CN115624546A - Application of 5-hydroxyflavone in osteoarthritis treatment medicine and preparation of sustained release agent thereof - Google Patents
Application of 5-hydroxyflavone in osteoarthritis treatment medicine and preparation of sustained release agent thereof Download PDFInfo
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- CN115624546A CN115624546A CN202211201223.5A CN202211201223A CN115624546A CN 115624546 A CN115624546 A CN 115624546A CN 202211201223 A CN202211201223 A CN 202211201223A CN 115624546 A CN115624546 A CN 115624546A
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- hydroxyflavone
- osteoarthritis
- organic solvent
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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Abstract
The invention discloses application of 5-hydroxyflavone in a medicament for treating osteoarthritis and preparation of a sustained release agent thereof, and relates to the technical field of medicines. The application of 5-hydroxyflavone in preparing the medicine for preventing and/or treating osteoarthritis is disclosed, and the effective component in the medicine includes 5-hydroxyflavone. The inventors have found that 5-hydroxyflavone can alleviate traumatic osteoarthritis in mice caused by severing the medial meniscal tibial plateau ligament. Namely, the 5-hydroxyflavone has good application prospect in preparing the medicament for treating and/or preventing osteoarthritis. The invention also improves the drug delivery mode, and the drug delivery mode is made into a slow release preparation, so that the effect of effectively treating osteoarthritis for a long time can be expected to be achieved through one-time administration of the drug in the joint cavity in clinic.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of 5-hydroxyflavone in a medicine for treating osteoarthritis and preparation of a sustained release agent thereof.
Background
OA is a degenerative disease of the aged bone and joints, mainly caused by degeneration of articular cartilage, is the most common osteoarticular disease, and is also the main cause of chronic disability in the elderly [3]. The occurrence of OA is associated with a variety of factors, including age, sex, genetics, obesity, and trauma [4].
The pathogenesis of OA is complex, and pathological changes involve cartilage, subchondral bone, synovium, meniscus and ligaments, etc. Under physiological conditions, both articular cartilage and subchondral bone are in a dynamic anabolic and catabolic balance, and the maintenance of this balance is an important guarantee for the joint to perform its physiological functions [5]. Various factors affecting the pathogenesis of OA: such as mechanical stress, circulating hormone levels, cytokines, etc. are broadly classified into mechanical and biological factors, which act on articular cartilage and/or subchondral bone to disrupt the physiological homeostasis of articular cartilage and subchondral bone, resulting in decreased extracellular matrix synthesis and increased breakdown of articular cartilage, and (or) uncoupling of subchondral bone osteogenesis and bone resorption, resulting in degenerative changes of joints, and finally, in the onset of OA [6, 7].
Because the pathogenesis of OA is complex and not yet fully elucidated, current therapeutic approaches for OA can only alleviate symptoms, and targeted therapeutic drugs that effectively delay the onset and progression of OA are lacking. Common drugs for alleviating the symptoms of OA include non-steroidal anti-inflammatory drugs (NSAIDs), non-narcotic analgesics, glucocorticoids, and the like. However, these treatment strategies do not delay or reverse the destruction of articular cartilage nor modulate articular cartilage homeostasis to avoid further damage to articular cartilage. Therefore, there is a high necessity to develop a drug capable of preventing and even reversing cartilage degeneration, thereby treating and preventing osteoarthritis.
In view of this, the invention is particularly proposed.
Disclosure of Invention
The invention aims to provide application of 5-hydroxyflavone in a medicament for treating osteoarthritis and preparation of a sustained release agent thereof, and experiments prove that the 5-hydroxyflavone can relieve traumatic osteoarthritis of mice caused by cutting medial meniscus tibial plateau ligament. Namely, the 5-hydroxyflavone has good application prospect in preparing the medicament for treating and/or preventing osteoarthritis.
The invention is realized by the following steps:
the inventor finds that: the application of 5-hydroxyflavone in preparing medicine for treating and/or preventing osteoarthritis includes 5-hydroxyflavone as effective component.
The 5-hydroxyflavone belongs to one of flavonoid compounds, and only a few researches on synthetic extraction or pharmacokinetics are found at present by consulting domestic and foreign documents. However, in the current literature reports, it is known that flavonoids are a group of natural substances with various phenolic structures, and exist in fruits, vegetables, grains, bark, roots, stems, flowers, tea and wine. Flavonoids are now recognized as an essential component in a variety of nutraceutical, pharmaceutical, medical and cosmetic applications. This is due to their antioxidant, anti-inflammatory, anti-mutagenic and anti-cancer properties, as well as their ability to modulate key cellular enzymes. Therefore, the clinical application value of the 5-hydroxyflavone needs to be greatly explored.
The structural formula of 5-hydroxyflavone (5-hydroxy flavone) is as follows:
the inventor finds that the 5-hydroxyflavone has a good reversing effect when used for treating the degeneration of the articular cartilage, and has an application prospect in preparing the medicament for treating and/or preventing osteoarthritis. Moreover, the 5-hydroxyflavone is a natural substance with a plurality of phenolic structures, exists in fruits, vegetables, grains, barks, roots, stems, flowers, tea and wine, has wide existence range, has good clinical use safety basis, and is more convenient to popularize and apply.
In a preferred embodiment of the use of the invention, the osteoarthritis is selected from the group consisting of knee osteoarthritis, elbow osteoarthritis, shoulder osteoarthritis, hip osteoarthritis, spinal osteoarthritis, cervical osteoarthritis and lumbar osteoarthritis.
In an alternative embodiment, 5-hydroxyflavone has a therapeutic effect in both cartilage degenerated joints. Such as in a degenerative disc joint.
In an alternative embodiment, the knee osteoarthritis is selected from traumatic knee osteoarthritis or degenerative knee osteoarthritis.
In other embodiments, elbow joint osteoarthritis, shoulder joint osteoarthritis, hip joint osteoarthritis, crotch joint osteoarthritis, spondyloarthropathies, cervical osteoarthritis, and lumbar osteoarthritis include, without limitation: traumatic or degenerative osteoarthritis.
The application comprises at least one of the following functions:
promoting cartilage formation, slowing osteoarthritis progression, reversing cartilage loss, and reversing cartilage degeneration.
