CN110115766B - Compound preparation containing flurbiprofen axetil and preparation method thereof - Google Patents
Compound preparation containing flurbiprofen axetil and preparation method thereof Download PDFInfo
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- CN110115766B CN110115766B CN201810115299.3A CN201810115299A CN110115766B CN 110115766 B CN110115766 B CN 110115766B CN 201810115299 A CN201810115299 A CN 201810115299A CN 110115766 B CN110115766 B CN 110115766B
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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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
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- 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
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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
Abstract
The invention discloses a compound preparation containing flurbiprofen axetil, which contains two effective medicinal active ingredients of flurbiprofen axetil and a proton pump inhibitor, wherein the content of the flurbiprofen axetil in a unit dose is 20 mg-100mg, and the content of the proton pump inhibitor in the unit dose is 5mg-100 mg.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a compound preparation containing flurbiprofen axetil, in particular to a compound preparation consisting of flurbiprofen axetil and a proton pump inhibitor and a preparation method thereof.
Background
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely applied to clinic as drugs with the functions of resisting inflammation, easing pain, relieving fever and reducing platelet adhesion, but have more gastrointestinal tract side effects and different clinical manifestations, from no symptoms to dyspepsia, abdominal distension, abdominal pain, ulcer, bleeding, perforation and the like, serious patients can even endanger life, and the harm of gastric mucosa injury is not changed along with dosage forms. Therefore, the active prevention of gastrointestinal mucosal lesions associated with ulcers and bleeding caused by NSAIDs is receiving clinical attention.
Flurbiprofen is a widely used non-steroidal anti-inflammatory drug in clinic, has the effects of relieving fever, resisting inflammation, relieving pain and the like,
the clinical application is mostly in the treatment of inflammatory diseases and physiological pain of patients. Most of the currently marketed preparations are mainly orally administered, although they have a certain clinical effect, they are likely to cause adverse reactions such as gastrointestinal dysfunction of patients after administration, and many patients cannot take oral drugs to relieve pain when treating physiological pain after surgical treatment or due to cancer, and flurbiprofen injection containing 50m g flurbiprofen acetate in 5m L emulsion is mainly used to reduce adverse clinical reactions such as irritation to gastric mucosa and to take effect faster than oral drugs, compared with cancer pain and postoperative pain.
At present, the commercial flurbiprofen axetil injection is sold under the trade name of Kaixie, which takes a lipid microsphere (also called fat emulsion) preparation as a carrier, has the advantages of stronger drug effect, quicker response, longer duration, no influence on awakening of a patient in an anesthesia state and the like, and is not easy to cause adverse reactions such as gastric mucosal injury and the like. Although the probability of stomach injury of a patient in use is greatly reduced to a certain extent, the risk of gastrointestinal bleeding or perforation of the patient with the existing gastrointestinal medical history or the elderly is still high.
A large number of researches prove that the Proton Pump Inhibitors (PPIs) have the effective effect of preventing and treating the NSAIDs-related gastrointestinal mucosal injury, can obviously improve the gastrointestinal symptoms of patients, prevent gastrointestinal bleeding and improve the tolerance of the mucosa to the NSAIDs; in addition, PPIs can correct cell growth cycle kinetics disrupted by NSAIDs to protect the gastric mucosa. Evidence-based medicine shows that the PPIs have better curative effect and safety than misoprostol and H2 receptor antagonist. Due to their potent antacid action, PPIs have been promoted to be widely used in the treatment of symptoms represented by stress ulcers or NSAIDs-associated gastric mucosal lesions.
