WO2017157350A1 - 依达拉奉剂型 - Google Patents

依达拉奉剂型 Download PDF

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WO2017157350A1
WO2017157350A1 PCT/CN2017/081405 CN2017081405W WO2017157350A1 WO 2017157350 A1 WO2017157350 A1 WO 2017157350A1 CN 2017081405 W CN2017081405 W CN 2017081405W WO 2017157350 A1 WO2017157350 A1 WO 2017157350A1
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lipid
edaravone
solid phase
group
drug delivery
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PCT/CN2017/081405
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English (en)
French (fr)
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周新富
帕里克安基特
加尔桑贾伊
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福建天泰医药科技有限公司
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Priority to EP17765892.9A priority Critical patent/EP3431075A4/en
Priority to EP23203751.5A priority patent/EP4289482A3/en
Priority to SG11201808019WA priority patent/SG11201808019WA/en
Priority to US16/084,668 priority patent/US11020375B2/en
Publication of WO2017157350A1 publication Critical patent/WO2017157350A1/zh

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Definitions

  • the invention belongs to the field of pharmacy.
  • the present invention relates to novel edaravone pharmaceutical dosage forms, especially oral dosage forms, and to the use of edaravone for the effective treatment of human oxidative stress related diseases.
  • Free radicals are a common result of aerobic metabolism in normal cells.
  • the body's built-in antioxidant system plays a decisive role in preventing damage caused by free radicals.
  • the imbalanced defense mechanisms of antioxidants, the excessive production of free radicals or the introduction of living systems from the environment lead to serious obstacles to neurodegeneration.
  • Neuronal degeneration of the neurodegenerative disease suffers from loss of function or senses.
  • oxidative stress (OS) causes free radicals to attack nerve cells, and the contribution to neurodegeneration is catastrophic.
  • ROS reactive oxygen species
  • AD Alzheimer's disease
  • PD Parkinson's disease
  • MS multiple sclerosis
  • ALS amyotrophic lateral sclerosis
  • RA rheumatoid arthritis
  • ischemia Post-infusion injury myocardial infarction
  • cardiovascular disease chronic inflammation
  • stroke and septic shock According to the World Health Organization (WHO), the world's top 10 lethal diseases are ischemic heart disease, stroke, chronic obstructive pulmonary disease (COPD), lower respiratory tract infection, tracheal/bronchial/lung cancer, HIV/AIDS, diarrhea.
  • COPD chronic obstructive pulmonary disease
  • oxidative stress is the leading cause of most diseases in the top 10 lethal diseases, especially ischemic heart disease, stroke, COPD, HIV/AIDS and diabetes.
  • the global market for diseases related to oxidative stress is more than $200 billion.
  • oxidative stress is fundamental to many chronic, degenerative, and lethal diseases, this suggests that antioxidants are urgently needed to help control ROS levels in the body. Therefore, as a strong and potential free radical scavenger or antioxidant, edaravone can play an important role in reducing ROS levels and reducing oxidative stress. It is expected that edaravone will be used to treat or minimize the risk of lethal disease in the near future.
  • Edaravone also known as MCI-186, chemical name: 3-methyl-1-phenyl-2-pyrazolin-5-one, molecular formula C 10 H 10 N 2 O, molecular weight 174.19, Structure:
  • edaravone shows beneficial effects in inflammation, matrix metalloproteinases, nitric oxide production, and apoptosis.
  • Mitsubishi Tanabe Pharm Corp. (Osaka, Japan) first developed edaravone and was listed as Radicut in 2001, becoming the world's first neurovascular protective drug.
  • the Japanese Ministry of Public Health and Welfare approved the drug for the treatment of patients with cerebral infarction and acute ischemic stroke (AIS).
  • edaravone Since then, edaravone has not only been used to treat AIS, but also to treat ROS-related diseases such as cardiovascular disease and stroke. Although edaravone is a commonly prescribed drug in Japan, India and China, it has not been approved in the United States and other Western countries, mainly due to its toxicity in the liver and kidneys and lack of clinical research to support edaravone. Beneficial effect. Many countries are still working on clinical research in edaravone.
  • Edaravone is designed as a phenol-like compound, and phenol is one of the functional groups of all phenolic antioxidants, wherein the phenolic antioxidant consists of a hydroxyl group (-OH) attached to an aromatic ring and is responsible for antioxidant properties.
  • the phenolic antioxidant consists of a hydroxyl group (-OH) attached to an aromatic ring and is responsible for antioxidant properties.
  • the free radical By donating a hydrogen ion to the free radical, which in turn becomes a group, the phenol quenches the free radical.
  • electrons on the phenol are stabilized by localization of the aromatic ring via resonance electrons, and the activity is lowered. But due to toxicity and corrosivity, even if free radical scavenging Role and proven to be a potential antioxidant, phenols are not suitable for pharmaceutical use.
  • edaravone is expected to have the same activity as phenols and exhibits similar antioxidant and free radical scavenging effects.
  • Edaravone can be classified into three different tautomeric forms, namely amine, keto and enol.
  • the aromatic hydroxy group is produced via keto-enol tautomerization.
  • edaravone has no toxic effects of phenols, which is one of the reasons why edaravone is more advantageous than phenols.
  • Edaravone has a pKa of 7.0, so about 50% of edaravone is ionized under physiological pH conditions and exists in an anionic form.
  • the anionic form of edaravone is also a more reactive form that readily reacts with ROS in the brain to produce an antioxidant effect.
  • the advantage of edaravone compared to other free radical scavengers is that it easily crosses the blood-brain barrier because edaravone is a low molecular weight lipophilic molecule. It has solubility characteristics in both water and lipids. Therefore, it can easily cross the blood-brain barrier and reach the target in the brain.
  • the ratio of plasma levels of edaravone to cerebrospinal fluid levels is expected to be 50-65%. These characteristics may be due to the neuroprotective effects of edaravone in cerebral infarctions, while other antioxidants do not.
  • edaravone has low permeability, poor water solubility, poor bioavailability and stability, short half-life, side effects such as hepatotoxicity and nephrotoxicity, and any oxidative properties should be In the case of aggressive diseases, it is a major obstacle to achieving the desired efficacy in preclinical and clinical studies.
  • the present application adopts a formulation strategy based on a lipid, a solid phase dispersion and a co-solvent, thereby obtaining the best therapeutic effect of the novel dosage form.
  • Lipid-based drug delivery systems have shown great potential for drug candidates that are difficult to administer in the form of oral administration, and several successfully marketed drugs have been introduced. Pre-dissolving the drug in a lipid, a surfactant, or a mixture of a lipid and a surfactant negates the dissolution/dissolution step, which is a key rate-limiting factor for oral absorption of a poorly water-soluble drug, which results in improved bioavailability. Bypassing the liver reduces hepatotoxicity (via lymphatic absorption) and reduces nephrotoxicity (unknown mechanism).
  • Lipid-based drug delivery systems include lipid solutions, lipid suspensions, surfactant or polymer-lipid mixed micelles, self-microemulsifying drug delivery systems, and nanoemulsion formulations.
  • Solid phase dispersion technology is the solid phase, in which one or more active ingredients are dispersed in an inert matrix to achieve improved bioavailability (by increasing solubility, dissolution rate and penetration) Sex), sustained release of the drug, changes in solid phase properties, and stability.
  • Cosolvent-based strategies Some poorly water-soluble molecules are sufficiently soluble in solutions consisting of aqueous/organic cosolvents, but some poorly water-soluble molecules are only in all organic solutions or from a solvent. Solubilized in a solution consisting of or consisting of a mixture of solvents/surfactants. This strategy is most widely used for drug delivery in the form of drug candidates that are difficult to administer in order to increase bioavailability.
  • the main object of the present invention is to effectively use edaravone to achieve optimal therapeutic effects by achieving desired bioavailability, extended half-life, and reduced liver and kidney-related side effects.
  • Solid, semi-solid and liquid formulations of edaravone are cosolvent-based systems, lipid solutions, lipid suspensions, self-microemulsifying drug delivery systems, nanoemulsions, micelles [1-4] and solid phase dispersions .
  • the present invention provides a practical solution to edaravone in the form of a solid dosage form such as a tablet, or a powdered filler in a hard gelatin capsule, or a liquid dosage form such as a liquid filler in a hard or soft gelatin capsule. .
  • the present invention relates to the following edaravone formulation 1 (lipid formulation) and a process for its preparation:
  • the present invention provides a lipid-based drug delivery system comprising the active ingredient edaravone or a pharmaceutically acceptable salt thereof, and a lipid.
  • a lipid refers to all natural or synthetic fats containing triglycerides and saturated and unsaturated fatty acids of different carbon chain lengths, preferably Caproyl 90, Capmul MCM and Caproyl PGMC.
  • the lipid comprises a natural product oil, a semi-synthetic lipid (prepared by chemically combining a medium chain saturated fatty acid derived from a natural product vegetable oil or glycerol with one or more hydrophilic chemical moieties) and a fully synthetic lipid ( Mainly natural glycolic acid).
  • Water-insoluble lipids include beeswax, oleic acid, soybean fatty acid, vitamin E, corn oil mono-di-triglyceride, medium chain (C8/C10) monoglyceride and diglyceride, propylene glycol ester of fatty acid, and the like.
  • Lipids are triglycerides and can be further classified into long chain triglycerides (LCT), medium chain triglycerides (MCT) and short chain triglycerides (SCT).
  • long-chain triglycerides include hydrogenated soybean oil, hydrogenated vegetable oil, corn oil, olive oil, soybean oil, peanut oil, sesame oil and the like.
  • Medium chain triglycerides include caprylic/maronic triglycerides from cocoa butter or palm seed oil.
  • corn oil, cottonseed oil, Captex 355, peceol, peanut oil, caprylic acid triglyceride, castor oil, sesame oil, Miglyol 812, sunflower oil, Capmul MCM, Capryol PGMC or the like can be used as a lipid.
  • a lipid-based drug delivery system comprises a therapeutic agent (edarabi), an oily medium/lipid, a surfactant, a co-surfactant, a cosolvent, a liposome, and/or a solid lipid nanoparticle. Wait.
  • the lipid based drug delivery system further comprises excipients and/or additives.
  • the excipient is a chemical triglyceride, a partial triglyceride, a semi-synthetic oily ester and a semi-synthetic nonionic surfactant ester, or is selected from the group consisting of water-insoluble beeswax, oleic acid, soy fatty acid, vitamin E, corn oil Mono-di-triglycerides, medium chain (C8/C10) monoglycerides and diglycerides of fatty acids and propylene glycol esters of fatty acids.
  • Additives include solid phase adsorbents, water soluble and fat soluble antioxidants, acidulants, chelating agents, and buffers.
  • the solid phase adsorbent comprises a silicon-based adsorbent and a non-silicon-based adsorbent, the silicon-based adsorbent comprises Aerosil 200 and magnesium metasilicate, and the non-silicon-based adsorbent comprises microcrystalline cellulose, talc, anhydrous dibasic calcium phosphate. (DCPA), a water-soluble polymer composed of a group such as an alkyl cellulose, a hydroxyalkyl cellulose, a hydroxyalkyl alkyl cellulose sugar or the like.
  • DCPA dibasic calcium phosphate
  • the chelating agent is at least one selected from the group consisting of ethylenediamine, calcium disodium edetate, and disodium edetate.
  • Acidifying agents include, but are not limited to, citric acid, acetic acid, fumaric acid, hydrochloric acid, and nitric acid.
  • Buffering agents include, but are not limited to, potassium metaphosphate, potassium dihydrogen phosphate, sodium acetate, sodium citrate.
  • Water-soluble or fat-soluble antioxidants include, but are not limited to, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylhydroxytoluene, hypophosphorous acid, thioglycerol, propyl gallate, sodium ascorbate, sodium hydrogen sulfite, formaldehyde Sodium hyposulfite, hyposulfite, sodium metabisulfite.
  • lipid-based drug delivery system further comprises a specific Capryol TM PGMC, RH 40, Labrasol, TPGS 1000, Transcutol P and/or Aerosil 200.
  • the lipid-based drug delivery system further comprises a water-soluble organic solvent, a surfactant, a co-surfactant, a polymer solubilizer, a phospholipid, an acidulant, a buffer, a stabilizer, an antioxidant, a preservative, and/or Or a solid phase adsorbent.
  • the water-soluble organic solvent includes, but is not limited to, PEG 200-10,000, polyvinyl caprolactam (PCL), polyvinyl acetate (PVA) or a copolymer thereof, and water-soluble form of vitamin E and ethanol, wherein PEG 200-10,000 includes, for example, PEG.