In an alternative embodiment, 5-hydroxyflavone is used to treat pain caused by osteoarthritis. The pain is moderate to severe. In a preferred embodiment, the pain is selected from the group consisting of post-inactivity pain, weight bearing pain, fatigue induced pain, periarticular tenderness, radiation pain (e.g., knee pain with hip degenerative disease), resting pain after a prolonged period of time at the same location, persistent pain, spontaneous pain, athletic pain, nocturnal pain, muscle pain, end of range of motion pain, and spontaneous painful bone pain and resting pain.
It is within the scope of the present invention to provide a drug that provides a slight relief or a substantial relief of pain from osteoarthritis.
Painful osteoarthritis is osteoarthritis as defined by ICD-10 (International Statisische Klassifikocation der Krankheiten und Verwender Gesundheitsprobleme), WHO edition, preferably 2007 edition. Preferably, the osteoarthritis is selected from the group consisting of polyarthritis [ M15], hip arthropathy [ M16], knee arthropathy [ M17], osteoarthritis of the first carpometacarpal joint [ M18], another type of osteoarthritis [ M19] and vertebral ankylosis [ M47]. The indices in parentheses refer to the ICD-10 nomenclature.
If the osteoarthritis is a polyarthritis [ M15], it is preferably selected from the group consisting of primary, systemic (bone) arthritis [ M15.0], herben nodules (with arthropathy) [ M15.1], bucharles nodules (with arthropathy) [ M15.2], secondary, multiple osteoarthritis (posttraumatic polyarthritis) [ M15.3], erosive (bone) arthritis [ M15.4], other polyarthritis [ M15.8] and unspecified polyarthritis (unspecified systemic (bone) arthritis) [ M15.9].
If the osteoarthritis is a hip degenerative disease (hip osteoarthritis) [ M16], it is preferably selected from the group consisting of bilateral primary hip degenerative diseases [ M16.0], other primary hip degenerative diseases (unilateral or not specified) [ M16.1], dysplastic bilateral hip degenerative diseases [ M16.2], other dysplastic hip degenerative diseases (unilateral or not specified) [ M16.3], bilateral, post-traumatic hip degenerative diseases [ M16.4], other post-traumatic hip degenerative diseases [ M16.5] (unilateral or not specified), other, bilateral secondary hip degenerative diseases [ M16.6], other secondary hip degenerative diseases (unilateral or not specified) [ M16.7] and unspecified hip degenerative diseases [ M16.9].
If osteoarthritis is a knee joint disease [ M17], it is preferably selected from bilateral primary knee joint diseases [ M17.0], other primary knee joint diseases [ M17.1], bilateral, post-traumatic knee joint diseases [ M17.2], other post-traumatic knee joint diseases [ M17.3] (unilateral or not), other, bilateral secondary knee joint diseases [ M17.4], other secondary knee joint diseases [ M17.5] and unspecified knee joint diseases [ M17.9].
If osteoarthritis is of the first carpometacarpal joint [ M18], it is preferably selected from bilateral primary osteoarthritis of the first carpometacarpal joint [ M18.0], other primary osteoarthritis of the first carpometacarpal joint [ M18.1] or otherwise, bilateral osteoarthritis of the first carpometacarpal joint [ M18.2] or otherwise, posttraumatic osteoarthritis of the first carpometacarpal joint [ M18.3] (unilateral or otherwise), other or bilateral secondary osteoarthritis of the first carpometacarpal joint [ M18.4], other secondary osteoarthritis of the first carpometacarpal joint (unilateral or otherwise) [ M18.5] or unspecified osteoarthritis of the first carpometacarpal joint [ M18.9].
If osteoarthritis is another type of osteoarthritis [ M19], it is preferably selected from the group consisting of primary osteoarthritis of other joints (unspecified primary osteoarthritis) [ M19.0], post-traumatic osteoarthritis of other joints (unspecified post-traumatic osteoarthritis) [ M19.1], other secondary osteoarthritis (unspecified secondary osteoarthritis) [ M19.2], other prescribed osteoarthritis [ M19.8] and unspecified osteoarthritis [ M19.9].
In the preferred embodiment of the present invention, the dosage form of the drug includes, but is not limited to, tablets, capsules, suspensions, solutions, emulsions, powders, granules, injections, lyophilized powder injections, liniments, paints, plastics, ointments, lotions, suppositories, aerosols, sprays, dusts, ointments, plasters, cataplasms or patches.
In an alternative embodiment, the pharmaceutical dosage form is an injection. The mode of selecting the injection can avoid that the 5-hydroxyflavone is cleared by rapid metabolism in vivo due to poor water solubility and low gastrointestinal absorption rate, so that the bioavailability is extremely low. Therefore, the mode of injection is expected to be clinically effective for the treatment of osteoarthritis for a long period of time by once administration of the joint cavity.
In a preferred embodiment of the present invention, the medicament further comprises a pharmaceutically acceptable additive or adjuvant.
In an alternative embodiment, the pharmaceutically acceptable additive or adjuvant is selected from one or more of the following: solvents, buffers, emulsifiers, suspending agents, disintegrating agents, dispersing agents, binders, excipients, stabilizers, chelating agents, diluents, gelling agents, preservatives, wetting agents, lubricants, absorption delaying agents, flavoring agents, sweeteners, pigments, and liposomes.
In a preferred embodiment of the invention, the drug comprises a carrier, wherein the carrier is a polymer, a liposome, ethanol or a polyalcohol.
When the carrier is a polymer, the polymer may be biodegradable or non-biodegradable. In one aspect, the polymer comprises a carbohydrate, such as starch, cellulose, and dextran. In another aspect, the polymer includes proteins such as collagen, gelatin, fibrinogen, and albumin. In another aspect, the polymer comprises a polyester (e.g., poly (D, L-lactide)), poly (D, L-lactide-co-glycolide), or polyglycolide. In another aspect, the polymer comprises poly (e-caprolactone), polyhydroxybutyrate, polyalkylcarbonate, polyanhydride, or polyorthoester. In another aspect, the polymer comprises an Ethylene Vinyl Acetate (EVA), silicone rubber, polyurethane, or acrylic polymer or copolymer. In another aspect, the polymeric carrier comprises polyethylene glycol. In another aspect, the polymeric carrier comprises a 4-arm sulfhydryl PEG and a 4-arm NHS PEG and may optionally further comprise collagen or a collagen derivative, such as methylated collagen.
