsion injection homogenizing process of KolliphorHS15, there are a large amount of solids that (Fig. 4 b) is precipitated.
The above is only a preferred embodiment of the present invention, it is not intended to restrict the invention, it is noted that for this skill
For the those of ordinary skill in art field, without departing from the technical principles of the invention, can also make it is several improvement and
Modification, these improvements and modifications also should be regarded as protection scope of the present invention.
Claims (10)
1. a kind of Dexibuprofen fat emulsion injection preparation method, which comprises the following steps:
(1) Dexibuprofen is dissolved in the long chain fatty acids, medium chain fatty acid and solubilizer, forms oil-phase solution；The increasing
Solvent is -15 hydroxy stearic acid ester of polyethylene glycol；
The emulsifier, osmotic pressure regulator and water are mixed, aqueous phase solution is formed；The emulsifier is phospholipids compounds；
(2) oil-phase solution and aqueous phase solution are mixed, stirring and emulsification pretreatment at 20~75 DEG C, in 500~900bar
PH adjusting agent is added under pressure after homogeneous and adjusts pH to 4.0~9.0, the Dexibuprofen Fat Emulsion note is obtained after filtering, sterilizing
Penetrate liquid.
2. preparation method according to claim 1, which is characterized in that in step (1), the long chain fatty acids are soybean
Oil；50~150g of long chain fatty acids is added in every 1000mL Dexibuprofen fat emulsion injection.
3. preparation method according to claim 1, which is characterized in that in step (1), the medium chain fatty acid is middle chain
Triglyceride；50~150g of medium chain fatty acid is added in every 1000mL Dexibuprofen fat emulsion injection.
4. preparation method according to claim 1, which is characterized in that in step (1), the phospholipids compounds are egg
Yellow lecithin；6~18g of emulsifier is added in every 1000mL Dexibuprofen fat emulsion injection.
5. preparation method according to claim 1, which is characterized in that in step (1), the osmotic pressure regulator is sweet
Oil；Osmotic pressure regulator 25g is added in every 1000mL Dexibuprofen fat emulsion injection.
6. preparation method according to claim 1, which is characterized in that in step (2), the pH adjusting agent is hydroxide
Sodium or hydrochloric acid.
7. preparation method according to claim 1, which is characterized in that in step (2), homogenization cycles are 3~8 times.
8. preparation method according to claim 1, which is characterized in that in step (2), homogenizing temperature is 20~75 DEG C.
9. Dexibuprofen fat emulsion injection prepared by a kind of preparation method of any of claims 1-8, special
Sign is, includes the component of following quality: 2~100g of Dexibuprofen, long chain fatty acids 50 in every 1000mL fat emulsion injection
~150g；50~150g of medium chain fatty acid；- 15 0.5~200g of hydroxy stearic acid ester of polyethylene glycol；Phospholipids compounds 6~
18g；Osmotic pressure regulator 25g；Surplus is water and pH adjusting agent, the pH of the Dexibuprofen fat emulsion injection is 4.0~
9.0。
10. Dexibuprofen fat emulsion injection according to claim 9, which is characterized in that every 1000mL Fat Emulsion injection
It include the component of following quality: 20~60g of Dexibuprofen, 50~100g of long chain fatty acids in liquid；50~100g of medium chain fatty acid；
- 15 2~50g of hydroxy stearic acid ester of polyethylene glycol；8~16g of phospholipids compounds；Osmotic pressure regulator 25g；Surplus is water and pH
Regulator, the pH of the Dexibuprofen fat emulsion injection are 4.0~9.0.
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| CN201910765859.4A CN110339165A (en) | 2019-08-19 | 2019-08-19 | A kind of Dexibuprofen fat emulsion injection and preparation method thereof |
| PCT/CN2020/103928 WO2021031791A1 (en) | 2019-08-19 | 2020-07-24 | Dexibuprofen fat emulsion injection and preparation method therefor |
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| WO2021031791A1 (en) * | 2019-08-19 | 2021-02-25 | 苏州大学 | Dexibuprofen fat emulsion injection and preparation method therefor |
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| CN103622907A (en) * | 2013-11-18 | 2014-03-12 | 中国人民解放军第二军医大学 | Ibuprofen fat emulsion injection and preparation method thereof |
| CN105168117A (en) * | 2015-10-04 | 2015-12-23 | 临沂大学 | Dexibuprofen microemulsion gel and preparation method thereof |
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| BRPI0713054A2 (en) * | 2006-06-30 | 2012-04-17 | Mcneil Ppc Inc | solid capsules filled with ibuprofen-containing liquid |
| CN103479575B (en) * | 2013-09-23 | 2015-08-05 | 安徽丰原药业股份有限公司 | A kind of ibuprofen fat emulsion injection and preparation method thereof |
| CN104546706B (en) * | 2013-10-22 | 2017-10-27 | 北京联合大学生物化学工程学院 | A kind of (S)-ibuprofen emulsion for injection and preparation method thereof |
| CN104706575A (en) * | 2013-12-16 | 2015-06-17 | 天津迈迪瑞康生物医药科技有限公司 | Flurbiprofen axetil fat emulsion concentrate and preparation method and use thereof |
| CN106109412A (en) * | 2016-07-27 | 2016-11-16 | 武汉科福新药有限责任公司 | Flurbiprofen axetil lipid microsphere injection and preparation method thereof |
| CN110339165A (en) * | 2019-08-19 | 2019-10-18 | 苏州大学 | A kind of Dexibuprofen fat emulsion injection and preparation method thereof |
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| CN103622907A (en) * | 2013-11-18 | 2014-03-12 | 中国人民解放军第二军医大学 | Ibuprofen fat emulsion injection and preparation method thereof |
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| WO2021031791A1 (en) * | 2019-08-19 | 2021-02-25 | 苏州大学 | Dexibuprofen fat emulsion injection and preparation method therefor |
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