  • Surfactants include water soluble surfactants and water insoluble surfactants.
  • the co-surfactants are based on polyethylene glycol, polypropylene glycol, ethanol and glycerol, especially PEG 300, PEG 400, propylene glycol, glycerol, ethanol, Transcutol HP and Transcutol P.
  • Polymer solubilizers include, but are not limited to, Soluplus, chitosan, polyvinylpyrrolidone (PVP), PVP/VA, HPC, HPMC, HPMCAS, eudragit E100, based on dimethylaminoethyl methacrylate, butyl methacrylate A cationic copolymer with methyl methacrylate used as both a polymer solubilizer and as a stabilizer.
  • the lipid-based drug delivery system further comprises a polymeric carrier selected from the group consisting of Soluplus, hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), chitosan, PVP, PVP/VA, HPC, hydroxypropyl methylcellulose acetate (HPMCAS), eudragit E100, cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate, preferably Soluplus, hydroxy Propyl methylcellulose (HPMC) or polyethylene glycol.
  • a polymeric carrier selected from the group consisting of Soluplus, hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), chitosan, PVP, PVP/VA, HPC, hydroxypropyl methylcellulose acetate (HPMCAS), eudragit E100, cationic copolymer based on dimethylaminoethyl methacrylate, but
  • the lipid-based drug delivery system is selected from the group consisting of a lipid solution, a lipid suspension, a surfactant or a polymer-lipid mixed micelle, a self-micron emulsified drug delivery system (SMEDDS), and a nanoemulsion formulation.
  • SMEDDS is a solid phase and further comprises an adsorbent, preferably Aerosil 200.
  • the nanoemulsion formulation further comprises a water/buffer.
  • the invention also provides a method of preparing a lipid-based drug delivery system comprising the following steps:
  • the active ingredient edaravone or a pharmaceutically acceptable salt thereof is dissolved in a lipid, a surfactant, or a mixture of a lipid and a surfactant.
  • the present invention relates to the following edaravone preparation 2 (solid phase dispersion) and a preparation method thereof:
  • the present invention provides a solid phase dispersion formulation comprising the active ingredient edaravone or a pharmaceutically acceptable salt thereof, and a polymeric carrier.
  • the polymeric carrier is a water soluble polymer selected from the group consisting of N-vinyl lactam homopolymers, N-vinyl lactam copolymers, cellulose esters, cellulose ethers, polyalkylene oxides, poly Acrylates, polymethacrylates, homopolymers and copolymers of acrylic acid, homopolymers and copolymers of methacrylic acid, polyacrylamide, polyvinyl alcohol, vinyl acetate polymer, vinyl acetate copolymer, carboxy Vinyl polymers, oligosaccharides, polysaccharides, and mixtures thereof.
  • the water-soluble polymer is selected from the group consisting of alkyl cellulose, hydroxyalkyl cellulose, hydroxyalkyl alkyl cellulose, methyl cellulose (MC), ethyl cellulose (EC), hydroxyethyl cellulose.
  • HEC hydroxypropylcellulose
  • HPMC hydroxypropylmethylcellulose
  • HEMC hydroxypropylmethylcellulose succinate
  • hydroxypropylmethyl Cellulose acetate succinate carboxymethylethylcellulose, sodium carboxymethylcellulose, potassium carboxymethylcellulose, cellulose acetate succinate, cellulose acetate phthalate, hydroxypropyl Methylcellulose phthalate, polyacrylic acid copolymer, poly(meth)acrylic acid polymer, poly(hydroxyalkyl acrylate), poly(hydroxyalkyl methacrylate), polyvinylpyrrolidone ( PVP), vinylpyrrolidone homopolymer, vinylpyrrolidone copolymer, povidone, vinylpyrrolidone-vinyl acetate copolymer (copovidone), copolymer of vinyl acetate, vinyl propionate Copolymer, copolymer of vinyl acetate and crotonic acid, polyethylene glyco
  • the polymeric carrier is selected from the group consisting of Soluplus, hydroxypropylmethylcellulose (HPMC), polyethylene glycol (PEG), chitosan, PVP, PVP/VA, HPC, hydroxypropylmethylcellulose Acetate (HPMCAS), eudragit E100, a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate, especially selected from the group consisting of Soluplus, hydroxypropyl methylcellulose (HPMC) or polyethylene glycol (PEG).
  • the solid phase dispersion formulation further comprises a surfactant (negative, positive or amphoteric surfactant).
  • the surfactant is selected from the group consisting of sodium dodecyl sulfate, sodium dodecyl sulfate (SDS), sodium lauryl sulfate (SLS), polyoxyethylene sorbitan long-chain fatty acid ester, vitamin E-TPGS, and gall bladder. Salt, sodium deoxycholate, sodium glycocholate, polyoxyethylene polyoxypropylene glycol, and combinations thereof.
  • the surfactant is TPGS 1000.
  • the solid phase dispersion formulation specifically includes edaravone, Soluplus, and optionally TPGS 1000.
  • the solid phase dispersion further comprises a pharmaceutically acceptable excipient selected from the group consisting of a disintegrant, a lubricant, a glidant, an anti-adhesive agent, an inert filler, a wetting agent, and a pH modification.
  • a pharmaceutically acceptable excipient selected from the group consisting of a disintegrant, a lubricant, a glidant, an anti-adhesive agent, an inert filler, a wetting agent, and a pH modification.
  • Agents, binders, solubility modifiers, recrystallization inhibitors, diluents, and combinations thereof are examples of a lubricant, a glidant, an anti-adhesive agent, an inert filler, a wetting agent, and a pH modification.
  • the solid phase dispersion can be formulated into tablets, rings, patches, capsules, pills, granules, fine granules or powders.
  • the invention also provides a method for preparing a solid phase dispersion preparation comprising the following steps:
  • the active ingredient edaravone or a pharmaceutically acceptable salt thereof is dispersed in a polymeric carrier and optionally a surfactant, prepared by a process selected from the group consisting of: ice bath agitation, film cooling, liquid nitrogen, spray coagulation, heat melt extrusion, Meltrex TM, melt agglomeration, or solvent evaporation (drying, vacuum drying, rotary evaporation, hot plate heating, spray drying, freeze drying, supercritical anti-solvent, co-precipitation, electro-spinning, spray-freeze-dried, ultra Quick drying, fluid bed coating) and solvent melting.
  • a surfactant prepared by a process selected from the group consisting of: ice bath agitation, film cooling, liquid nitrogen, spray coagulation, heat melt extrusion, Meltrex TM, melt agglomeration, or solvent evaporation (drying, vacuum drying, rotary evaporation, hot plate heating, spray drying, freeze drying, supercritical anti-solvent, co-precip
  • the present invention relates to the following edaravone preparation 3 (micelle preparation) and a preparation method thereof:
  • the present invention provides a micelle-based formulation comprising the active ingredient edaravone or a pharmaceutically acceptable salt, a polymeric carrier and a water/buffer.
  • An effective amount of the therapeutic agent edaravone is encapsulated in the micelle.
  • the polymeric carrier is selected from the group consisting of Soluplus, hydroxypropylmethylcellulose (HPMC), polyethylene glycol (PEG), chitosan, PVP, PVP/VA, HPC, hydroxypropylmethylcellulose Acetate (HPMCAS), eudragit E100, cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate, preferably Soluplus, hydroxypropyl methylcellulose (HPMC) ) or polyethylene glycol (PEG).
  • HPMC hydroxypropylmethylcellulose
  • PEG polyethylene glycol
  • chitosan PVP
  • PVP/VA HPC
  • HPC hydroxypropylmethylcellulose Acetate
  • HPC hydroxypropylmethylcellulose Acetate
  • HPC hydroxypropylmethylcellulose Acetate
  • HPC hydroxypropylmethylcellulose Acetate
  • HPC hydroxypropylmethylcellulose Acetate
  • HPC hydroxypropylmethylcellulose
  • the micelle-based formulation further comprises a surfactant, a solid phase adsorbent, an acidulant and/or an antioxidant.
  • the micelle-based formulation specifically includes edaravone, Soluplus, TPGS1000, and PBS.
  • the invention also provides a method for preparing a micelle-based preparation comprising the following steps:
  • the active ingredient edaravone or a pharmaceutically acceptable salt thereof, a polymeric carrier and an optional surfactant are dissolved in ethanol, and the organic solvent is removed by rotary evaporation. The resulting film is vacuum dried, then added with a buffer to hydrate and sonicated.
  • the invention also provides a method of protecting a therapeutic agent, edaravone, comprising encapsulating the therapeutic agent in a micelle-based formulation.
  • the present invention relates to the following edaravone preparation 4 (cosolvent preparation) and a preparation method thereof:
  • the present invention provides a co-solvent-based formulation comprising the active ingredient edaravone or a pharmaceutically acceptable salt thereof, and 1-99% (v/v) of a water-soluble organic solvent and/or a surfactant or Auxiliary surfactant.
  • the water-soluble organic solvent includes, but is not limited to, PEG 200-10,000, propylene glycol, glycerin, Transcutol HP, Transcutol P, Cremophor RH 40, Cremophor EL, Labrasol, TPGS 1000, Tween 20, Tween 80, water soluble form.
  • Vitamin E and ethanol wherein PEG 200-10,000 includes, for example, PEG 300, PEG 400, PEG 1,000, and PEG 6,000.
  • the co-solvent-based formulation further comprises a surfactant, a phospholipid, a vitamin E, an antioxidant, a preservative, a solid phase adsorbent and/or a water/buffer to promote solubilization, improve permeability and stability. Sex.
  • the cosolvent-based formulation specifically includes one or more of PEG300, Labrasol, Transcutol P, TPGS 1000, and Cremophor RH 40.
  • the invention also provides a preparation method of a formulation based on a cosolvent, comprising the following steps:
  • the active ingredient edaravone or a pharmaceutically acceptable salt thereof is dissolved in a water-soluble organic solvent and/or a surfactant.
  • the present invention relates to the following dosage forms and routes of administration of edaravone formulations:
  • the above edaravone preparation 1-3 which is a solid dosage form selected from the group consisting of a tablet, a capsule, a powder or a strip, by oral, parenteral, inhalation, topical or transdermal, intranasal, ocular Administration into the inner, inner ear, rectal, and intravaginal routes.
  • the above edaravone preparation 1-4 which is a liquid dosage form selected from the group consisting of a solution, a suspension, an emulsion, a cosolvent-based system, an aerosol, by oral, parenteral, inhalation, topical or transdermal, Intranasal, intraocular, inner ear, rectal, intravaginal routes of administration.
  • the above edaravone preparation 1-4 which is a semi-solid dosage form, the semi-solid dosage form being selected from the group consisting of Creams, creams, gels, pastes, for topical or systemic purposes, are administered by topical or transdermal routes.
  • the invention also relates to the treatment of diseases and pharmaceutical uses of the following edaravone formulations:
  • the present invention provides edaravone formulations 1-4 for the treatment of diseases associated with oxidative stress.
  • the present invention provides the use of edaravone formulations 1-4 in the manufacture of a medicament for the treatment of oxidative stress related diseases.
  • the oxidative stress-related diseases include senile/aging diseases (arthritis, diabetes, osteoarthritis, cataract, macular degeneration, prostate disease), cardiovascular diseases (atherosclerosis, heart failure, heart) Disease, renal failure, hypertension, stroke, poor blood circulation, cholesterol and plaque formation, reperfusion injury), cancer (prostate cancer, breast cancer, lung cancer, colon cancer, bladder cancer, uterine cancer, ovarian cancer, lymphoma) , skin cancer, stomach cancer, liver cancer and other wasting diseases), neurodegenerative diseases (Alzheimer's disease / Alzheimer's disease, Parkinson's disease, multiple sclerosis, schizophrenia, dementia, Huntington's disease), liver disease (toxic hepatitis, viral hepatitis (A, B and C), chronic hepatitis), lung disease (asthmatic emphysema, pneumonia, (acute and chronic) bronchitis, cystic fibrosis, pulmonary fibrosis, chronic obstructive pulmonary disease ( CO
  • the edaravone formulation of the present invention or a component thereof, whether used alone or in combination, is intended to modify/improve the existing properties of edaravone such as solubility, chemical stability (hydrolysis, oxidation, heat, light) , sustained release, pharmacokinetic properties, such as permeability of the small intestine, bioavailability, half-life, metabolism and excretion.
  • the edaravone is present in an amount of from 0.001 to 1000 mg/ml, preferably from 0.1 to 100 mg/ml, more preferably from 10 to 20 mg/ml.