In an alternative embodiment, the polymer is selected from the group consisting of starch, cellulose, dextran, polylactic-co-glycolic acid, chlorinated chitosan, collagen, gelatin, fibrinogen, albumin, polyester, and polyethylene glycol.
In an alternative embodiment, where the drug is an injection, the drug is injected into the joint cavity. The inventor finds that the medicine can be effectively used for delaying the progress of osteoarticular diseases by being injected into the articular cavity.
In an alternative embodiment, the medicament further comprises a combination selected from the group consisting of an organic diphosphate, a chemotherapeutic agent, a radioactive agent, a TNF-antagonist, a non-steroidal anti-inflammatory agent, a steroid, an antioxidant, an angiogenesis inhibitor, a matrix metalloproteinase inhibitor, a vitamin, a selective estrogen receptor modulator, an estrogen-progesterone, an androgen, calcitonin, an antibiotic, a cathepsin K inhibitor, an inhibin, an integrin receptor antagonist, an osteoblast anabolic agent or a selective serotonin reuptake inhibitor, glucosamine, hyaluronic acid, or a mixture thereof.
In a preferred embodiment of the invention, the medicament further comprises a pharmaceutically acceptable salt.
Suitable pharmaceutically acceptable salts include salts of inorganic acids such as hydrochloric, hydrobromic and sulfuric acids, and salts of organic acids such as methanesulfonic acid, fumaric acid, maleic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, lactic acid, citric acid, glutamic acid, acetylsalicylic acid, nicotinic acid, aminobenzoic acid, d-acid, hippuric acid, phosphoric acid and aspartic acid. Preferred salts are the hydrochloride or phosphate salts.
Excipients may be, for example: water, ethanol, 2-propanol, glycerol, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, glucose, fructose, lactose, sucrose, dextrose, molasses, starch, modified starch, gelatin, sorbitol, inositol, mannitol, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, cellulose acetate, shellac, cetyl alcohol, polyvinyl pyrrolidone, paraffin, wax, natural and synthetic rubbers, acacia gum, alginates, dextran, saturated and unsaturated fatty acids, stearic acid, magnesium stearate, zinc stearate, glyceryl stearate, sodium lauryl sulfate, edible oils, sesame oil, coconut oil, peanut oil, soybean oil, lecithin, sodium lactate, polyoxyethylene and polyoxypropylene fatty acid esters, sorbitan fatty acid esters, sorbic acid, benzoic acid, citric acid, ascorbic acid, tannic acid, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, magnesium oxide, zinc oxide, silicon dioxide, titanium oxide, titanium dioxide, magnesium sulfate, zinc sulfate, calcium carbonate, calcium phosphate, dicalcium phosphate, potassium bromide, potassium iodide, pectin, talc, kaolin, povidone, and bentonite.
It is noted that the diseased "subject", "patient" or "animal" treated according to the disclosed methods can be a human or non-human mammal, and thus, the diseased "subject", "patient" or "animal" can be a human and a dog, cat, mouse, rat, cow, sheep, pig, goat, or primate, and can include laboratory animals, livestock, and livestock.
The inventor also provides a preparation method of the slow release agent of the 5-hydroxyflavone coated by the macromolecular compound, which comprises the following steps: mixing polylactic acid-glycolic acid copolymer, 5-hydroxyflavone and a first organic solvent, adding an emulsifier mixed with a second organic solvent, and carrying out ultrasonic treatment;
the mixing mass ratio of the polylactic acid-glycolic acid copolymer to the 5-hydroxyflavone is 10-30, and 0.2-2mg of 5-hydroxyflavone is mixed with 0.1-2mL of the first organic solvent per 0.2-2mg of the 5-hydroxyflavone.
The sustained release agent provided by the invention can be directly injected without the help of an organic solvent, so that adverse reactions and safety accidents caused by the organic solvent are reduced, the retention time in the body is long, repeated injection is not needed, the cost of repeated administration is greatly reduced, and the pain and the irritation of a patient are reduced.
The coating of the hydrophilic high molecular compound is beneficial to improving the hydrophilicity of the medicine and is beneficial to better diluting and releasing the medicine. Under the conditions of the mixing quality and the mixing volume ratio, the slow release agent with good hydrophilicity can be prepared.
The mixing mass ratio of the polylactic acid-glycolic acid copolymer to the 5-hydroxyflavone is 10-25, for example, the mixing mass ratio is 10-20.
In a preferred embodiment of the present invention, the mixing volume ratio of the first organic solvent or the second organic solvent to the emulsifier is 0.1-2. For example, 0.1 to 1.8; 1-1.5:10.
In an alternative embodiment the organic solvent is selected from one or more of acetone, chloroform, methylamine, dimethylamine, diethyl ether, pentane, dichloromethane or carbon disulphide, more preferably the organic solvent is selected from dichloromethane. The dichloromethane has good volatility and low toxicity. The dichloromethane is selected as the organic solvent, so that the toxic and side effects can be reduced to the maximum extent. Preferably, the first organic solvent and the second organic solvent are both dichloromethane. The first organic solvent and the second organic solvent are selected to be of the same type, so that the problem that the organic solvent is difficult to remove due to different volatilization temperatures of the solvents is solved.
In an alternative embodiment, the sonication time is 30-40min. The ultrasonic treatment is used for promoting the emulsifier to be mixed with the raw materials more fully. And carrying out ultrasonic treatment for 30-40 minutes to obtain cloudy white liquid.
In an alternative embodiment, the sonication further comprises removing the first organic solvent and the second organic solvent using a rotary evaporator. In addition, after the treatment by the rotary evaporator, the method also comprises the step of vacuumizing to remove the organic solvent. Removing the organic solvent to obtain the 5-hydroxyflavone sustained-release nano-particles. In an alternative embodiment, the vacuum pump is turned on to evacuate for 30 to 40 minutes.
In an alternative embodiment, the removal of the first organic solvent and the second organic solvent by evaporation further comprises filtration.
Filtering with filter membrane with pore diameter of 200 nm to obtain clear stable liquid, which is 5-hydroxy flavone sustained release preparation coated with polymer with uniform particle diameter. The slow release particles of 5-hydroxyflavone coated by the macromolecular compound prepared by the invention have the particle size of 80-150 nanometers.