CN0180616.3 discloses a pharmaceutical composition in the form of an emulsion preconcentrate suitable for oral administration, which comprises a releasable non-steroidal anti-inflammatory drug, a surfactant and an oil or semisolid fat, and which forms an oil-in-water emulsion upon contact with gastric juice, and which can be used in combination with a proton pump inhibitor, by placing the above composition and an enterically coated proton pump inhibitor in the same kit (i.e. capsule); patent CN200780022230.6 discloses a pharmaceutical composition of tegaserod and a proton pump inhibitor, comprising tegaserod and a proton pump inhibitor, which is used for treating or preventing gastric injury caused by NSAID drugs; patent No. cn201480033480.x discloses a method of treatment of intestinal diseases induced by NSAID drug administration followed by rifaximin and proton pump inhibitor administration to patients with pain or inflammation for the prevention or treatment of gastric injury induced by NSAID drug; in order to prevent the gastrointestinal damage of ketoprofen, document CN201410317848.7 has developed a compound preparation containing ketoprofen and omeprazole, which is characterized in that the ketoprofen is a micro sustained-release tablet, the omeprazole is an enteric pellet, and then the micro tablet and the pellet are filled into the same capsule for simultaneous administration to patients.
In the above documents CN200780022230.6 and CN201480033480.x disclose a method for treating gastric injury caused by NSAID, which is directed to the treatment after gastric injury caused by NSAID, although documents CN0180616.3 and CN201410317848.7 are expressed as compound preparations, two different active substances are substantially prepared into different small dosage forms, and in a filled capsule, because two dosage forms actually exist in the capsule, after a patient takes the drug, the drug release time is uncertain due to different dosage forms, so that the onset time of the drug is different, and the effect of preventing gastric injury caused by NSAID used is difficult to be achieved.
Disclosure of Invention
In order to achieve the above objects and overcome the disadvantages of the prior art, the present invention discloses a flurbiprofen axetil-containing compound preparation, which contains two kinds of pharmaceutically active ingredients, wherein one kind of the pharmaceutically active ingredient is flurbiprofen axetil, and the other kind of the pharmaceutically active ingredient is a proton pump inhibitor.
In the compound preparation of flurbiprofen axetil, one of the active pharmaceutical ingredients is flurbiprofen axetil, and the content of the unit dose in the preparation is 20 mg-100mg, preferably 25 mg-80 mg, and more preferably 30 mg-60 mg.
In the compound preparation of flurbiprofen axetil, the other pharmaceutical active ingredient is a proton pump inhibitor, and the Proton Pump Inhibitor (PPI) is a potential inhibitor of gastric acid chalk and inhibits H+、 K+-atpase (the enzyme involved in the final step of hydrogen ion production in parietal cells), the term proton pump inhibitor including but not limited to omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole, ilaprazole and lamiprazole, including isomers, enantiomers and tautomers thereof and basic salts thereof, wherein the proton pump inhibitor is present in a unit dose formulation in an amount of 5mg to 100mg, preferably 10mg to 80 mg.
Proton pump inhibitors generally include benzimidazole compounds, the proton pump inhibitors useful in the present invention are known compounds and can be produced by known processes, and in certain preferred embodiments, the proton pump inhibitor is the racemic compound of omeprazole or the (-) enantiomer of omeprazole (i.e., esomeprazole), lansoprazole, or pantoprazole.
In the compound preparation of flurbiprofen axetil, the proton pump inhibitor is omeprazole, and the content of the unit dosage preparation of the flurbiprofen axetil is 10mg to 50mg, preferably 12mg to 40mg, and further preferably 15mg to 35 mg.
In the compound preparation of flurbiprofen axetil, the proton pump inhibitor is lansoprazole, and the content of the unit dosage preparation of the proton pump inhibitor is 10 mg-80 mg, preferably 15 mg-70 mg, and further preferably 20 mg-50 mg.
In the compound preparation of flurbiprofen axetil, the proton pump inhibitor is esomeprazole, and the content of the unit dosage preparation is 10 mg-50 mg, preferably 12 mg-40 mg, and further preferably 15 mg-35 mg.
In the compound preparation of flurbiprofen axetil, the proton pump inhibitor is pantoprazole, and the content of the unit dosage preparation is 10mg to 50mg, preferably 12mg to 40mg, and further preferably 15mg to 35 mg.
The "unit dose" as referred to herein is a unit dose, which is a dose in each individual small package, such as a tablet or capsule in a solid preparation, and a single dose is each tablet or each capsule, and an injection means that each component is a unit dose.