  • the dose of edaravone is from 0.001 to 1000 mg per unit, preferably from 0.1 to 100 mg per unit, more preferably from 10 to 20 mg per unit.
  • the invention adopts a solid phase dispersion strategy to provide a novel edaravone dosage form, which greatly improves its solubility, stability and bioavailability.
  • solubility of the present invention is 16 times higher than that of the intravenous (iv) dosage form, and the bioavailability is comparable.
  • Figure 1 shows the solubility (mg/gm) of edaravone in different media.
  • Figure 2 shows the screening of a drug carrier system (Soluplus) based on the edaravone solubility study.
  • Figure 3 shows the solubility of edaravone in different types of formulations (Examples 1-11).
  • Figure 4 shows the in vitro safety of different types of edaravone formulations (Examples 1-11).
  • Figure 5 shows the particle size distribution of the micelle preparation of the present invention (Example 6).
  • Figure 6 shows the dissolution of the solid phase dispersion (Example 8) of the present invention in different simulated body fluids.
  • Figure 7 shows the bioavailability of the SMEDDS (Examples 1 and 2) of the present invention.
  • Figure 8A shows the stability of edaravone in bio-related media at different pH.
  • Figure 8B shows the stability of the solid dispersion formulation of the invention (Example 8) in biologically relevant media at different pH.
  • the required amount of oil (Capmul PGMC), surfactant (Cremophor RH 40, Labrasol and TPGS 1000) and co-surfactant (Transcutol P) were accurately weighed into small glass vials. Then, the above components were mixed by gentle stirring and vortex mixing, and heated at 37 ° C in an incubator. Add the required amount of edaravone and vortex to mix until the edaravone is completely dissolved.
  • a liquid phase SMEDDS formulation was prepared as above. After the required amount of Aerosil 200 was added, it was diluted with a minimum amount of miliQ water and stirred at room temperature for 2 hours. The resulting mixture was allowed to stand for 15 minutes, equilibrated and filtered through a 0.45 ⁇ m syringe filter (PVDF). Freeze the solution at -80 ° C for at least 6 hours before lyophilization, then place on Novalyphe-NL 500 (Savant Instruments Corp., Holbrook, NY) was lyophilized for at least 24 hours at -45 ° C and 7102 mbar pressure. Finally, the solid phase SMEDDS is stored in a desiccator.
  • PVDF 0.45 ⁇ m syringe filter
  • Example 5 the required amount of oil (Capmul PGMC), surfactant (Cremophor RH 40, Labrasol and TPGS 1000) and co-surfactant (Transcutol P) were accurately weighed into small glass vials. Then, the above components were mixed by gentle stirring and vortex mixing, and heated at 37 ° C in an incubator. Add the required amount of edaravone and vortex to mix until the edaravone is completely dissolved. The required amount of miliQ water was added dropwise until a clear, clear formulation was obtained.
  • Example 6 the desired amounts of edaravone, Soluplus and TPGS 1000 were dissolved in ethanol.
  • the organic solvent was removed by a Buchi rotary evaporator II.
  • the resulting membrane was dried overnight in a vacuum desiccator, then hydrated with 10 ml of 1 x PBS buffer (pH 7.4), incubated at 37 ° C for 30 minutes, and then sonicated for a few minutes.
  • the resulting mixture was filtered through a 0.45 ⁇ m syringe filter (PVDF).
  • PVDF 0.45 ⁇ m syringe filter
  • edaravone, Soluplus and TPGS 1000 were dissolved in ethanol according to Examples 7 and 8.
  • the organic solvent was removed by a Buchi rotary evaporator II.
  • the formed film was dried overnight in a vacuum desiccator.
  • the dried sample was scraped from the flask and collected in a mortar.
  • the powder was crushed with a mortar and made into a uniform form.
  • Examples 1-11 provide formulations for a variety of different formulations, including formulations based on lipids, micelles, solid phase dispersions, and co-solvents, respectively. The advantages of these formulations are detailed below by way of effect examples.
  • Sample analysis was performed on a HPLC (Shimadzu, Kyoto, Japan) system equipped with a UV-VIS detector [SPD-20A], a DGU-20A3 online degasser, a CBM-20A system controller, and a SIL-20AHT automatic addition.
  • Sampler, and LC Chromopac data processor solution The column was analyzed using a Zorbax Eclipse XDB-C18 (4.6*150*3.5 mm 3 ).
  • the mobile phase of the sample analysis consisted of methanol, miliQ water and acetic acid at a ratio of 100:100:1 (v/v/v).
  • the injection volume was 20 ⁇ l
  • the flow rate was 1 ml/min
  • the detection wavelength was 240 nm.
  • the present invention utilizes both aqueous and non-aqueous solubilizing agents, either alone or in combination.
  • Self-microemulsified drug delivery systems ie, lipid-based drug delivery systems
  • media oil, surfactants, co-surfactants
  • Labrasol, Transcutol P, PEG 300, Caproyl PGMC And Cremophor RH 40 is the preferred medium for edaravone.
  • polymeric carrier is the most important step in the preparation of solid phase dispersions (SD).
  • SD solid phase dispersions
  • 1%, 2%, 3%, 4%, 5% and 6% w/v of different carrier solutions were added.
  • An excess of edaravone was added to the above solution, followed by continuous rotation at room temperature for 24 hours using a mechanical shaker (Axyos Technologies, Brisbane, Australia) throughout the test.
  • each vial was centrifuged at 3000 rpm for 5 minutes, filtered through a 0.45 ⁇ m PVDF syringe filter, and excess insoluble edaravone was discarded. Subsequently, the filtrate was diluted with methanol.
  • Triple solubility analysis was performed using an earlier developed and validated HPLC method.
  • the inventors used different drug to polymer ratios (1:1, 1:3, 1:5, 1:7, 1:8, 1:10,1). Numerous batches of solid phase dispersions were prepared at 13 and 1:16). The solid phase dispersion was prepared using solvent evaporation technique and Buchi Rotary Evaporator II. The required amount of drug and Soluplus were dissolved in ethanol and the mixture was dried under vacuum (500-600 mbar) at 55-60 °C. The inventors compared the solubility of the optimized ratio to the physical mixture of the same drug with the polymer (1:5). A physical mixture of edaravone and Soluplus was prepared by mixing with a mortar and pestle.
  • DMEM medium Dulbecco's Modified Eagle Medium
  • FBS fetal bovine serum
  • penicillin-streptavidin Prime solution.
  • the cells were cultured in an incubator at 37 ° C under 5% CO 2 .
  • SH-5YSY cells were seeded at a density of 5 x 10 3 cells/well in 96-well plates. After 24 hours, the original medium was replaced with or without the medium containing the formulation. The preparation was prepared using sterile water. Cell viability was measured by MTT ([3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide], thiazolyl blue) method. After 20 hours, 20 ⁇ L of MTT (Sigma-Aldrich, USA, 5 mg/ml in PBS) was added to each well and incubated for 1 hour. 150 ⁇ L of DMSO was added to dissolve the insoluble purple formazan product to produce a colored solution. The optical density (OD) was read at a wavelength of 600 nm on a multi-hole scanning spectrophotometer (BIO-RAD model 2550 EIA reader).
  • MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylte
  • Characterization parameters of the micelle preparation of the invention (Example 6): particle size 15.68, polydispersity index 0.361, drug loading 10.11 mg/ml.
  • the dissolution study of the solid phase dispersion was carried out using a USP Type II paddle device (AT 7Smart, Sotax GmbH, Germany). Operating parameters: 50 rpm, 37 ⁇ 0.5 ° C, SGF (simulated gastric juice) pH 1.2 (USP), FaSIF pH 5.0 (fasting simulated intestinal fluid), FeSIF (feeding simulated intestinal fluid) pH 6.5, and SIF (simulated intestinal fluid) 7.5 pH (USP).
  • An equivalent amount of 100 mg of edaravone was filled into a "2" hard gelatin capsule. The capsule is placed in a sink and placed in a dissolution vessel. Samples were taken at different time intervals and replaced each time with an equal amount of fresh dissolution medium. Samples were filtered through a 0.45 [mu]m PVDF syringe filter and analyzed by previously developed HPLC methods.
  • Example 8 the solid phase dispersion of Example 8 was used to prepare a solid dosage form, such as a tablet or capsule, and then a dissolution study was performed to predict its behavior in a variety of different biological fluids.
  • formulations based on solid phase dispersions provide sustained release after initial burst release.
  • Rats Male Sprague-Dawley rats (250 ⁇ 10 g) were obtained at least 1 week prior to the start of the trial for laboratory use. It regulates the environment, food and water. Rats were anesthetized before surgery A longitudinal incision is made in the neck and closer to the jugular vein area. Subsequently, the catheter was filled with 20 units/ml of heparin saline and inserted into the jugular vein until the first silica gel plug. Stitch the rubber plug and muscle to secure it there. The other end of the catheter is subcutaneously through the neck, closer to the ears. Finally, the catheter was filled with 500 units/ml heparin saline and inserted into the free end of the catheter. After the surgery was completed, the rats were placed in different cages to recover. The next day, a pharmacokinetic study was performed on each rat. Prior to dosing, the animals were fasted for 12 hours with free access to drinking water.
  • the edaravone suspension was prepared by adding edaravone to a 0.5% sodium carboxymethylcellulose (CMC-Na) solution and then sonicating for a few minutes to obtain a homogeneous suspension.
  • CMC-Na sodium carboxymethylcellulose
  • the two groups of rats were orally administered edaravone suspension and SMEDDS at a dose equivalent to 30 mg/kg of edaravone.
  • Another group of rats was administered by the intravenous (iv) route (divafosone at a dose of 3 mg/kg). After administration of the drug and formulation by oral gavage, 0.2 ml of blood samples were taken at time intervals of 0, 15, 30, 45, 60, 90, 12, 180, 240, 300, 360, 420 and 480 minutes.
  • the catheter was flushed with the same amount of heparin saline each time the blood sample was collected. After the blood sample was collected, it was centrifuged at 5000 rpm and 4 ° C for 5 minutes to separate the plasma from the blood. Plasma was stored at -20 °C after separation until analysis. 200 ⁇ l of plasma was acidified with 40 ⁇ l of 30% HClO 4 to precipitate the protein. Thereafter, it was centrifuged at 16,000 rpm for 6 minutes at 4 °C. The contents were diluted with methanol/water (50:50) and filtered through a 0.22 [mu]m membrane filter prior to injection into LC/MS/MS.
  • Mobile phase A was an aqueous solution of 5% methanol and 0.1% formic acid
  • mobile phase B was an aqueous solution of 95% methanol and 0.1% formic acid.
  • the gradient set by the mobile phase schedule was: starting 15% MPB, up to 70% MPB at 7.5 minutes, maintaining 100% MPB for 0.5 minutes, then 15% MPB for 2 minutes to prepare for analysis of the next sample. Each sample The total run time for the analysis was 10 minutes.
  • the column eluate was introduced into negative ion mode electrospray (ESI) mass spectrometry.
  • the operational parameters of the ion source include analyte dependent parameters and source dependent parameters, optimized for optimal performance from mass spectrometer analysis.
  • MRM analysis by monitoring precursor ions yielded a mass-to-charge ratio (m/z) as follows: edaravone 175.0/133.10 and antipyrine 189.1/147.1. Zero air is used as the source gas, and nitrogen is used as both the curtain gas and the collision gas. The peak area, internal standard (IS), and a known concentration of calibrator were used as calibration curves for the ratio of compound/IS areas. The limit of quantification is 5 ng/ml. The intra- and inter-day variability of each compound was within 15%.
  • Simulated gastrointestinal fluids were prepared according to the USP method.
  • SGF simulated gastric juice
  • SIF simulated intestinal fluid pH 6.8
  • pH 7.4 In order to determine the chemical stability of the solid phase dispersion formulation, an aqueous solution of miliQ was prepared and employed. The SD preparation is dissolved in the above buffer. Samples were taken at predetermined time intervals and filtered through a 0.45 ⁇ m PVDF syringe filter. All samples were analyzed by HPLC triple.