In an alternative embodiment, the emulsifier is a polyvinyl alcohol phosphate buffer.
The inventor also provides a preparation method of the liposome-coated 5-hydroxyflavone sustained release preparation, which comprises the following steps:
(a) Mixing lecithin, cholesterol, 5-hydroxyflavone and an organic solvent, and performing rotary evaporation treatment and vacuum pumping treatment to obtain a white covering; the mixing mass ratio of the lecithin, the cholesterol and the 5-hydroxyflavone is 10-30:2-6:0.2 to 2; mixing 5-hydroxyflavone 0.2-2mg per dose with 5-15mL of organic solvent;
(b) Then mixing the white covering with a phosphate buffer solution to obtain liposome 5-hydroxyflavone sustained-release nanoparticles;
(c) And (4) extruding and filtering.
In an alternative embodiment, 10mg of lecithin, 2mg of cholesterol and 2mg of 5-hydroxyflavone are weighed out and dissolved in 15mL of dichloromethane; the temperature of a water bath kettle of the rotary evaporator is set to 36-42 ℃, a vacuum pump is started to pump vacuum for 30-40 minutes, and then a layer of white covering is formed in the reactor.
In an optional embodiment, 0.5ml of phosphate buffer liquid with the mass fraction of 50% is added into the white covering, and after 3-5 minutes of ultrasonic treatment, cloudy white liquid is obtained, namely the liposome 5-hydroxyflavone slow-release nano-particles with different particle sizes.
The liposome-coated 5-hydroxyflavone sustained-release agent is helpful for obtaining a fat-soluble sustained-release agent, and can be diluted by adopting a fat-soluble solvent. The sustained release preparation has the application prospects of promoting cartilage formation, slowing OA progress and cartilage loss, and can be used for preparing medicines for treating osteoarthritis.
For example, the mixing mass ratio of lecithin, cholesterol and 5-hydroxyflavone is 10-25:2-6:1-2.
In an alternative embodiment, the mixture of the white covering and the phosphate buffer, that is, the liposome 5-hydroxyflavone sustained-release nanoparticles with different particle sizes, is extruded and filtered by a filter membrane with a pore size of 200 nm, and is repeated for 100-200 times to obtain a clear and stable liquid, that is, the liposome 5-hydroxyflavone sustained-release preparation with uniform particle size.
The inventor also provides a preparation method of the 5-hydroxyflavone sustained-release injection, which comprises the following steps: mixing the liposome-coated 5-hydroxyflavone sustained release preparation prepared by the above preparation method with a carrier selected from the group consisting of polymer, liposome, ethanol and polyalcohol.
The injection has the application prospects of promoting cartilage formation, slowing OA progress and cartilage loss, and can be used for preparing a medicine for treating osteoarthritis.
In an alternative embodiment, the polymer is selected from the group consisting of starch, cellulose, dextran, polylactic-co-glycolic acid, chlorinated chitosan, collagen, gelatin, fibrinogen, albumin, polyester, and polyethylene glycol.
In an alternative embodiment, the carrier is selected from a mixed gel prepared from chitosan chloride and sodium beta-glycerophosphate in a volume ratio of 8. Under the mixing ratio condition, the chitosan hydrogel medicine can be prepared.
The inventor also provides a polymer-coated 5-hydroxyflavone sustained-release preparation prepared by the preparation method, a liposome-coated 5-hydroxyflavone sustained-release preparation prepared by the preparation method or a 5-hydroxyflavone sustained-release injection prepared by the preparation method.
The invention has the following beneficial effects:
the invention provides application of 5-hydroxyflavone in a medicament for treating osteoarthritis, and experiments prove that the 5-hydroxyflavone can relieve traumatic osteoarthritis of mice caused by cutting off medial meniscus tibial plateau ligaments. Namely, the 5-hydroxyflavone has good application prospect in preparing the medicament for treating and/or preventing osteoarthritis.
The 5-hydroxyflavone has good reversing effect on the joint cartilage degeneration treatment, and has application prospect in preparing medicaments for treating and/or preventing osteoarthritis. Moreover, the 5-hydroxyflavone is a natural substance with a plurality of phenolic structures, is widely existed in fruits, vegetables, grains, barks, roots, stems, flowers, tea and wine, has good clinical use safety foundation and is more convenient to popularize and apply.
In addition, the invention also improves the drug delivery mode, and the drug delivery mode is made into a slow release preparation, so that the effect of effectively treating osteoarthritis for a long time can be expected to be achieved through one-time administration of the drug in the joint cavity in clinic.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
FIG. 1 is a graph of experimental results of 5-hydroxyflavone being able to alleviate IL-1 β -induced degeneration of tibial plateau cartilage of explants;
FIG. 2 is a graph showing the analysis of the reversion of knee joint cartilage degeneration after 4 weeks or 8 weeks of OA induction by DMM surgery on mice by safranin O-fast green staining;
FIG. 3 is a graph showing immunohistochemical analysis of 5-hydroxyflavone on the reversal of chondrocyte extracellular matrix Collagen (Collagen II) loss or knee joint cartilage degeneration after 4 or 8 weeks of DMM surgery induced OA in mice;
FIG. 4 is a graph showing the reversal of the loss of extracellular matrix proteoglycan (Aggrecan) in mice after 4 or 8 weeks of OA induction by DMM surgery with immunohistochemical analysis of 5-hydroxyflavone.
Detailed Description
Reference will now be made in detail to embodiments of the invention, one or more examples of which are described below. Each example is provided by way of explanation, not limitation, of the invention. In fact, it will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. For instance, features illustrated or described as part of one embodiment, can be used on another embodiment to yield a still further embodiment.
The practice of the present invention will employ, unless otherwise indicated, conventional techniques of cell biology, molecular biology (including recombinant techniques), microbiology, biochemistry and immunology, which are within the skill of the art. Such techniques are well explained in the literature, e.g. "molecular cloning: a Laboratory Manual, second edition (Sambrook et al, 1989); oligonucleotide Synthesis (oligo Synthesis) (eds. M.j. Goal, 1984); animal Cell Culture (Animal Cell Culture), ed.r.i. freshney, 1987; methods in Enzymology (Methods in Enzymology), academic Press, inc. (Academic Press, inc.), "Handbook of Experimental Immunology" ("D.M.Weir and C.C.Black well"), gene Transfer Vectors for Mammalian Cells (J.M.Miller and M.P.Calos.), "Current Protocols in Molecular Biology" (F.M.Ausubel et al., 1987), "PCR, polymerase Chain Reaction (PCR: the Polymerase Chain Reaction) (Mullis et al., 1994), and" Current Protocols in Immunology "(blood), each of which is incorporated herein by reference, cold, 1991.