The flurbiprofen axetil compound preparation can be an injection preparation, wherein the injection preparation is a fat emulsion, a lipid microsphere, a freeze-dried powder injection and a water injection, and a sustained-release preparation taking the fat emulsion and the lipid microsphere as carriers is preferred.
The fat emulsion or the fat microsphere exists in the form of emulsion droplet particles, is an oil-in-water emulsion, the emulsion droplet is wrapped with flurbiprofen axetil and active ingredients of proton pump inhibitor medicines, when the emulsion droplet particles reach a focus part, the emulsion droplet particles are gradually aggregated and broken, the medicines are released, the bioavailability of the medicines is greatly improved, the stability of the emulsion droplet particles is kept on the premise that the medicines exert the medicine effect, and the particle size of the emulsion droplet particles is the basis for basically keeping the stability of the emulsion droplet particles. However, in the preparation process, the type, content, pH change and the like of the auxiliary materials can affect the particle size of the emulsion droplets, when the particle size is too large, adverse events such as embolism and the like are easily caused, the emulsion droplets are too large and are easy to aggregate, the balance of oil and water phases can be destroyed, along with the extension of storage events, oil droplets can be separated out, irreversible changes such as demulsification and the like are generated, and when the particle size of the emulsion droplets is too small, active medicine components cannot be effectively wrapped, so that the effective treatment effect is difficult to achieve. The average particle size of the fat emulsion or the fat microspheres is less than 350nm, preferably less than 320nm, further preferably 30nm to 300nm, more preferably 50nm to 280nm, and still more preferably 55nm to 250 nm.
The proton pump inhibitor has low solubility, is sensitive to light, heat and temperature, is relatively stable in an alkaline environment, is activated in an acidic environment and is rapidly degraded, but in the case of an injection preparation, if the alkalinity is too strong, injection pain is easily caused, and discomfort reaction of a subject is enhanced, so that the pH of the preparation is strictly controlled, and the pH range is 6.0-9.0, and further preferably 6.5-8.5. Wherein the pH regulator is selected from citric acid, hydrochloric acid, phosphoric acid, glacial acetic acid, and sodium (potassium) hydroxide, and the buffer agent is selected from one or more of disodium hydrogen phosphate and sodium dihydrogen phosphate.
The emulsion droplet particles are prepared by emulsifying oil for injection by an emulsifier, and active substances are added into the solution, and simultaneously, a surfactant is added, so that the surfactant can effectively reduce the surface tension of the emulsifier, so that the active ingredients of the medicine are preserved and adsorbed, the dissolving amount of the active ingredients is increased, the medicine carrying concentration of the medicine is finally increased, and the solubility of the medicine is improved.
The oil for injection is a solvent which can dissolve active ingredients of medicines, effectively dissolves the activity of the medicines and improves the bioavailability of the oil for injection, the oil for injection can be soybean oil, sesame oil, saffron oil, castor oil, tea oil, safflower oil, peanut oil, olive oil, corn oil, synthetic ethyl oleate and butyl oleate, wherein the soybean oil is selected from long-chain triglyceride, medium-chain triglyceride, glycerol monooleate and glycerol monolinonic acid ester, different types of oil have great influence on the physicochemical property and the stability of a fat emulsion preparation, and researches show that the long-chain triglyceride can provide necessary fatty acid and energy, but the long-chain triglyceride can enter mitochondrial metabolism depending on carnitine transport, the oxidative metabolism speed is slow, and the long-term application can cause the dysfunction of an immune system, the accumulation of a reticuloendothelial system, the fatty pigmentation in the liver and the spleen and other toxic and side effects, the medium-chain triglyceride is different from the long-chain triglyceride, the relative molecular weight of the medium-chain triglyceride is smaller than that of the long-chain triglyceride, the water solubility of the medium-chain triglyceride is 100 times higher than that of the long-chain triglyceride, the medium-chain triglyceride is quickly and completely oxidized, is not easily phagocytized and deposited by reticuloendothelial cells of organs such as liver, spleen, lung and the like to damage the immunologic function, can reduce the existence of a large amount of linoleic acid and further maintain the balance of fatty acid structures, but the single use of the medium-chain triglyceride can not provide essential fatty acid and can also cause metabolic acidosis and nervous system side effects, so the oil for injection used by the invention is preferably soybean oil, and is further preferably a mixture of the medium-chain triglyceride and the medium-chain triglyceride of the soybean oil.