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Abstract

依达拉奉剂型及其在制备用于治疗氧化性应激相关疾病的药物中的用途，所述剂型选自基于脂质的递送系统、固体分散体、胶束和基于助溶剂的制剂。

Description

依达拉奉剂型 技术领域
本发明属于制药领域。具体而言，本发明涉及新型依达拉奉药物剂型，尤其是口服剂型，以及利用依达拉奉有效治疗人类氧化性应激相关疾病的用途。
背景技术
自由基是正常细胞有氧代谢的常见结果。人体的内置抗氧化系统在预防因自由基引起的损伤方面起到了决定性作用。然而，抗氧化剂的失衡防御机制、自由基的过度生产或从环境引入生命系统导致通向神经变性的严重障碍。神经细胞转神经变性疾病中遭受机能或感官的丧失。除若干环境或遗传因素之外，氧化性应激(OS)引起自由基攻击神经细胞，给神经变性的贡献是灾难性的。虽然氧对生命是必不可少的，但代谢失衡和过量活性氧(ROS)生成是全球慢性疾病和变性疾病例如衰老和其他变性疾病的主要病因，这些变性疾病诸如人类的阿尔茨海默病(AD)、帕金森氏病(PD)、多发性硬化症(MS)、肌萎缩性侧束硬化症(ALS)、动脉粥样硬化症、癌症、糖尿病、类风湿关节炎(RA)、缺血性灌注后损伤、心肌梗塞、心血管病、慢性炎症、中风和感染性休克。根据世界卫生组织(WHO)的报告，全世界前10种致死性疾病为缺血性心脏病、中风、慢性阻塞性肺病(COPD)、下呼吸道感染、气管/支气管/肺癌、HIV/AIDS、腹泻、糖尿病、高血压和肺结核(前1至前10，降序排列)。全球有2880万个患者在2012年因这些疾病死亡(主要由排序在前4的致死性疾病所导致)。缺血性心脏病占所有死亡的近25.7％，中风占近23.3％，而COPD和下呼吸道感染分别占总死亡的近10.7％。各种研究表明，氧化性应激是前10种致死性疾病中大多数疾病，尤其是缺血性心脏病、中风、COPD、HIV/AIDS和糖尿病的主因。与氧化性应激相关疾病的全球市场在2000亿美元以上。
由于氧化性应激是许多慢性、变性和致死性疾病的根本所在，这提示迫切需要抗氧化剂来帮助控制体内ROS水平。因此，作为强烈和潜在的自由基清除剂或抗氧化剂，依达拉奉能在降低ROS水平和减少氧化性应激方面发挥重要作用。可以预期，依达拉奉在不久的将来可用于治疗致死性疾病，或者使其风险最小化。
依达拉奉(edaravone)，又称为MCI-186，化学名：3-甲基-1-苯基-2-吡唑啉-5-酮，分子式C10H10N2O，分子量174.19，结构式：
Figure PCTCN2017081405-appb-000001
它是强烈的合成氧自由基清除剂，具有抗氧化作用，以减少氧化性应激，并且经由非酶促脂质过氧化和脂氧合酶途径抑制脂质过氧化。除此之外，依达拉奉还在炎症、基质金属蛋白酶、一氧化氮产生和细胞凋亡方面显示有益效果。Mitsubishi Tanabe Pharm Corp.(日本大阪)首先开发出依达拉奉，并在2001年以Radicut上市，成为世界上第一个神经血管保护药物。2001年，日本公共卫生和福利部批准该药用于治疗脑梗、急性缺血性中风(AIS)患者。从那时起，依达拉奉不仅常用于治疗AIS，还用于治疗ROS相关疾病，诸如心血管病和中风。尽管依达拉奉在日本、印度和中国为常用处方药物，但其在美国和其他西方国家尚未得到批准，这主要是由于其在肝脏和肾脏中的毒性以及缺乏临床研究支撑依达拉奉的有益效果。仍有许多国家正致力于依达拉奉的临床研究。
依达拉奉设计成酚样化合物，而酚是所有酚类抗氧化剂的官能团之一，其中酚类抗氧化剂由与芳香环连接的羟基(-OH)组成，并且负责抗氧化特性。通过捐献一个氢离子给自由基，继而变成一基团，酚类淬灭自由基。然而，酚上电子通过芳香环经由共振电子去局部化而稳定，且活性下降。但是由于毒性和腐蚀性，即便显现出自由基清除 作用和已证明是潜在的抗氧化剂，酚类并不适用于制药用途。
另一方面，尤其存在芳香羟基，依达拉奉预期具有与酚类相同的活性，并显示相似的抗氧化和自由基清除效果。依达拉奉可被分类为三种不同的互变异构形式，即胺形、酮形和烯醇形。芳香羟基经由酮-烯醇互变异构而产生。然而，与酚类相反，依达拉奉没有酚类的毒性作用，这是依达拉奉比酚类更具优势的缘由之一。
依达拉奉的pKa为7.0，因此生理pH条件下，约50％的依达拉奉是离子化的，并且以阴离子形式存在。依达拉奉的阴离子形式也是更具反应性的形式，其在大脑中很容易与ROS反应，产生抗氧化作用。依达拉奉相比其他自由基清除剂(诸如艾地苯醌、黄芩素和儿茶酚)的优势在于，容易透过血脑屏障，这是因为依达拉奉是低分子量的亲脂分子，在水和脂质中均有溶解特性。因此，它可很容易地穿过血脑屏障，抵达脑中靶点发挥作用。依达拉奉的血浆水平与脑脊液水平之比预计在50-65％。这些特性可能是依达拉奉在脑梗中具有神经保护作用，而其他抗氧化剂没有该作用的原因。
目前市场上只有依达拉奉的肠胃外给药制剂，例如注射液，但该制剂从患者的顺从性上看，不适合长期治疗，因此为了实现最佳疗效，迫切需要依达拉奉的其他剂型，尤其口服剂型。然而，本发明人和其他研究者的初步数据表明，依达拉奉的透过性低，水溶性、生物利用度和稳定性差，半衰期短，肝毒和肾毒等副作用，对任何氧化性应激相关疾病而言，都是临床前和临床研究中取得预期疗效的主要障碍。
依达拉奉口服给药的研究可参见中国专利申请CN101953832A，其公开了β-环糊精包合依达拉奉的口服药物组合物及其制备方法，其中该组合物的质量比组成为依达拉奉1份，环糊精6-100份。但本领域对效果更好的剂型仍存在需求。
发明概述
为了解决上述技术问题，本申请采用基于脂质、固相分散体和助溶剂的制剂策略，从而获得了新型剂型的最佳疗效。
1)基于脂质的药物递送系统：基于脂质的药物递送系统已显示以口服给药形式难以制药的候选药物的巨大潜力，并已推出若干成功上市的药品。将药物预先溶解在脂质、表面活性剂，或脂质与表面活性剂的混合物中，可忽略溶解/溶出步骤，这是口服吸收水溶性差药物的关键限速因素，其结果提高了生物利用度，绕道肝脏减少了肝毒(经淋巴吸收)，并且能够减少肾毒(机制不明)。基于脂质的药物递送系统包括脂质溶液、脂质悬浮液、表面活性剂或聚合物-脂质混合的胶束、自微乳化药物递送系统和纳米乳液制剂。
2)基于固相分散体的策略：固相分散体技术是在固体阶段，将一种或多种活性成分分散在惰性基质中，从而实现提高的生物利用度(通过增加溶解度、溶出率和渗透性)、药物的缓释、固相性质的改变以及稳定性。
3)基于助溶剂的策略：有些水溶性差的分子在由水性/有机助溶剂组成的溶液中是足以增溶的，但也有些水溶性差的分子仅在全部为有机的溶液，或者由一种溶剂组成或由溶剂/表面活性剂的混合物组成的溶液中才增溶。该策略最广泛用于口服给药形式难以制药的候选药物，以提高生物利用度。
本发明的主要目的是有效使用依达拉奉，通过实现理想的生物利用度，延长的半衰期，减少的与肝和肾相关的副作用，从而获得最佳疗效。依达拉奉的固体、半固体和液体制剂是基于助溶剂的系统、脂质溶液、脂质悬浮液、自微乳化药物递送系统、纳米乳液、胶束[1-4]和固相分散体。本发明尤其为依达拉奉以下列形式提供了实用的解决之道：固体剂型，如片剂，或硬明胶胶囊中的粉末填料，或液体剂型， 如硬胶囊或软明胶胶囊中的液体填料。
具体而言，本发明涉及下列依达拉奉制剂1(脂质制剂)及其制备方法：
本发明提供一种基于脂质的药物递送系统，其包括活性成分依达拉奉或其可药用盐，以及脂质。
根据本发明，脂质是指所有含甘油三酯和不同碳链长度的饱和及不饱和脂肪酸的天然或人工合成脂肪，优选Caproyl 90、Capmul MCM和Caproyl PGMC。
根据本发明，脂质包括天然产物油、半合成脂质(通过化学组合来自天然产物植物油的中链饱和脂肪酸或甘油与一种或多种亲水性化学部分而制备)和全合成脂质(主要是天然乙醇酸)。水不溶性脂质包括蜂蜡、油酸、大豆脂肪酸、维生素E、玉米油单-二-甘油三酯、中链(C8/C10)甘油单酯和甘油二酯、脂肪酸的丙二醇酯等。
脂质为甘油三酯，可进一步分类为长链甘油三酯(LCT)、中链甘油三酯(MCT)和短链甘油三酯(SCT)。其中，长链甘油三酯包括氢化大豆油、氢化植物油、玉米油、橄榄油、豆油、花生油、芝麻油等。中链甘油三酯包括来自可可油或棕榈籽油的辛酸/葵酸甘油三酯等。具体地，在基于脂质的药物递送系统中，玉米油、棉籽油、Captex355、油酸甘油酯(peceol)、花生油、辛酸甘油三酯、蓖麻油、芝麻油、Miglyol 812、葵花油、Capmul MCM、Capryol PGMC等可用作脂质。
根据本发明，基于脂质的药物递送系统包括治疗剂(依达拉奉)、油性介质/脂质、表面活性剂、辅助表面活性剂、助溶剂、脂质体和/或固体脂质纳米粒子等。
根据本发明，基于脂质的药物递送系统还包括赋形剂和/或添加剂。其中，赋形剂为化学甘油三酯、部分甘油三酯、半合成油性酯和半合成非离子表面活性剂酯，或者选自水不可溶的蜂蜡、油酸、大豆脂肪酸、维生素E、玉米油单-二-甘油三酯、中链(C8/C10)甘油单酯和甘油二酯和脂肪酸的丙二醇酯。
添加剂包括固相吸附剂、水溶性和脂溶性抗氧化剂、酸化剂、螯合剂和缓冲剂。其中固相吸附剂包括硅基吸附剂和非硅基吸附剂，硅基吸附剂包括Aerosil 200和偏硅酸镁铝，非硅基吸附剂包括微晶纤维素、滑石、无水磷酸氢二钙(DCPA)、由烷基纤维素、羟烷基纤维素、羟烷基烷基纤维素糖等基团组成的水溶性聚合物。螯合剂为选自乙二胺、乙二胺四乙酸二钠钙和乙二胺四乙酸二钠的至少一种。酸化剂包括但不限于柠檬酸、乙酸、富马酸、盐酸和硝酸。缓冲剂包括但不限于偏磷酸钾、磷酸二氢钾、醋酸钠、柠檬酸钠。水溶性或脂溶性抗氧化剂包括但不限于抗坏血酸、抗坏血酸棕榈酸酯、丁基羟基茴香醚、丁基羟基甲苯、次磷酸、硫代甘油、没食子酸丙酯、抗坏血酸钠、亚硫酸氢钠、甲醛次硫酸氢钠、次硫酸盐、焦亚硫酸钠。
根据本发明，除依达拉奉之外，基于脂质的药物递送系统具体还包括CapryolTM PGMC、
Figure PCTCN2017081405-appb-000002
RH 40、Labrasol、TPGS 1000、Transcutol P和/或Aerosil 200。
根据本发明，基于脂质的药物递送系统还包括水溶性有机溶剂、表面活性剂、辅助表面活性剂、聚合物增溶剂、磷脂、酸化剂、缓冲剂、稳定剂、抗氧化剂、防腐剂和/或固相吸附剂。其中，水溶性有机溶剂包括但不限于PEG 200-10,000、聚乙烯己内酰胺(PCL)、聚乙酸乙烯酯(PVA)或其共聚物、水溶性形式的维生素E和乙醇，其中PEG200-10,000包括例如PEG 300，PEG 400，PEG 1,000和PEG 6,000，既用作水溶性有机溶剂，也用作增溶剂。表面活性剂包括水溶性表面活性剂和非水溶性表面活性剂。水溶性表面活性剂是其中脂肪酸为不饱 和或饱和的膳食油的衍生物，通过PEG与水解植物油反应、醇与氧化乙烯反应生成烷基醚乙氧基化物、或者基于聚山梨醇酯的植物油与氧化乙烯反应而合成，包括但不限于Cremophor RH 40、Labrasol、TPGS1000、Tween 20、Cremophor E1和Tween 80。辅助表面活性剂基于聚乙二醇、聚丙二醇、乙醇和甘油，尤其是PEG 300、PEG 400、丙二醇、甘油、乙醇、Transcutol HP和Transcutol P。聚合物增溶剂包括但不限于Soluplus，壳聚糖，聚乙烯吡咯烷酮(PVP)，PVP/VA，HPC，HPMC，HPMCAS，eudragit E100，基于甲基丙烯酸二甲基氨基乙酯、甲基丙烯酸丁酯和甲基丙烯酸甲酯的阳离子共聚物，既用作聚合物增溶剂，也用作稳定剂。