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The features and properties of the present invention are described in further detail below with reference to examples.
Example 1
This example prepares a polymeric compound coated 5-hydroxyflavone sustained release formulation.
The method specifically comprises the following steps:
(1) Weighing 10mg of polylactic acid-glycolic acid copolymer and 0.2mg of 5-hydroxyflavone, and adding 0.1mL of dichloromethane for dissolving; 0.1mL of dichloromethane is added dropwise into 10mL of emulsifier, namely polyvinyl alcohol phosphate buffer; then mixing the emulsifier with the raw materials, and carrying out ultrasonic treatment for 30-40 minutes to obtain cloudy white liquid which is 5-hydroxyflavone sustained-release nanoparticles with different particle sizes suspended in the emulsifier.
(2) Setting the temperature of a water bath kettle of a rotary evaporator to 36-42 ℃, opening a vacuum pump to vacuumize for 30-40 minutes, and removing the organic solvent dichloromethane to obtain the 5-hydroxyflavone slow-release nanoparticle solution.
(3) Filtering the above solution with filter membrane with pore diameter of 200 nm to obtain clear stable liquid, which is liposome 5-hydroxyflavone sustained release preparation with uniform particle diameter. The particle size of the liposome 5-hydroxyflavone sustained-release particles prepared by the invention is 80-150 nanometers.
Example 2
This example prepares a liposome-encapsulated 5-hydroxyflavone sustained release formulation.
The method comprises the following steps:
(1) Preferably weighing 30mg of lecithin, 6mg of cholesterol and 2mg of 5-hydroxyflavone, and adding 5-15mL of dichloromethane for dissolving; the temperature of a water bath kettle of the rotary evaporator is set to 36-42 ℃, a vacuum pump is started to pump vacuum for 30-40 minutes, and then a layer of milky covering is formed in the reactor.
(2) And (2) adding 0.5ml of phosphate buffer solution with the mass fraction of 50% into the cloudy white covering obtained in the step (1), and carrying out ultrasonic treatment for 3-5 minutes to obtain cloudy white liquid which is liposome-coated 5-hydroxyflavone slow-release liquid with different particle sizes.
(3) And (3) extruding and filtering the cloudy white liquid obtained in the step (2) by using a liposome extrusion filter membrane with the pore diameter of 200 nanometers, and repeating for 100-200 times to obtain clear and stable liquid, namely the liposome-coated 5-hydroxyflavone sustained release agent with uniform particle size.
Example 3
This example prepared a sustained release injection of 5-hydroxyflavone. The 5-hydroxyflavone sustained-release injection provided by the invention can be directly injected without the help of an organic solvent, reduces adverse reactions and safety accidents caused by the organic solvent, has long retention time in vivo, does not need repeated injection for many times, reduces the cost of repeated administration, and reduces the pain feeling and irritation of patients.
The preparation method comprises the following steps:
the method comprises the following steps: obtaining the sustained-release granules of the cationic liposome encapsulated and loaded with 5-hydroxyflavone.
Step two:
(1) Preparing a chlorinated chitosan solution with temperature sensitivity of 37 ℃.
0.2g of chitosan chloride is stirred in 10ml of triple distilled water to respectively prepare 2 percent chitosan chloride aqueous solution. The chitosan chloride can not be dissolved completely instantly, is suspended into flocculent in the solution, and can be placed in a refrigerator at 4 ℃ overnight. Dissolving in triple distilled water to obtain milky clear jelly-like liquid with uniform properties, sterilizing under high pressure, and storing in refrigerator at 4 deg.C.
(2) Preparing a beta-sodium glycerophosphate solution.
4.5g of sodium β -Glycerophosphate (GP) was dissolved in 10ml of triple distilled water to prepare a 45% GP-water solution and a 45% GP1DMEM solution. The salt is easily dissolved, and is colorless clear liquid when dissolved in triple distilled water, and is sterilized by filtration with 0.22 μm filter membrane, and placed in 4 deg.C refrigerator for use.
Step three:
preparation of a mixture of chitosan chloride and sodium beta-glycerophosphate: the chitosan chloride solution and the sodium beta-glycerophosphate solution are mixed in a ratio of 8:2 fully mixing the materials on an ice box to form a clear jelly-like substance, and standing the clear jelly-like substance at 37 ℃ for 20min to form a solid gel.
Step four:
and (3) wrapping the cationic liposome prepared in the example 2 by using the sustained release particles loaded with the 5-hydroxyflavone, and mixing the sustained release particles with the chitosan hydrogel obtained in the step three to obtain the 5-hydroxyflavone sustained release agent.
Experimental example 1
This example demonstrates that 5-hydroxyflavone can counteract IL-1 β -induced cartilage degeneration under IL-1 β induction.
(1) Establishment of explant tibial plateau cartilage degeneration model
In the experiment, C57 suckling mice born for 1 day are selected, after neck removal and death, the tibia platforms of the suckling mice are taken out through aseptic operation, the suckling mice are cultured in a complete culture medium for 3 days, IL-1 beta (5 ng/ml) and 5-hydroxyflavone (2 mu M/ml) are respectively added according to groups, and once liquid is changed for 2 days, and the suckling mice are cultured for 2 weeks.