The weight-volume ratio of the oil for injection of the present invention in the unit dosage formulation is 0.1% to 20.0%, preferably 0.5% to 15.0%, further preferably 0.8% to 12.0%, and more preferably 0.5% to 10%.
The emulsifier can effectively disperse the oil for injection into emulsion droplet particles and effectively preserve or adsorb active ingredients of the medicine, and is selected from lecithin, hydroxy lecithin, soybean lecithin, hydrogenated soybean lecithin and yolk lecithin, wherein the soybean lecithin comprises the soybean lecithin, the hydrogenated soybean lecithin, the high-purity soybean lecithin and the refined soybean lecithin, and the yolk lecithin comprises the yellow lecithin, the hydrogenated yolk lecithin, the high-purity yolk lecithin and the refined yolk lecithin.
The weight/volume ratio of the emulsifier in the unit dosage preparation is 0.05% -5%, preferably 0.1% -4%, further preferably 0.2% -3.5%, and more preferably 0.5% -3.0%.
The surfactant is an amphiphilic compound having surface activity, such as a block copolymer. Preferred surfactants of the invention are non-ionic surfactants such as poloxamers, cholesterol, sodium deoxycholate, polyglycerol palmitate diol esters, monoglycerol acetate, sorbitol esters, 15-hydroxystearic acid polyethylene glycol esters (Solutol HS-15) or polyoxyethylene sorbitan palmitate.
The surfactant of the present invention is present in a weight ratio of 0.1% to 10%, preferably 0.2% to 8%, further preferably 0.3% to 6.5%, and more preferably 0.5% to 5.5% in a unit dose formulation.
In the specific embodiment of preparing the fat emulsion or lipid microsphere preparation of the invention, acceptable pharmaceutic adjuvants such as an isotonic regulator, an antioxidant or a co-emulsifier can be added according to the needs. Wherein the isotonic regulator can be one or more of glucose, glycerol, sodium chloride, sorbitol, xylitol or mannitol, and the antioxidant can be one or more of sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium thiosulfate, ascorbic acid, propyl gallate, ascorbyl palmitate, tert-butyl p-hydroxyanisole (BHA), di-tert-butyl p-cresol (BHT), vitamin E, cysteine or methionine.
The auxiliary emulsifier can be one or more of glycerol, oleic acid, polyethylene glycol, 1, 2-propylene glycol, n-butanol, ethylene glycol, propylene glycol or polyglycerol ester.
The formulations of the present invention may be administered orally, parenterally, topically or rectally, in a form suitable for each route of administration. For example, they are administered by injection, infusion, in the form of tablets or capsules, by inhalation by injection, ointment, suppository, and the like, preferably parenterally, topically, or rectally.
"parenteral administration" and "parenterally administered" as used herein refer to modes of administration other than enteral and topical administration. Typically by injection means and includes, without limitation, intravenous, intramuscular, intraarterial, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and concern.
The flurbiprofen axetil compound preparation according to the present invention is used for treating inflammation in a subject, wherein the inflammation is selected from fever, arthritis, asthma, bronchitis, menstrual pain, imperatoria, bursitis, inflammatory disorders of the skin, gastrointestinal disorders, vascular diseases, migraine, adventitial inflammation of tuberosity, thyroiditis, aplastic anemia, hodgkin's disease, scleroderma, rheumatic fever, myasthenia gravis, sarcoidosis, nephrotic syndrome, irritable bowel syndrome, functional dyspepsia, behcet's syndrome, polymyositis, allergy, conjunctivitis, post-injury swelling, and cardiac ischemia, and in certain embodiments, the arthritis is selected from rheumatoid arthritis, spondyloarthritis, gouty arthritis, systemic lupus erythematosus, osteoarthritis, and juvenile arthritis.