根据本发明，基于脂质的药物递送系统还包括聚合物载体，选自Soluplus、羟丙基甲基纤维素(HPMC)、聚乙二醇(PEG)、壳聚糖、PVP、PVP/VA、HPC、羟丙基甲基纤维素乙酸酯(HPMCAS)、eudragit E100、基于甲基丙烯酸二甲基氨基乙酯、甲基丙烯酸丁酯和甲基丙烯酸甲酯的阳离子共聚物，优选Soluplus、羟丙基甲基纤维素(HPMC)或聚乙二醇。
根据本发明，基于脂质的药物递送系统选自脂质溶液、脂质悬浮液、表面活性剂或聚合物-脂质混合胶束、自微米乳化药物递送系统(SMEDDS)和纳米乳液制剂。
根据本发明，在基于脂质的药物递送系统中，SMEDDS为固相，还包括吸附剂，优选Aerosil 200。
根据本发明，在基于脂质的药物递送系统中，纳米乳液制剂还包括水/缓冲剂。
本发明还提供基于脂质的药物递送系统的制备方法，包括下列步骤：
将活性成分依达拉奉或其可药用盐溶解在脂质、表面活性剂，或脂质与表面活性剂的混合物中。
本发明涉及下列依达拉奉制剂2(固相分散体)及其制备方法：
本发明提供一种固相分散体制剂，其包括活性成分依达拉奉或其可药用盐，以及聚合物载体。
根据本发明，聚合物载体为水溶性聚合物，选自N-乙烯基内酰胺均聚物、N-乙烯基内酰胺共聚物、纤维素酯、纤维素醚、聚亚烷基氧化物、聚丙烯酸酯、聚甲基丙烯酸酯、丙烯酸的均聚物和共聚物、甲基丙烯酸的均聚物和共聚物、聚丙烯酰胺、聚乙烯醇、乙酸乙烯酯聚合物、乙酸乙烯酯共聚物、羧乙烯基聚合物、寡糖、多糖及其混合物。
根据本发明，水溶性聚合物选自烷基纤维素、羟烷基纤维素、羟烷基烷基纤维素、甲基纤维素(MC)、乙基纤维素(EC)、羟乙基纤维素(HEC)、羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC)、羟乙基甲基纤维素(HEMC)、羟丙基甲基纤维素琥珀酸酯、羟丙基甲基纤维素乙酸琥珀酸酯、羧甲基乙基纤维素、羧甲基纤维素钠、羧甲基纤维素钾、纤维素乙酸琥珀酸酯、纤维素乙酸邻苯二甲酸酯、羟丙基甲基纤维素邻苯二甲酸酯、聚丙烯酸共聚合物、聚(甲基)丙烯酸聚合物、聚(羟烷基丙烯酸酯)、聚(羟烷基甲基丙烯酸酯)、聚乙烯吡咯烷酮(PVP)、乙烯基吡咯烷酮均聚物、乙烯基吡咯烷酮共聚物、聚维酮、乙烯基吡咯烷酮-乙烯基乙酸酯共聚物(共聚维酮)、乙酸乙烯酯的共聚合物、丙酸乙烯酯的共聚物、乙酸乙烯酯和巴豆酸的共聚物、聚乙二醇、聚乙烯醇、部分水解的聚乙酸乙烯酯、明胶、藻酸钠、可溶性淀粉、阿拉伯胶、糊精、透明质酸、软骨素硫酸钠、藻酸丙二醇酯、琼脂、黄芪胶、黄原胶、氨基烷基甲基丙烯酸酯共聚物、聚乙酸乙烯酯-二乙基氨基乙酸酯、甲基丙烯酸酯共聚物、甲基丙烯酸共聚物L、甲基丙烯酸共聚物LD、甲基丙烯酸共聚物S、聚乙二醇(macrogol)、聚氧乙烯、聚氧丙烯、环氧乙烷(EO)和环氧丙烷(PO) 的共聚物、卡拉胶、半乳甘露聚糖及其组合物。
根据本发明，所述聚合物载体选自Soluplus、羟丙基甲基纤维素(HPMC)、聚乙二醇(PEG)、壳聚糖、PVP、PVP/VA、HPC、羟丙基甲基纤维素乙酸酯(HPMCAS)、eudragit E100、基于甲基丙烯酸二甲基氨基乙酯、甲基丙烯酸丁酯和甲基丙烯酸甲酯的阳离子共聚物，尤其选自Soluplus、羟丙基甲基纤维素(HPMC)或聚乙二醇(PEG)。
根据本发明，固相分散体制剂还包括表面活性剂(阴性、阳性或两性表面活性剂)。其中表面活性剂选自十二烷基磺酸钠、十二烷基硫酸钠(SDS)，月桂基硫酸钠(SLS)、聚氧乙烯山梨醇酐长链脂肪酸酯、维生素E-TPGS、胆盐、脱氧胆酸钠、甘胆酸钠、聚氧乙烯聚氧丙烯二醇及其组合。优选的，表面活性剂为TPGS 1000。
根据本发明，固相分散体制剂具体包括依达拉奉、Soluplus以及任选的TPGS 1000。
根据本发明，固相分散体还包括可药用赋形剂，所述赋形剂选自崩解剂、润滑剂、助流剂、抗粘附剂、惰性填料、润湿剂、pH改性剂、粘合剂、溶解度改性剂、重结晶抑制剂、稀释剂及其组合。
根据本发明，固相分散体可制成片剂、环、贴剂、胶囊、丸剂、粒剂、细颗粒或粉末。
本发明还提供固相分散体制剂的制备方法，包括下列步骤：
将活性成分依达拉奉或其可药用盐分散在聚合物载体和任选的表面活性剂中，通过选自下列的步骤制备：融冰浴搅拌、薄膜冷却、液氮、喷雾凝结、热熔挤出、MeltrexTM、熔融凝聚、或溶剂蒸发(烘干、真空干燥、旋转蒸发、热板加热、喷雾干燥、冷冻干燥、超临界抗溶剂、共沉淀、静电纺丝、喷雾冷干、超快冷干、流体床涂布)和溶剂 熔融。
本发明涉及下列依达拉奉制剂3(胶束制剂)及其制备方法：
本发明提供一种基于胶束的制剂，其包括活性成分依达拉奉或可药用盐、聚合物载体和水/缓冲剂。有效量的治疗剂依达拉奉包合在胶束中。
根据本发明，所述聚合物载体选自Soluplus、羟丙基甲基纤维素(HPMC)、聚乙二醇(PEG)、壳聚糖、PVP、PVP/VA、HPC、羟丙基甲基纤维素乙酸酯(HPMCAS)、eudragit E100、基于甲基丙烯酸二甲基氨基乙酯、甲基丙烯酸丁酯和甲基丙烯酸甲酯的阳离子共聚物，优选Soluplus、羟丙基甲基纤维素(HPMC)或聚乙二醇(PEG)。
根据本发明，基于胶束的制剂还包括表面活性剂、固相吸附剂、酸化剂和/或抗氧化剂。
根据本发明，基于胶束的制剂具体包括依达拉奉、Soluplus、TPGS1000和PBS。
本发明还提供基于胶束的制剂的制备方法，包括下列步骤：
将活性成分依达拉奉或其可药用盐、聚合物载体和任选的表面活性剂溶解在乙醇中，旋转蒸发去除有机溶剂，形成的膜真空干燥后，加入缓冲剂水合，超声处理。
本发明还提供保护治疗剂依达拉奉的方法，包括将该治疗剂封装在基于胶束的制剂中。
本发明涉及下列依达拉奉制剂4(助溶剂制剂)及其制备方法：
本发明提供一种基于助溶剂的制剂，其包括活性成分依达拉奉或其可药用盐，以及1-99％(v/v)的水溶性有机溶剂和/或表面活性剂或 辅助表面活性剂。
根据本发明，所述水溶性有机溶剂包括但不限于PEG 200-10,000、丙二醇、甘油、Transcutol HP、Transcutol P、Cremophor RH 40、Cremophor EL、Labrasol、TPGS 1000、Tween 20、Tween 80、水溶性形式的维生素E和乙醇，其中PEG 200-10,000包括例如PEG 300、PEG400、PEG 1,000和PEG 6,000。
根据本发明，基于助溶剂的制剂其还包括表面活性剂、磷脂、维生素E、抗氧化剂、防腐剂、固相吸附剂和/或水/缓冲剂，旨在助溶、提高通透性和稳定性。
根据本发明，除依达拉奉之外，基于助溶剂的制剂具体还包括PEG300、Labrasol、Transcutol P、TPGS 1000和Cremophor RH 40中的一种或多种。
本发明还提供基于助溶剂的制剂的制备方法，包括下列步骤：
将活性成分依达拉奉或其可药用盐溶解在水溶性有机溶剂和/或表面活性剂中。
本发明涉及下列依达拉奉制剂的剂型和给药途径：
上述依达拉奉制剂1-3，其为固体剂型，所述固体剂型选自片剂、胶囊、粉末或条(strip)，通过口服、肠胃外、吸入、局部或经皮、鼻内、眼内、内耳、直肠、阴道内途径给药。
上述依达拉奉制剂1-4，其为液体剂型，所述液体剂型选自溶液、悬浮液、乳液、基于共溶剂的系统、气溶胶，通过口服、肠胃外、吸入、局部或经皮、鼻内、眼内、内耳、直肠、阴道内途径给药。
上述依达拉奉制剂1-4，其为半固体剂型，所述半固体剂型选自药 膏、霜剂、凝胶、糊剂，为局部或全身目的，通过外用(topical)或经皮途径给药。
本发明还涉及下列依达拉奉制剂的疾病治疗方法和制药用途：
本发明提供依达拉奉制剂1-4用于治疗与氧化性应激相关疾病。
本发明提供依达拉奉制剂1-4在制备用于治疗氧化性应激相关疾病的药物中的应用。
根据本发明，所述氧化性应激相关疾病包括老年性/衰老性疾病(关节炎、糖尿病、骨关节炎、白内障、黄斑变性、前列腺病)、心血管病(动脉硬化症、心衰、心脏病、肾衰、高血压、中风、血液循环不畅、胆固醇和斑块形成、再灌注损伤)、癌症(前列腺癌、乳腺癌、肺癌、肠癌、膀胱癌、子宫癌、卵巢癌、淋巴瘤、皮肤癌、胃癌、肝癌和其他消耗性疾病)、神经变性疾病(阿尔茨海默病/老年痴呆症、帕金森氏病、多发性硬化症、精神分裂症、痴呆、亨廷顿舞蹈病)、肝病(中毒性肝炎、病毒性肝炎(A、B和C)、慢性肝炎)、肺病(哮喘肺气肿、肺炎、(急慢性)支气管炎、囊性纤维化、肺纤维化、慢性阻塞性肺病(COPD)、成人呼吸窘迫综合征(ARDS))、消化道疾病(炎性肠病、溃疡性肠炎、克罗恩病、胃炎、胃癌、胃溃疡、胰腺炎)、肾衰和肾透(肾衰、肾毒、透析引起的氧化性应激)、感染性疾病和免疫病(病毒性感染HIV和AIDS、中毒性肝炎和肝硬化、病毒性肝炎(A、B和C)、疱疹、感冒、细菌感染、慢性疲劳综合征、自身免疫功能障碍)、皮肤病(牛皮癣、湿疹、SLE(系统性红斑狼疮)、血管炎、多肌炎、蕈样真菌病、硬皮病、类天疱疮、过敏性皮炎、接触性皮炎、脂溢性皮炎、疱疹样皮炎、聚合性痤疮、普通粉刺、UV照射皮肤损伤)、五官科疾病(白内障、青光眼、黄斑变性、听力损失、耳部感染、鼻窦炎、牙周病、鼻、口腔和咽喉(上呼吸道)疾病)、妊娠、哺乳和分娩相关疾病(子痫前期、子痫、高血压、糖尿病)、运动性疾病(训练过度综合征及其相关氧化性应激)、男科疾病(前 列腺增生、前列腺癌、脱发、男性不孕症)、女性不孕症、关节病和慢性炎症，尤其选自老年痴呆症、ALS、帕金森氏病、缺血性心脏病、脑梗/中风、COPD、HIV/AIDS和糖尿病。
本发明的依达拉奉制剂或其组分，无论是单用还是联用，旨在修饰/改善依达拉奉现有的属性，诸如溶解度、化学稳定性(水解、氧化、热、光)、缓释性，药代动力学性质，诸如小肠的通透性、生物利用度、半衰期，代谢和排泄等。
在本发明所有的依达拉奉制剂中，如果是液体剂型，则依达拉奉的含量为0.001-1000mg/ml，优选0.1-100mg/ml，更优选10-20mg/ml。如果是固体剂型，则依达拉奉的剂量为0.001-1000mg/单位，优选0.1-100mg/单位，更优选10-20mg/单位。
本发明采用固相分散体策略提供一种新型依达拉奉剂型，大幅提高了其溶解度、稳定性和生物利用度。例如，通过Soluplus，本发明的溶解度相比静脉内(iv)给药剂型，溶解度提高了16倍，而生物利用度相当。
附图说明
为了更清楚地描述本发明的技术方案，下面将结合附图作简要介绍。显而易见，这些附图仅是本申请记载的一些具体实施方式。本发明包括但不限于这些附图。