(2) Tissue fixation and paraffin section preparation
(1) Fixing the explant in the step (1) in 4% paraformaldehyde fixing solution at 4 ℃ for 24 hours; (2) the fixed tissue was washed twice with PBS for 5 minutes each. Subsequently, decalcification was carried out to obtain a decalcification solution of 0.5M EDTA at pH 7.4. The decalcifying liquid is replaced every 2 to 3 days, and the total decalcification time is one week. (3) Dewatering with automatic dewatering machine, transparent and wax dipping. The ethanol solution is dehydrated step by step, and the specific procedure is as follows: 50% ethanol solution for 1 hour; 70% ethanol solution for 1 hour; 80% ethanol solution for 1 hour; 95% ethanol solution for 1 hour; 100% ethanol I,1 hour; 100% ethanol II,1 hour; (4) transparent, namely, the ethanol solution is replaced by dimethylbenzene, and the specific procedure is as follows: xylene I,30 minutes; xylene II,30 minutes; (5) wax dipping, namely paraffin replacing dimethylbenzene solution, and the specific procedure is as follows: a mixed solution of xylene and paraffin (1 ratio), treated at 65 ℃ for 40 minutes; treating paraffin I at 65 ℃ for 40 minutes; paraffin II, treated at 65 ℃ for another 40 minutes and then cooled to room temperature; (6) embedding tissues by using an LEICA EG1160 paraffin embedding machine, wherein the integrity of a wax block is ensured without cracks during embedding; (7) trimming the edge of the wax block, and slicing by using an LEICA RM2235 slicer, wherein the application force is uniform, the slicing is uniform, and the excessive force and the excessive speed are avoided. The slice thickness is 4 μm; (8) and spreading the cut paraffin sections on water at 40 ℃, selecting the sections with intact articular surfaces, and fishing and sticking the sections by using an adhesive glass slide.
(3) Safranin O staining
Preparing a reagent:
the 1% safranin O dye solution is prepared by deionized water, and the powder is filtered by filter paper after being dissolved.
The experimental steps are as follows: A. baking slices: picking the paraffin section with intact articular surface in the step (2), and baking the section in a thermostat at 65 ℃ for 1-2 hours; B. dewaxing, i.e. xylene displacement of paraffin wax: xylene I,10 minutes; xylene II,10 minutes; C. hydration, namely replacing dimethylbenzene with ethanol, and the specific process comprises the following steps: 100% ethanol I,10 min; 100% ethanol II,10 min; 95% ethanol solution for 8 minutes; 80% ethanol solution for 8 minutes; 70% ethanol solution for 5 minutes; 50% ethanol solution, 5 minutes;
D. cleaning to remove ethanol: PBS wash 3 times for 5 minutes each; E. dyeing with 1% safranin O dye liquor for 30sec, slightly washing with water, and washing off floating color; F. after drying at 37 ℃, the gel is sealed by neutral resin and observed and photographed.
As shown in FIG. 1, it is clear from FIG. 1 that 5-hydroxyflavone is able to alleviate IL-1 β -induced degeneration of tibial plateau cartilage of explants. Under IL-1 β induction, safranin O staining area decreased, while 5-hydroxyflavone was able to counteract this induced cartilage degeneration, resulting in an increase in safranin O staining area.
Experimental example 2
In this example, the reverse of knee joint cartilage degeneration after 4 weeks or 8 weeks of OA induction by DMM surgery on mice was analyzed by safranin O-fast green staining.
(1) Establishment of osteoarthritis model
In this experiment, a meniscal instability (DMM) method was selected as the experimental osteoarthritis mouse model. Wild type male C57Bl/6J, 12-14 weeks old, was selected for molding. The right knee infraversion lateral meniscal tibial plateau of the experimental group mice was resected. The sham group only performed a skin incision of the right knee. Mice were sacrificed 4 or 8 weeks post-surgery and joint specimens were taken for subsequent testing.
(2) Joint cavity injection administration
And (2) injecting the joint specimen in the step (1) into a joint cavity by adopting a 33-gauge and a microinjector, wherein the dosage of the medicine injected by an administration group is 1mg/kg, the concentration of the medicine is 4mg/ml, the injection volume is about 5 mu l each time, the administration is started on the 3 rd day after the operation, the injection is performed once a week, and the solvent DMSO is injected into a control group.
(3) Fixation of tissue and preparation of Paraffin sections
(1) Stripping the complete right knee joint tissue, and fixing in 4% paraformaldehyde fixing solution at 4 ℃ for 24 hours; (2) the fixed tissue was washed twice with PBS for 5 minutes each. Subsequently, decalcification was carried out to obtain a decalcification solution of 0.5M EDTA at pH 7.4. The decalcification solution is replaced every 2-3 days, and the total decalcification time is 4 weeks. (3) Dewatering with automatic dewatering machine, transparent and wax-dipping. The ethanol solution is dehydrated step by step, and the specific procedures are as follows: 50% ethanol solution for 1 hour; 70% ethanol solution for 1 hour; 80% ethanol solution for 1 hour; 95% ethanol solution for 1 hour; 100% ethanol I,1 hour; 100% ethanol II,1 hour; (4) transparent, namely, the ethanol solution is replaced by the dimethylbenzene, and the specific procedure is as follows: xylene I,30 minutes; xylene II,30 minutes; (5) wax dipping, namely paraffin replacing dimethylbenzene solution, and the specific procedure is as follows: mixed solution of xylene and paraffin (1 ratio), treated at 65 ℃ for 40 minutes; treating paraffin I at 65 ℃ for 40 minutes; paraffin II, treated at 65 ℃ for another 40 minutes and then cooled to room temperature; (6) embedding tissues by using an LEICA EG1160 paraffin embedding machine, wherein the integrity of a wax block is ensured without cracks during embedding; (7) trimming the edge of the wax block, and slicing by using an LEICA RM2235 slicer, wherein the application force is uniform, the slicing is uniform, and the excessive force and the excessive speed are avoided. The slice thickness is 4 μm; (8) and spreading the cut paraffin sections on water at 40 ℃, selecting the sections with intact articular surfaces, and fishing and sticking the sections by using an adhesive glass slide.
(4) Safranin O-fast green staining
Preparing a reagent:
the 1% safranin O dye solution and the 0.2% fast green dye solution are both prepared by deionized water, and the powder is filtered by filter paper after being dissolved.
The experimental steps are as follows:
the steps of slicing the specimen, baking, dewaxing and gradient alcohol hydration are the same as those of experimental example 1;
a: dyeing with 0.2% fast green dye liquor for 20sec, and rinsing;
b: differentiating the differentiation liquid for 15sec without rinsing;
c: dyeing with 1% safranine O dye liquor for 30sec, and rinsing;
d: drying at 37 ℃, sealing the neutral gum, and observing and photographing.
And (3) analyzing a dyeing result: referring to fig. 2, (a, B) safranin O-fast green staining was used to analyze the reversal of knee joint cartilage degeneration after 4 weeks of mice induced OA by DMM surgery with 5-hydroxyflavone (n = 8). (C, D) safranin O-fast green staining analysis of the reversal of knee joint cartilage degeneration after 8 weeks of DMM surgery induced OA in mice with 5-hydroxyflavone (n = 8).