The flurbiprofen axetil compound preparation is used for treating pain of a subject, wherein the pain is selected from menstrual pain, lumbago, neck pain, bone pain, postpartum pain, headache, pain related to migraine, toothache, sprain, strain, arthritis, osteoarthritis, gout, mandatory spondylitis, bursitis, burn, fracture, immunity and autoimmunity, cell neoplastic transformation or metastatic tumor growth, cancer pain and postoperative pain of surgery and dentistry.
The compound preparation of flurbiprofen axetil is mainly used for treating rheumatoid arthritis, osteoarthritis, mandatory spondylitis, traumatic pain, cancer pain and postoperative pain of surgery and dentistry.
The flurbiprofen axetil compound preparation is suitable for patients with existing gastrointestinal tract injuries, wherein the stomach injuries comprise Inflammatory Bowel Diseases (IBD) and functional intestinal diseases (FBD), including dyspepsia, gastroesophageal reflux on the FBD and various forms of visceral pain. In certain embodiments, the gastric injury is caused by an NSAID drug, and in particular embodiments, the pain or inflammation according to the invention is selected from mucosal injury, gastric muscle dysfunction, gastritis, gastric erosion, gastric ulcer, or gastric lesion.
The flurbiprofen axetil-containing compound preparation of the present invention is an injection of fat emulsion, and specific examples thereof include preparations filled in containers (e.g., ampoules, cillin, drug-loaded syringes) as long as the preparation is suitable for use as an injection, and the form of the preparation containing fat emulsion is not limited.
The invention discloses a fat emulsion or lipid microsphere preparation containing flurbiprofen axetil and a proton pump inhibitor compound for the first time, the preparation can treat inflammation or pain, can effectively prevent and/or treat stomach injury caused by NSAID (NSAID drugs), and particularly for the old patients with the past history of stomach injury, the preparation can effectively prevent stomach injury, so that the administration of the patients is safer, and the occurrence of side reactions is greatly reduced; the compound preparation can achieve the dual effects of treating inflammation and preventing gastric injury by being taken by a patient once, and the patient does not need to take medicines respectively, so that the patient can take medicines more conveniently, and the compliance of the patient in taking medicines is improved; finally, the compound preparation has stable formulation, can be stored for a long time, and greatly meets the clinical medication safety.
Drawings
FIG. 1 is a graph showing the effect of animal experiments.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Example 1 flurbiprofen axetil and omeprazole fat emulsion
| | Sample | 1 | |
| Flurbiprofen axetil | 5.0g | 5.0g | |
| Omeprazole | 1.0g | 2.0g | |
| Soybean oil | 17.5g | 17.5g | |
| Egg yolk lecithin | 7.5g | 7.5g | |
| Solutol HS-15 | 15g | 15g | |
| Vitamin E | 3.0g | 3.0g | |
| Glycerol | 12g | 12g | |
| Water (W) | Adding water to 500ml | Adding water to 500ml | |
| pH | 8.1 | 8.1 |
The preparation method comprises the following steps: uniformly mixing the soybean oil and the egg yolk lecithin according to the prescription amount, adjusting the pH value by using citric acid and sodium dihydrogen phosphate, adding the pharmaceutical active ingredients of flurbiprofen and omeprazole, and uniformly dispersing; adding Solutol HS-15 in the amount of the prescription, and uniformly mixing; adding glycerol according to the prescription amount, adding a proper amount of water until the volume of the solution is 500mL, mixing and emulsifying, and shearing by using a high-pressure homogenizer; filtering the obtained solution, bottling, and sterilizing.
Example 2 flurbiprofen axetil and lansoprazole fat emulsion
| Prescription composition | Content (c) of |
| Flurbiprofen axetil | 5.0g |
| Lansoprazole | 3.0g |
| Soybean oil | 20g |
| Egg yolk lecithin | 10g |
| Poloxamers | 12g |
| Vitamin E | 3.0g |
| Glycerol | 12g |
| Water (W) | Adding water to 500ml |
| Ph | 7.6 |
The preparation method comprises the following steps: as in example 1.