图1显示依达拉奉在不同介质中的溶解度(mg/gm)。
图2显示在依达拉奉溶解度研究的基础上，筛选药物载体系统(Soluplus)。
图3显示依达拉奉在不同类型的制剂(实施例1-11)中的溶解度。
图4显示不同类型的依达拉奉制剂(实施例1-11)的体外安全性。
图5显示本发明胶束制剂(实施例6)的粒径分布。
图6显示本发明固相分散体(实施例8)在不同模拟体液中的溶出。
图7显示本发明SMEDDS(实施例1和2)的生物利用度。
图8A显示依达拉奉在不同pH的生物相关介质中的稳定性。
图8B显示本发明固体分散体制剂(实施例8)在不同pH的生物相关介质中的稳定性。
具体实施方式
为了进一步理解本发明，下面将结合实施例对本发明的优选方案进行描述。这些描述只是举例说明本发明新型依达拉奉药物制剂的特征和优点，而非限制本发明的保护范围。
下表列出本发明所用组分及其化学名称[5]：
Figure PCTCN2017081405-appb-000003
Figure PCTCN2017081405-appb-000004
实施例1
基于脂质的自微乳化药物递送系统(SMEDDS)制剂
成分 数量
依达拉奉 10mg/ml
CapryolTM PGMC 30％
Cremophor RH 40 23.33％
Labrasol∶TPGS 1000(4∶1) 23.33％
Transcutol P 23.33％
实施例2
基于基质的SMEDDS制剂
成分 数量
依达拉奉 10mg/ml
CapryolTMPGMC 30％
Cremophor RH 40 23.33％
Labrasol∶TPGS 1000(4∶1) 23.33％
Transcutol P 23.33％
Aerosil 200(吸附剂) 5％w/v
实施例3
基于脂质的SMEDDS制剂
成分 数量
依达拉奉 10mg/ml
CapryolTM PGMC 30％
Cremophor RH 40 23.33％
Labrasol 23.33％
Transcutol P 23.33％
实施例4
基于脂质的SMEDDS制剂
成分 数量
依达拉奉 10mg/ml
CapryolTM PGMC 30％
Labrasol 46.66％
Transcutol P 23.33％
Aerosil 200(吸附剂) 5％w/v
实施例5
基于脂质的纳米乳液制剂
成分 数量
依达拉奉 10mg/ml
CapryolTM PGMC 30％
Cremophor RH 40 23.33％
Labrasol∶TPGS 1000(4∶1) 23.33％
Transcutol P 23.33％
水 足量
实施例6
胶束制剂
成分 数量(mg)
依达拉奉 100
Soluplus∶TPGS 1000 500∶200
PBS(pH 7.4) 10ml
实施例7
固相分散体制剂
成分 数量(mg)
依达拉奉 100
Soluplus∶TPGS 1000 500∶75
实施例8
固相分散体制剂
成分 数量(mg)
依达拉奉 100
Soluplus 500
实施例9
基于助溶剂的制剂
成分 数量
依达拉奉 20mg/ml
Cremophor RH 40 250mg
PEG 300 250mg
TPGS 1000 125mg
水 375mg
实施例10
基于助溶剂的制剂
成分 数量
依达拉奉 20 mg/ml
Labrasol 500 mg
TPGS 1000 125 mg
水 375 mg
实施例11
基于助溶剂的制剂
成分 数量
依达拉奉 20 mg/ml
PEG 300 500 mg
TPGS 1000 125 mg
水 375 mg
制备例1
液相自微乳化药物递送系统(SMEDDS，实施例1和3)的制备
根据实施例1和3，将所需量的油(Capmul PGMC)，表面活性剂(Cremophor RH 40，Labrasol和TPGS 1000)和辅助表面活性剂(Transcutol P)准确称重至小玻璃瓶中。然后，通过轻轻搅拌和旋涡混合，将上述组分混合，并在保温箱中37℃下加热。加入所需量的依达拉奉，旋涡混合，直至依达拉奉完全溶解。
制备例2
固相自微乳化药物递送系统(实施例2和4)的制备
如上制备液相SMEDDS制剂。加入所需量的Aerosil 200之后，以最少量的miliQ水稀释，室温搅拌2小时。所得混合物放置15分钟，平衡后通过0.45μm针头过滤器(PVDF)过滤。冷冻干燥之前，将溶液在-80℃下冷冻至少6小时，然后置于Novalyphe-NL 500(Savant  Instruments Corp.，Holbrook，NY)中-45℃和7102mbar压力下冻干至少24小时。最后，将固相SMEDDS存储在干燥器中。
制备例3
基于纳米乳液的系统(实施例5)的制备
根据实施例5，将所需量的油(Capmul PGMC)，表面活性剂(Cremophor RH 40，Labrasol和TPGS 1000)和辅助表面活性剂(Transcutol P)准确称重至小玻璃瓶中。然后，通过轻轻搅拌和旋涡混合，将上述组分混合，并在保温箱中37℃下加热。加入所需量的依达拉奉，旋涡混合，直至依达拉奉完全溶解。逐滴加入所需量的miliQ水，直至获得清亮透明制剂。
制备例4
胶束制剂(实施例6)的制备
根据实施例6，将所需量的依达拉奉、Soluplus和TPGS 1000溶解在乙醇中。通过Buchi旋转蒸发仪II去除有机溶剂。形成的膜在真空干燥器中干燥过夜，然后以10ml 1×PBS缓冲剂(pH 7.4)水合，37℃下温育30分钟，接着超声处理几分钟。所得混合物通过0.45μm针头过滤器(PVDF)过滤。
制备例5
基于固相分散体的制剂(实施例7和8)的制备
根据实施例7和8，将所需量的依达拉奉、Soluplus和TPGS 1000溶解在乙醇中。通过Buchi旋转蒸发仪II去除有机溶剂。形成的膜在真空干燥器中干燥过夜。干燥样品从烧瓶刮下，并收集在研钵中。用研杵压碎粉末，并制成均匀形式。
制备例6
基于助溶剂的制剂(实施例9-11)的制备
根据实施例9-11，将除依达拉奉之外的所有组分准确称量至小玻璃瓶中。然后，通过轻轻搅拌和旋涡混合，将上述组分混合，并在保温箱中37℃下加热。加入所需量的依达拉奉，旋涡混合，直至依达拉奉完全溶解。
实施例1-11提供了多种不同制剂的配方，分别包括基于脂质、胶束、固相分散体和助溶剂的制剂。下文通过效果例详细说明这些制剂的优点。
效果例1
依达拉奉在不同介质中的溶解度研究
选择药物介质对开发液体口服制剂至关重要。在分开的玻璃瓶中，加入图1所示的每个介质1ml。向上述溶液加入过量的依达拉奉，接着在测试全程，利用机械振动器(Axyos Technologies，Brisbane，Australia)室温下连续旋转24小时。达到平衡后，各小瓶以3000rpm离心5分钟，通过0.45μm PVDF针头过滤器过滤，丢弃过量的不溶性依达拉奉。随后，滤液以甲醇稀释。采用早些开发和验证的HPLC方法，进行三重溶解度分析。样品分析在HPLC(Shimadzu，Kyoto，Japan)系统上操作，该系统装配有UV-VIS检测器[SPD-20A]，DGU-20A3在线脱气器，CBM-20A系统控制器，SIL-20AHT自动加样器，和LC Chromopac数据处理器解决方案。采用Zorbax Eclipse XDB-C18(4.6*150*3.5mm3)分析柱。样品分析的移动相由100∶100∶1(v/v/v)之比的甲醇、miliQ水和乙酸组成。注射体积20μl，流速1ml/min，检测波长240nm。
为了制备依达拉奉制剂，本发明将水性和非水性增溶剂单独或组合使用。通过选择介质(油类、表面活性剂、辅助表面活性剂)，来制备自微乳化药物递送系统(SMEDDS)(即基于脂质的药物递送系统)。
从图1可见，Labrasol，Transcutol P，PEG 300，Caproyl PGMC 和Cremophor RH 40是依达拉奉的优选介质。
效果例2
药物载体系统Soluplus的筛选
筛选载体
选择聚合物载体对制备固相分散体(SD)而言是最重要的步骤。在分开的玻璃瓶中，加入1％，2％，3％，4％，5％和6％w/v的不同载体溶液。向上述溶液加入过量的依达拉奉，接着在测试全程，利用机械振动器(Axyos Technologies，Brisbane，Australia)室温下连续旋转24小时。达到平衡后，各小瓶以3000rpm离心5分钟，通过0.45μm PVDF针头过滤器过滤，丢弃过量的不溶性依达拉奉。随后，滤液以甲醇稀释。采用早些开发和验证的HPLC方法，进行三重溶解度分析。
优化基于固相分散体的系统
为了优化药物与聚合物之比，实现最大溶解度，发明人采用不同的药物与聚合物之比(1∶1，1∶3，1∶5，1∶7，1∶8，1∶10，1∶13和1∶16)制备了众多批次的固相分散体。利用溶剂蒸发技术和Buchi旋转蒸发仪II制备固相分散体。将所需量的药物和Soluplus溶解在乙醇中，该混合物在55-60℃下真空(500-600mbar)干燥。发明人比较了优化比与相同药物与聚合物(1∶5)的物理混合物的溶解度。利用研钵和研杵混合制备依达拉奉和Soluplus的物理混合物。分析前，产品收集并存储在干燥器中。在分开的玻璃瓶中，各加入1ml水。向上述溶液加入过量的依达拉奉，接着在测试全程，利用机械振动器(Axyos Technologies，Brisbane，Australia)室温下连续旋转24小时。达到平衡后，各小瓶以3000rpm离心5分钟，通过0.45μm PVDF针头过滤器过滤，丢弃过量的不溶性依达拉奉。随后，滤液以甲醇稀释。采用早些开发和验证的HPLC方法，进行三重溶解度分析。
参见图2，研究表明，Soluplus对溶解度的改善是浓度依赖性的。本发明人进一步优化了药物与聚合物的比例，并且发现当药物与 Soluplus之比为1∶5时，基于该优化的固相分散体系统在水中溶解度显著改善，能力提高18倍。药物与聚合物之优化比1∶5的物理混合物(PM)，其溶解度增加2倍以上。
效果例3
依达拉奉在不同类型的制剂中的溶解度
实施例1-5和9-11制剂的溶解度研究
在分开的玻璃瓶中，各加入1ml所述制剂。向上述溶液加入过量的依达拉奉，接着在测试全程，利用机械振动器(Axyos Technologies，Brisbane，Australia)室温下连续旋转24小时。达到平衡后，各小瓶以3000rpm离心5分钟，通过0.45μm PVDF针头过滤器过滤，丢弃过量的不溶性依达拉奉。随后，滤液以甲醇稀释。采用早些开发和验证的HPLC方法，进行三重溶解度分析。
实施例6制剂的溶解度研究
将过量的依达拉奉和所需量的Soluplus和TPGS 1000溶解在乙醇中。通过Buchi旋转蒸发仪II去除有机溶剂。形成的膜在真空干燥器中干燥过夜，然后以10ml 1×PBS缓冲剂(pH 7.4)水合，37℃下温育30分钟，接着超声处理几分钟。各样品以3000rpm离心5分钟。所得混合物通过0.45μm针头过滤器(PVDF)过滤。采用早些开发和验证的HPLC方法，进行三重溶解度分析。