By safranin O-fast green staining, the morphological structure change of knee joint cartilage of mice, the change of the number, the size and the arrangement rule of chondrocytes, the change of the position of a tide line, the change of proteoglycan components in cartilage matrixes and the like can be observed.
As a result of staining, nuclei were stained blue, growth plate cartilage and articular cartilage were stained red, and bone, subchondral bone and other tissues were stained green.
To further quantify the staining results for statistical analysis, we assessed the severity of osteoarthritis by a histological-histochemical scoring method for osteoarthritis. And at least three different experimenters independently perform the scoring, and after the scoring is finished, the average score of the scores obtained by the three experimenters is taken as the final score. The scoring criteria were referenced to a modified OARSI scoring system, with higher scores indicating more severe osteoarthritis.
The results show that: 5-hydroxyflavone is injected into the joint cavity, and the 5-hydroxyflavone can well relieve traumatic osteoarthritis of mice caused by cutting off medial meniscus tibial plateau ligaments.
Example 3
Immunohistochemical analysis was performed in this experimental example.
(1) The procedure of slicing the specimen, baking, dewaxing, and gradient alcohol hydration was the same as in example 1.
Antigen retrieval: the cells are placed in 0.01M citric acid buffer (pH = 6.0) for repairing at 60 ℃ for 18-24 hours. After the repair is finished, taking out the slices (placing the slices in repair liquid), and naturally cooling to room temperature; cleaning to remove the antigen retrieval liquid: PBS washes 3 times, 5 minutes each;
(2) inactivating endogenous peroxidase: 3% of H 2 O 2 Covering the specimen with a solution (prepared by deionized water), and incubating for 10 minutes at room temperature in a dark place; cleaning to remove H 2 O 2 : PBS washes 3 times, 5 minutes each;
(3) the method comprises the following steps Covering the specimen with a special sealing liquid for normal goat serum, and incubating for 60 minutes at room temperature;
(4) primary antibody incubation: gently wipe off the blocking solution, cover the diluted primary antibody solution (prepared with antibody dilutions (1% BSA, 0.2% Trixton X-100, in PBS)) on the specimen, incubate overnight at 4 ℃ in a wet box; the next day, placing in an incubator at 37 ℃ for rewarming for 60 minutes; washing the surplus primary antibody: PBS washes 3 times, 5 minutes each; a first antibody: COL2A1 rabbitpab abcronal cat No.: a1560 Cargo number Aggrecan rabbitpab: a8536.
(5) And (3) secondary antibody incubation: preparing a secondary antibody with required concentration by using the antibody diluent, wherein the secondary antibody used for immunohistochemical detection in the experiment is labeled by horseradish peroxidase, and incubating for 1 hour at 37 ℃ in a wet box; washing the surplus secondary antibody: PBS washes 3 times, 5 minutes each; secondary antibody: peroxidase-Affinipure Goat Anti-Rabbit IgG (H + L) cat #: 111-035-003.
(6) Color development: and (3) dropwise adding DAB color developing solution (used as a ready-to-use solution) and observing the dyeing state in real time under a microscope to master the proper dyeing degree, wherein the contrast group and the experimental group must strictly ensure that the color developing time is consistent. Stopping the reaction in deionized water immediately after the color development is finished; washing: washing with deionized water for 5 minutes;
(7) counterdyeing: i.e., nuclear staining. Dyeing in hematoxylin dye liquor for 10-30 seconds, and washing for 10 minutes by tap water; differentiation: adding 1% hydrochloric acid into 70% alcohol, and differentiating for 1-3 s; distilled water: washing for 5 minutes;
(8) and (3) dehydrating: the specific procedure is 50% ethanol solution for 3 minutes; 70% ethanol solution for 3 minutes; 80% ethanol solution for 3 minutes; 90% ethanol solution for 3 minutes; 100% ethanol I,3 min; 100% ethanol II,3 min; clear, i.e. xylene displaced ethanol: the specific steps are xylene I,3 minutes; xylene II,1 minute;
(9) sealing: mounting with a neutral resin, taking care not to generate bubbles, and then observing the photograph under an Olympus microscope (BX 51).
And (C) statistics of R: and counting the number of positive cells and the total number of the positive cells to detect the positive rate, thereby judging the reversion condition of the cartilage degeneration phenotype.
Results of the experiments are shown in fig. 3, (a, B) immunohistochemistry analysis of 5-hydroxyflavone reversal of chondrocyte extracellular matrix Collagen (Collagen ii) loss after 4 weeks of mice OA induction by DMM surgery (n = 8). (C, D) immunohistochemical analysis 5-hydroxyflavone reverses degeneration of knee joint cartilage after 8 weeks of OA induction in mice by DMM surgery (n = 8). The results show that: 5-hydroxyflavone is injected into the joint cavity, and the 5-hydroxyflavone can reverse the loss of cartilage extracellular matrix Collagen (Collagen II) and reverse the degeneration of knee joint cartilage after the cartilage is degenerated. Can well relieve the traumatic osteoarthritis of mice caused by cutting off medial meniscus tibial plateau ligament.
In fig. 4, (a, B) immunohistochemistry analysis 5-hydroxyflavone reverses cartilage extracellular matrix proteoglycan (Aggrecan) loss after 4 weeks of mice induced OA by DMM surgery (n = 8). (C, D) immunohistochemical analysis 5-hydroxyflavone reverses the loss of chondrocyte extracellular matrix proteoglycan (Aggrecan) after 8 weeks of mice induced OA by DMM surgery (n = 8). The results in FIG. 4 show that: 5-hydroxyflavone is injected into the joint cavity, the 5-hydroxyflavone can well reverse cartilage extracellular matrix proteoglycan (Aggrecan) loss, and traumatic osteoarthritis of mice caused by cutting medial meniscus tibial plateau ligaments can be relieved.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
- Use of 5-hydroxyflavone for the manufacture of a medicament for the treatment and/or prevention of osteoarthritis, characterized in that the active ingredient in said medicament comprises 5-hydroxyflavone.