Example 3 particle size measurements before and after sterilization of the samples prepared in examples 1 and 2
The particle size measurements before and after sterilization of the samples prepared in examples 1-9 were measured using a laser scattering particle sizer (model: Zetasizer, manufacturer: Malvern), and the results are shown in Table 1 below:
TABLE 1
As can be seen from the results in Table 1, the particle size of the emulsion drops of the fat emulsion prepared by the invention is stable before and after sterilization, so that the stability of the preparation is further ensured, and the medication safety of patients is ensured.
Example 4
4.1 selection of oil for injection in the formulation
The experiment inspects the influence of the type and the dosage of the injection medicine in the prescription on the preparation, and the prescription is as follows:
the particle size of the above samples was measured before and after sterilization, and the results are shown in table 2:
TABLE 2
4.2 screening of emulsifiers
The particle size of the above samples was measured before and after sterilization, and the results are shown in table 3:
TABLE 3
4.3 screening for surfactants
The particle size of the above samples was measured before and after sterilization, and the results are shown in table 4:
TABLE 4
4.4 investigation of pH in formulation
The particle size of the above samples was measured before and after sterilization, and the results are shown in table 5:
TABLE 5
From the above results, through the continuous research of the inventors, the fat emulsion disclosed by the invention has strong stability and can fully meet the clinical requirements.
Example 5 animal experiments
Male Wistar rats (beijing witnessee wals laboratory animal technology ltd) of 8 weeks old were purchased, and about 240g to 260g in weight, and were allowed to freely feed and take water, and after 7 days of preliminary feeding, 10 rats were tested in a total of 5 groups, divided into 1 control group and 4 test groups, in such a manner as to be administered as described in table 6 below, with 24 hours of fasting before the test and 1 hour of water deprivation.
TABLE 6
Fasted 11 days from the day before the test, the drug was administered intravenously on the day of the test, after 5 hours it was euthanized with carbon dioxide gas and the stomach was removed. The duodenum was ligated, and 6mL of neutral formalin was injected from the esophagus and placed in the neutral formalin solution for 30 minutes. The stomach was incised along the greater curvature, and after being gently washed with physiological saline, the bleeding was observed under a physical microscope. The area of bleeding, i.e., the area of ulcer, was measured in units of 0.5mm × 0.5mm, and the results are shown in FIG. 1.
The results show that the ulcer area of the flurbiprofen axetil fat emulsion preparation added with the proton pump inhibitor is obviously reduced, thereby showing that the compound preparation disclosed by the invention can effectively prevent and/or treat the gastric injury.
Claims (4)
1. A compound preparation containing flurbiprofen axetil is a fat emulsion or lipid microsphere injection containing two active pharmaceutical ingredients of flurbiprofen axetil and a proton pump inhibitor;
it also contains
Soybean oil in a weight-volume ratio of 0.5-10.0% in the unit dosage formulation;
egg yolk lecithin with the weight volume ratio of 0.5-3.0% in the unit dosage preparation;
15-hydroxystearic acid polyethylene glycol in a weight ratio of 0.5-5.5% in the unit dose formulation;
wherein the proton pump inhibitor is selected from omeprazole or lansoprazole;
the content of the flurbiprofen axetil in the unit dosage is 20 mg-100mg, and the content of the proton pump inhibitor in the unit dosage preparation is 5mg-100 mg;
the average grain diameter of the fat emulsion or the fat microspheres is less than 350 nm.
2. The combination formulation of claim 1, wherein the formulation has a pH of 6.0 to 9.0.
3. Compound formulation according to claim 1, characterized in that it can be administered parenterally, topically or rectally.
4. Compound formulation according to claim 1, characterized in that the formulation is used for the treatment of pain or inflammation.
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| EP1965774A2 (en) * | 2005-12-30 | 2008-09-10 | Cogentus Pharmaceuticals, Inc. | Oral pharmaceutical formulations containing non-steroidal anti-inflammatory drugs and acid inhibitors |
| CN107224585B (en) * | 2016-03-25 | 2020-10-27 | 南京优科制药有限公司 | A composition comprising a non-steroidal anti-inflammatory drug and a proton pump inhibitor |
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| CN110115766A (en) | 2019-08-13 |
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