实施例7和8制剂的溶解度研究
在分开的玻璃瓶中，各加入1ml水。向上述溶液加入过量的固相分散体，接着在测试全程，利用机械振动器(Axyos Technologies，Brisbane，Australia)室温下连续旋转24小时。达到平衡后，各小瓶以3000rpm离心5分钟，通过0.45μm PVDF针头过滤器过滤，丢弃过量的不溶性依达拉奉。随后，滤液以甲醇稀释。采用早些开发和验证的HPLC方法，进行三重溶解度分析。
结果表明，依达拉奉在本发明所有制剂(实施例1-11)中的溶解度均比在水中显著提高，SMEDDS实施例1-4尤其突出(参见图3)。
效果例4
采用SH-5Y5Y细胞系对本发明制剂的胞毒研究
细胞培养物分析
采用SH-SY5Y细胞系操作细胞培养物。DMEM培养基(Dulbecco’s Modified Eagle Medium)：营养混合物F12以1∶1之比在25ml细胞培养烧瓶中用于培养细胞，该营养混合物补充有10％胎牛血清(FBS)和1％青霉素-链霉素溶液。细胞在培养箱中在5％CO2条件下37℃进行培养。
MTT分析SH-SY5Y的细胞存活性
在96孔板中，以5×103细胞/孔的密度接种SH-5YSY细胞。24小时后，用或不用含有制剂的培养基替换原培养基。制剂的制备采用无菌水。细胞存活性通过MTT([3-(4，5-二甲基噻唑-2-基)-2，5-二苯基四氮唑溴盐]，噻唑蓝)方法测量。20小时后，每孔加入20μL MTT(Sigma-Aldrich，USA，5mg/ml的PBS)，温育1小时。加入150μL DMSO溶解不溶性紫色formazan产物，以生成有色溶液。在多孔扫描分光光度计(BIO-RAD型号2550EIA读出仪)上以600nm波长对光密度(OD)读数。
参见图4，所有制剂(实施例1-11)均未观察到显著毒性，体外安全性得到确认。胶束制剂(实施例6)和固相分散体(实施例7)，由于存在TPGS 1000(据报道有神经保护作用)，细胞存活还稍有改善。
效果例5
依达拉奉胶束的大小分布
胶束制剂的大小和大小分布通过动态光散射(DLS)(Malvern  Zeta Sizer Nano ZS)测量。样品制备是将胶束溶液以miliQ水稀释，并在测量前超声处理5分钟。采用上述方案，三重测量粒径和多分散性指数(PDI)。
图5的结果表明，粒径范围为纳米，其具有改善药物的细胞吸收的潜力，从而导致功效的提升。该结果还支撑了图4(实施例6)的结果。
本发明胶束制剂(实施例6)的表征参数：粒径15.68，多分散性指数0.361，载药量10.11mg/ml。
效果例6
固相分散体的溶出研究
采用USP II型桨装置(AT 7Smart，Sotax GmbH，Germany)进行固相分散体的溶出研究。操作参数：50rpm转速，37±0.5℃温度，SGF(模拟胃液)pH 1.2(USP)，FaSIF pH 5.0(禁食态模拟肠液)，FeSIF(进食态模拟肠液)pH 6.5，和SIF(模拟肠液)7.5pH(USP)。将100mg依达拉奉等量的制剂填入“2”号硬明胶胶囊。胶囊置于沉子内，并放入溶出容器中。不同时间间隔采集样品，并且每次用等量新鲜溶出介质替换。样品通过0.45μm PVDF针头过滤器过滤，并通过早先开发的HPLC方法分析。
参见图6，实施例8固相分散体用于制备固体剂型，例如片剂或胶囊，然后进行溶出研究，在多种不同的生物体液中预测其行为。
本发明人发现，基于固相分散体的制剂在初始突释后能提供缓释。
效果例7
依达拉奉SMEDDS制剂的生物利用度
试验开始前至少1周获取雄性SD大鼠(250±10g)，以便实验室中 为其调节环境、食物和水。术前麻醉大鼠。在颈部和更接近颈静脉区域作纵向切口。随后，以20单位/ml肝素生理盐水填充导管，并插入颈静脉，直至第一硅胶塞。缝合胶塞和肌肉将其固定在那儿。导管的另一端穿过颈部皮下，更接近双耳。最后，以500单位/ml肝素生理盐水填充导管，并塞进导管的游离端。手术完成后，将大鼠置于不同笼中恢复。第二天，对每只大鼠进行药代动力学研究。给药前，动物禁食12小时，随意饮用水。
依达拉奉悬浮液的制备是将依达拉奉加入0.5％羧甲基纤维素钠(CMC-Na)溶液，然后超声处理几分钟，得到均匀悬浮液。两组大鼠口服给药依达拉奉悬浮液和SMEDDS，剂量等同于30mg/kg的依达拉奉。另一组大鼠通过静脉内(iv)途径给药(剂量为3mg/kg的依达拉奉)。经口饲施用药物和制剂之后，在0，15，30，45，60，90，12，180，240，300，360，420和480分钟的时间间隔，采集0.2ml血样。每次血样采集时，导管都用相同量的肝素生理盐水冲洗。血样采集后，5000rpm、4℃离心5分钟，将血浆与血液分离。血浆分离后存储在-20℃，直到分析。200μl血浆以40μl 30％HClO4酸化，使蛋白沉淀。其后，4℃、16,000rpm离心6分钟。内容物以甲醇/水(50∶50)稀释，并在注射至LC/MS/MS前通过0.22μm膜过滤器过滤。
样品分析在Quadrapole LC/MS/MS(Shimadzu，Kyoto，Japan)系统上操作，该系统装配有API 3000质谱仪，Shimadzu SIL 20A自动加样器，Shimadzu LC20AD泵和分析1.6.2数据处理器。采用新开发和验证的LC/MS/MS方法，对血浆中依达拉奉的浓度定量。抽提物重构在甲醇/水(50∶50)中，注射至Shimadzu Nexera HPLC系统，在Kinetex C182.6mm×50mm×3mm柱(Phenomenex)分析，移动相流速0.2ml/min，注射体积15μl。移动相A(MPA)为5％甲醇和0.1％甲酸的水溶液，而移动相B(MPB)为95％甲醇和0.1％甲酸的水溶液。移动相时间表设定的梯度为：起始15％MPB，至第7.5分钟时70％MPB，维持100％MPB 0.5分钟，然后15％MPB 2分钟，以准备分析下一样品。各样品 分析的总运行时间为10分钟。将柱洗脱液引入负离子模式电喷雾(ESI)质谱分析。离子源的操作参数包括分析物依赖性参数和源依赖性参数，优化得到质谱仪分析的最佳性能。通过监控前体离子进行MRM分析，产生质荷比(m/z)如下：依达拉奉175.0/133.10和安替比林189.1/147.1。以0空气作为源气，而氮既用作气帘气也用作碰撞气。从化合物得到峰面积，内标(IS)，已知浓度的校准物用作构建化合物/IS面积之比的校准曲线。定量限为5ng/ml。各化合物的日内和日间变异性在15％内。
为了研究本发明自微乳化药物递送系统SMEDDS(实施例1和2)的生物利用度，以悬浮液形式(通过加入依达拉奉至0.5％羧甲基纤维素钠(CMC-Na)溶液而制备)口服给药以及iv途径给药的依达拉奉作对照。与依达拉奉悬浮液相比，SMEDDS的生物利用度显著提高(参见图7)。SMEDDS还改善了药物的半衰期，具有维持更长疗效的潜力。
效果例8
依达拉奉及其在固相分散体中的稳定性
模拟胃肠液(无酶和胆汁组分)按照USP方法制备。SGF(模拟胃液)pH 1.2(USP)和SIF(模拟肠液)pH 6.8(USP)和pH 7.4。为了确定固相分散体制剂的化学稳定性，制备和采用miliQ水溶液。SD制剂溶解于上述缓冲剂。以预定时间间隔采集样品，并通过0.45μm PVDF针头过滤器过滤。所有样品通过HPLC三重分析。
参见图8A，结果表明，依达拉奉在中性至碱性pH条件下显著降解，而在酸性pH下基本保持稳定。
参见图8B，结果表明，本发明的固体分散体(实施例8)在不同pH的生物介质中可保护依达拉奉免受降解。
以上实施例的说明只是用于帮助理解本发明的核心思想。应当指出，对于本领域的普通技术人员而言，在不脱离本发明原理的前提下，还可以对本发明的新型制剂及其制备方法进行若干改进和修饰，但这些改进和修饰也落入本发明权利要求请求保护的范围内。
参考文献
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Claims (49)

  1. 一种基于脂质的药物递送系统，其包括活性成分依达拉奉或其可药用盐，以及脂质。
  2. 权利要求1的基于脂质的药物递送系统，其中脂质为甘油三酯，包括长链甘油三酯(LCT)、中链甘油三酯(MCT)和短链甘油三酯(SCT)，其中长链甘油三酯选自氢化大豆油、氢化植物油、玉米油、橄榄油、豆油、花生油和芝麻油，中链甘油三酯选自来自可可油或棕榈籽油的辛酸/葵酸甘油三酯。
  3. 权利要求1或2的基于脂质的药物递送系统，其中脂质选自玉米油、棉籽油、Captex 355、油酸甘油酯(peceol)、花生油、辛酸甘油三酯、蓖麻油、芝麻油、Miglyol 812、葵花油、Capmul MCM和Capryol PGMC。
  4. 权利要求1或2的基于脂质的药物递送系统，其中所述脂质选自Caproyl 90、Capmul MCM和CaproylTMPGMC中的一种或多种。
  5. 权利要求1或2的基于脂质的药物递送系统，其还包括水溶性有机溶剂、表面活性剂、辅助表面活性剂、聚合物增溶剂、磷脂、酸化剂、缓冲剂、稳定剂、抗氧化剂、防腐剂和/或固相吸附剂。
  6. 权利要求5的基于脂质的药物递送系统，其中水溶性有机溶剂选自PEG 200-10,000、聚乙烯己内酰胺(PCL)、聚乙酸乙烯酯(PVA)或其共聚物、水溶性形式的维生素E和乙醇；表面活性剂是其中脂肪酸为不饱和或饱和的膳食油的衍生物，通过PEG与水解植物油反应、醇与氧化乙烯反应生成烷基醚乙氧基化物、或者基于聚山梨醇酯的植物油与氧化乙烯反应而合成；辅助表面活性剂基于聚乙二醇、聚丙二醇、乙醇和甘油；聚合物增溶剂选自Soluplus、壳聚糖、聚乙烯吡咯烷 酮(PVP)、PVP/VA、HPC、HPMC、HPMCAS、eudragit E100、基于甲基丙烯酸二甲基氨基乙酯、甲基丙烯酸丁酯和甲基丙烯酸甲酯的阳离子共聚物。
  7. 权利要求6的基于脂质的药物递送系统，其中PEG 200-10,000选自PEG 300，PEG 400，PEG 1,000和PEG 6,000；表面活性剂选自Cremophor RH 40、Labrasol、TPGS 1000、Tween 20、Cremophor E1和Tween 80；以及辅助表面活性剂选自PEG 300、PEG 400、丙二醇、甘油、乙醇、Transcutol HP和Transcutol P。
  8. 权利要求1或2的基于脂质的药物递送系统，其还包括赋形剂和/或添加剂。
  9. 权利要求8的基于脂质的药物递送系统，其中赋形剂为化学甘油三酯、部分甘油三酯、半合成油性酯和半合成非离子表面活性剂酯。
  10. 权利要求8的基于脂质的药物递送系统，其中赋形剂选自水不可溶的蜂蜡、油酸、大豆脂肪酸、维生素E、玉米油单-二-甘油三酯、中链(C8/C10)甘油单酯和甘油二酯和脂肪酸的丙二醇酯。