- 2. Use according to claim 1, characterized in that the osteoarthritis is selected from the group consisting of knee osteoarthritis, elbow osteoarthritis, shoulder osteoarthritis, hip osteoarthritis, spondyloarthropathies, cervical osteoarthritis and lumbar osteoarthritis;preferably, the knee osteoarthritis is selected from traumatic knee osteoarthritis or degenerative knee osteoarthritis;preferably, said application comprises at least one of the following actions:promoting cartilage formation, slowing osteoarthritis progression, reversing cartilage loss, and reversing cartilage degeneration.
- 3. The use of claim 2, wherein the medicament is in the form of a tablet, capsule, suspension, solution, emulsion, powder, granule, injection, lyophilized powder for injection, liniment, plastics, ointment, lotion, suppository, aerosol, spray, powder spray, ointment, plaster, cataplasma or patch;preferably, the medicament is in the form of injection.
- 4. The use of claim 3, wherein the medicament further comprises a pharmaceutically acceptable additive or adjuvant;preferably, the pharmaceutically acceptable additive or adjuvant is selected from one or more of the following: solvents, buffers, emulsifiers, suspending agents, disintegrating agents, dispersing agents, binders, excipients, stabilizers, chelating agents, diluents, gelling agents, preservatives, wetting agents, lubricants, absorption delaying agents, flavoring agents, sweeteners, pigments, and liposomes.
- 5. The use of claim 3, wherein the medicament comprises a carrier, the carrier being a polymer, a liposome, ethanol, and a polyol;preferably, the polymer is selected from the group consisting of starch, cellulose, dextran, polylactic-co-glycolic acid, chlorinated chitosan, collagen, gelatin, fibrinogen, albumin, polyester and polyethylene glycol;preferably, when the medicine is an injection, the medicine is injected into the joint cavity;preferably, the medicament further comprises a combination selected from the group consisting of an organic diphosphate, a chemotherapeutic agent, a radioactive agent, a TNF-antagonist, a non-steroidal anti-inflammatory agent, a steroid, an antioxidant, an angiogenesis inhibitor, a matrix metalloproteinase inhibitor, a vitamin, a selective estrogen receptor modulator, an estrogen-progesterone, an androgen, calcitonin, an antibiotic, a cathepsin K inhibitor, an inhibin, an integrin receptor antagonist, an osteoblast anabolic agent or a selective serotonin reuptake inhibitor, glucosamine, hyaluronic acid, or a mixture thereof.
- 6. A preparation method of a 5-hydroxyflavone sustained release agent coated by a macromolecular compound is characterized by comprising the following steps: mixing polylactic acid-glycolic acid copolymer, 5-hydroxyflavone and a first organic solvent, adding an emulsifier mixed with a second organic solvent, and carrying out ultrasonic treatment;the mixing mass ratio of the polylactic acid-glycolic acid copolymer to the 5-hydroxyflavone is 10-30, and 5-hydroxyflavone is mixed with 0.1-2mL of the first organic solvent per 0.2-2mg of the polylactic acid-glycolic acid copolymer and the 5-hydroxyflavone.
- 7. The production method according to claim 6, wherein a mixing volume ratio of the first organic solvent or the second organic solvent to the emulsifier is 0.1 to 2;the first organic solvent or the second organic solvent is selected from one or more of acetone, chloroform, methylamine, dimethylamine, diethyl ether, pentane, dichloromethane or carbon disulfide, more preferably, the first organic solvent or the second organic solvent is both selected from dichloromethane;preferably, the time of the ultrasonic treatment is 30-40min;preferably, the ultrasonic treatment further comprises removing the first organic solvent and the second organic solvent by using a rotary evaporator and vacuumizing;preferably, the removing of the first organic solvent and the second organic solvent further comprises filtering;preferably, the emulsifier is a polyvinyl alcohol phosphate buffer.
- 8. A preparation method of a liposome-coated 5-hydroxyflavone sustained release agent is characterized by comprising the following steps:(a) Mixing lecithin, cholesterol, 5-hydroxy flavone and an organic solvent, and performing rotary evaporation treatment and vacuum pumping treatment to obtain a white covering; the mixing mass ratio of the lecithin, the cholesterol and the 5-hydroxyflavone is 10-30:2-6:0.2 to 2; mixing 5-hydroxyflavone of 0.2-2mg with 5-15mL of organic solvent;(b) Then mixing the white covering with a phosphate buffer solution to obtain liposome 5-hydroxyflavone sustained-release nanoparticles;(c) Extruding and filtering;preferably, 10mg of lecithin, 2mg of cholesterol and 2mg of 5-hydroxyflavone are weighed and dissolved by adding 15mL of dichloromethane; setting the temperature of a water bath kettle of a rotary evaporator to 36-42 ℃, opening a vacuum pump to vacuumize for 30-40 minutes, and forming a layer of white covering in the reactor;preferably, 0.5ml of phosphate buffer liquid with the mass fraction of 50% is added into the white covering, and after 3-5 minutes of ultrasonic treatment, cloud-like white liquid is obtained, namely the liposome 5-hydroxyflavone slow-release nanoparticles with different particle sizes;preferably, the cloudy white liquid is extruded and filtered by a filter membrane with the pore diameter of 200 nanometers, and the filtering is repeated for 100 to 200 times to obtain clear and stable liquid, namely the liposome 5-hydroxyflavone sustained-release preparation with uniform particle size.
- 9. A preparation method of a 5-hydroxyflavone sustained-release injection is characterized by comprising the following steps: mixing the liposome-coated sustained-release agent of 5-hydroxyflavone prepared by the preparation method of claim 8 with a carrier selected from the group consisting of a polymer, a liposome, ethanol and a polyol;preferably, the polymer is selected from the group consisting of starch, cellulose, dextran, polylactic-co-glycolic acid, chlorinated chitosan, collagen, gelatin, fibrinogen, albumin, polyester, and polyethylene glycol;preferably, the carrier is selected from a mixed gel prepared by mixing chitosan chloride and sodium beta-glycerophosphate according to a volume ratio of 8.
- 10. The sustained-release preparation of 5-hydroxyflavone coated with a polymer compound prepared by the method according to any one of claims 6 to 7, the sustained-release preparation of 5-hydroxyflavone coated with a liposome prepared by the method according to claim 8, or the sustained-release injection of 5-hydroxyflavone prepared by the method according to claim 9.
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