  11. 权利要求8的基于脂质的药物递送系统，其中添加剂包括固相吸附剂、水溶性和脂溶性抗氧化剂、酸化剂、螯合剂和缓冲剂，其中固相吸附剂包括硅基吸附剂和非硅基吸附剂，硅基吸附剂选自Aerosil 200和偏硅酸镁铝，非硅基吸附剂选自微晶纤维素、滑石、无水磷酸氢二钙(DCPA)、由烷基纤维素、羟烷基纤维素、羟烷基烷基纤维素糖等基团组成的水溶性聚合物；螯合剂为选自乙二胺、乙二胺四乙酸二钠钙和乙二胺四乙酸二钠的至少一种；酸化剂选自柠檬酸、乙酸、富马酸、盐酸和硝酸；缓冲剂选自偏磷酸钾、磷酸二氢钾、醋酸钠、柠檬酸钠；水溶性或脂溶性抗氧化剂选自抗坏血酸、抗坏血酸棕榈酸酯、丁基羟基茴香醚、丁基羟基甲苯、次磷酸、硫代甘油、没 食子酸丙酯、抗坏血酸钠、亚硫酸氢钠、甲醛次硫酸氢钠、次硫酸盐、焦亚硫酸钠。
  12. 权利要求1的基于脂质的药物递送系统，除依达拉奉之外，其还包括CapryolTMPGMC、
    Figure PCTCN2017081405-appb-100001
    RH 40、Labrasol、TPGS 1000、Transcutol P和/或Aerosil 200。
  13. 权利要求1的基于脂质的药物递送系统，其还包括聚合物载体，其中所述聚合物载体选自Soluplus、羟丙基甲基纤维素(HPMC)、聚乙二醇(PEG)、壳聚糖、PVP、PVP/VA、HPC、羟丙基甲基纤维素乙酸酯(HPMCAS)、eudragit E100、基于甲基丙烯酸二甲基氨基乙酯、甲基丙烯酸丁酯和甲基丙烯酸甲酯的阳离子共聚物。
  14. 权利要求1的基于脂质的药物递送系统，其选自脂质溶液、脂质悬浮液、表面活性剂或聚合物-脂质混合的胶束、自微乳化药物递送系统(SMEDDS)和纳米乳液制剂。
  15. 权利要求14的基于脂质的药物递送系统，其中SMEDDS为固相，还包括固相吸附剂。
  16. 权利要求15的基于脂质的药物递送系统，其中所述固相吸附剂为Aerosil 200。
  17. 权利要求14的基于脂质的药物递送系统，其中纳米乳液制剂还包括水/缓冲剂。
  18. 权利要求1-17任一项的基于脂质的药物递送系统的制备方法，包括下列步骤：
    将活性成分依达拉奉或其可药用盐溶解在脂质、表面活性剂，或脂质与表面活性剂的混合物中。
  19. 一种固相分散体制剂，其包括活性成分依达拉奉或其可药用盐，以及聚合物载体。
  20. 权利要求19的固相分散体制剂，其中所述聚合物载体为水溶性聚合物，选自N-乙烯基内酰胺均聚物、N-乙烯基内酰胺共聚物、纤维素酯、纤维素醚、聚亚烷基氧化物、聚丙烯酸酯、聚甲基丙烯酸酯、丙烯酸的均聚物和共聚物、甲基丙烯酸的均聚物和共聚物、聚丙烯酰胺、聚乙烯醇、乙酸乙烯酯聚合物、乙酸乙烯酯共聚物、羧乙烯基聚合物、寡糖、多糖及其混合物。
  21. 权利要求19的固相分散体，其中所述聚合物载体选自烷基纤维素、羟烷基纤维素、羟烷基烷基纤维素、甲基纤维素(MC)、乙基纤维素(EC)、羟乙基纤维素(HEC)、羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC)、羟乙基甲基纤维素(HEMC)、羟丙基甲基纤维素琥珀酸酯、羟丙基甲基纤维素乙酸琥珀酸酯、羧甲基乙基纤维素、羧甲基纤维素钠、羧甲基纤维素钾、纤维素乙酸琥珀酸酯、纤维素乙酸邻苯二甲酸酯、羟丙基甲基纤维素邻苯二甲酸酯、聚丙烯酸共聚合物、聚(甲基)丙烯酸聚合物、聚(羟烷基丙烯酸酯)、聚(羟烷基甲基丙烯酸酯)、聚乙烯吡咯烷酮(PVP)、乙烯基吡咯烷酮均聚物、乙烯基吡咯烷酮共聚物、聚维酮、乙烯基吡咯烷酮-乙烯基乙酸酯共聚物(共聚维酮)、乙酸乙烯酯的共聚合物、丙酸乙烯酯的共聚物、乙酸乙烯酯和巴豆酸的共聚物、聚乙二醇、聚乙烯醇、部分水解的聚乙酸乙烯酯、明胶、藻酸钠、可溶性淀粉、阿拉伯胶、糊精、透明质酸、软骨素硫酸钠、藻酸丙二醇酯、琼脂、黄芪胶、黄原胶、氨基烷基甲基丙烯酸酯共聚物、聚乙酸乙烯酯-二乙基氨基乙酸酯、甲基丙烯酸酯共聚物、甲基丙烯酸共聚物L、甲基丙烯酸共聚物LD、甲基丙烯酸共聚物S、聚乙二醇(macrogol)、聚氧乙烯、聚氧丙烯、环氧乙烷(EO)和环氧丙烷(PO)的共聚物、卡拉胶、半乳甘露聚糖及其组合物。
  22. 权利要求19的固相分散体制剂，其中所述聚合物载体选自Soluplus、羟丙基甲基纤维素(HPMC)、聚乙二醇(PEG)、壳聚糖、PVP、PVP/VA、HPC、羟丙基甲基纤维素乙酸酯(HPMCAS)、eudragit E100、基于甲基丙烯酸二甲基氨基乙酯、甲基丙烯酸丁酯和甲基丙烯酸甲酯的阳离子共聚物。
  23. 权利要求19-22任一项的固相分散体制剂，其还包括表面活性剂。
  24. 根据权利要求23的固相分散体制剂，其中表面活性剂包括阴性、阳性或两性表面活性剂，并且选自十二烷基磺酸钠、十二烷基硫酸钠(SDS)，月桂基硫酸钠(SLS)、聚氧乙烯山梨醇酐长链脂肪酸酯、维生素E-TPGS、胆盐、脱氧胆酸钠、甘胆酸钠、聚氧乙烯聚氧丙烯二醇及其组合。
  25. 权利要求23的固相分散体制剂，其中所述表面活性剂为TPGS 1000。
  26. 权利要求19的固相分散体制剂，其包括依达拉奉、Soluplus以及任选的TPGS 1000。
  27. 权利要求19-22任一项的固相分散体制剂，其还包括可药用赋形剂，所述赋形剂选自崩解剂、润滑剂、助流剂、抗粘附剂、惰性填料、润湿剂、pH改性剂、粘合剂、溶解度改性剂、重结晶抑制剂、稀释剂及其组合。
  28. 权利要求19-22任一项的固相分散体制剂，其被制成片剂、环、贴剂、胶囊、丸剂、粒剂、细颗粒或粉末。
  29. 权利要求19-28任一项的固相分散体制剂的制备方法，包括下列步骤：
    将活性成分依达拉奉或其可药用盐分散在聚合物载体和任选的表面活性剂中。
  30. 权利要求29的制备方法，进一步包括选自下列的步骤：融冰浴搅拌、薄膜冷却、液氮、喷雾凝结、热熔挤出、MeltrexTM、熔融凝聚、或溶剂蒸发(烘干、真空干燥、旋转蒸发、热板加热、喷雾干燥、冷冻干燥、超临界抗溶剂、共沉淀、静电纺丝、喷雾冷干、超快冷干、流体床涂布)和溶剂熔融。
  31. 一种基于胶束的制剂，其包括活性成分依达拉奉或可药用盐、聚合物载体和水/缓冲剂，其中有效量的依达拉奉被包合在胶束中。
  32. 权利要求31的基于胶束的制剂，其中所述聚合物载体选自Soluplus、羟丙基甲基纤维素(HPMC)、聚乙二醇(PEG)、壳聚糖、PVP、PVP/VA、HPC、羟丙基甲基纤维素乙酸酯(HPMCAS)、eudragit E100、基于甲基丙烯酸二甲基氨基乙酯、甲基丙烯酸丁酯和甲基丙烯酸甲酯的阳离子共聚物。
  33. 权利要求31的基于胶束的制剂，其还包括表面活性剂、固相吸附剂、酸化剂和/或抗氧化剂。
  34. 权利要求31的基于胶束的制剂，其包括依达拉奉、Soluplus、TPGS 1000和PBS。
  35. 权利要求31-34任一项的基于胶束的制剂的制备方法，包括下列步骤：
    将活性成分依达拉奉或其可药用盐、聚合物载体和任选的表面活性剂溶解在乙醇中，旋转蒸发去除有机溶剂，形成的膜真空干燥后， 加入缓冲剂水合，超声处理。
  36. 一种保护治疗剂依达拉奉的方法，包括将该治疗剂封装在基于权利要求31-34任一项的胶束的制剂中。
  37. 一种基于助溶剂的制剂，其包括活性成分依达拉奉或其可药用盐以及1-99％(v/v)的水溶性有机溶剂和/或表面活性剂或辅助表面活性剂。
  38. 权利要求37的基于助溶剂的制剂，其中水溶性有机溶剂选自PEG 200-10,000、丙二醇、甘油、Transcutol HP、Transcutol P、Cremophor RH 40、Cremophor EL、Labrasol、TPGS 1000、Tween 20、Tween 80、水溶性形式的维生素E和乙醇。
  39. 权利要求38的基于助溶剂的制剂，其中PEG 200-10,000选自PEG 300、PEG 400、PEG 1,000和PEG 6,000。
  40. 权利要求37或38的基于助溶剂的制剂，其还包括表面活性剂、磷脂、维生素E、抗氧化剂、防腐剂、固相吸附剂和/或水/缓冲剂，旨在助溶、提高通透性和稳定性。
  41. 权利要求37的基于助溶剂的制剂，除活性成分依达拉奉之外，其还包括PEG 300、Labrasol、Transcutol P、TPGS 1000和Cremophor RH 40中的一种或多种。
  42. 权利要求37-41任一项的基于助溶剂的制剂的制备方法，包括下列步骤：
    将活性成分依达拉奉或其可药用盐溶解在水溶性有机溶剂和/表面活性剂中。
  43. 权利要求1-17任一项的基于脂质的药物递送系统、权利要求19-28任一项的固相分散体制剂、权利要求31-34任一项的基于胶束的制剂以及权利要求37-41任一项的基于助溶剂的制剂，其中在液体制剂中，依达拉奉的含量为0.001-1000 mg/ml，或者0.1-100 mg/ml，或者10-20 mg/ml，而在固体制剂中，依达拉奉的剂量为0.001-1000mg/单位，或者0.1-100 mg/单位，或者10-20 mg/单位。
  44. 权利要求1-17任一项的基于脂质的药物递送系统、权利要求19-28任一项的固相分散体制剂或者权利要求31-34任一项的基于胶束的制剂，其为固体剂型，所述固体剂型选自片剂、胶囊、粉末或条(strip)，通过口服、肠胃外、吸入、局部或经皮、鼻内、眼内、内耳、直肠、阴道内途径给药。
  45. 权利要求1-17任一项的基于脂质的药物递送系统、权利要求19-28任一项的固相分散体制剂、权利要求31-34任一项的基于胶束的制剂或者权利要求37-41任一项的基于助溶剂的制剂，其为液体剂型，所述液体剂型选自溶液、悬浮液、乳液、基于共溶剂的系统、气溶胶，通过口服、肠胃外、吸入、局部或经皮、鼻内、眼内、内耳、直肠、阴道内途径给药。
  46. 权利要求1-17任一项的基于脂质的药物递送系统、权利要求19-28任一项的固相分散体制剂、权利要求31-34任一项的基于胶束的制剂或者权利要求37-41任一项的基于助溶剂的制剂，其为半固体剂型，所述半固体剂型选自药膏、霜剂、凝胶、糊剂，通过外用或经皮途径为局部或全身目的而给药。
  47. 权利要求1-17任一项的基于脂质的药物递送系统、权利要求19-28任一项的固相分散体制剂、权利要求31-34任一项的基于胶束的制剂或者权利要求37-41任一项的基于助溶剂的制剂在制备用于治疗氧化性应激相关疾病的药物中的应用。
  48. 权利要求47的应用，其中所述氧化性应激相关疾病为衰老性疾病、心血管病、癌症、神经变性疾病、肝病、肺病、消化道疾病、肾衰和肾透、感染性疾病和免疫病、皮肤病、五官科疾病、妊娠、哺乳和分娩相关疾病、运动性疾病、男科疾病、女性不孕症、关节病或慢性炎症。
  49. 权利要求47或48的应用，其中所述氧化性应激相关疾病选自老年痴呆症、ALS、帕金森氏病、缺血性心脏病、脑梗/中风、COPD、HIV/AIDS和糖尿病。
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