WO2019019091A1 - Préparations pharmaceutiques à base de curcumine - Google Patents

Préparations pharmaceutiques à base de curcumine Download PDF

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WO2019019091A1
WO2019019091A1 PCT/CN2017/094665 CN2017094665W WO2019019091A1 WO 2019019091 A1 WO2019019091 A1 WO 2019019091A1 CN 2017094665 W CN2017094665 W CN 2017094665W WO 2019019091 A1 WO2019019091 A1 WO 2019019091A1
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drug delivery
delivery system
curcumin
group
lipid
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PCT/CN2017/094665
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Chinese (zh)
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周新富
安基特·帕里克
桑贾伊·加尔
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周意
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention belongs to the field of medicine.
  • the invention relates to novel curcumin pharmaceutical formulations.
  • the novel preparation can more effectively utilize curcumin for anti-oxidation, anti-inflammatory, anti-cancer, induce apoptosis, anti-angiogenesis, neuroprotection, anti-microbial, liver and kidney protection, inhibit blood vessel formation, prevent myocardial infarction, lower blood sugar, Anti-rheumatic and other pharmacological effects.
  • Curcumin is undoubtedly one of the most biologically active molecules discovered in nature to date. Curcumin interacts with a large number of intracellular extracellular targets in a biphasic dose-dependent manner. It controls inflammatory, oxidative stress, cell survival, cell secretion, homeostasis and proliferation. The mechanism of action generally points to cells that exhibit disordered physiology or abnormal states of apparent mutation. It can easily cross all physiological barriers, including the blood-brain barrier.
  • curcumin did not have any side effects when administered orally at 12 g/day.
  • Curcumin and turmeric products have been identified as safe food additives by the US Food and Drug Administration (FDA), the Canadian Natural Health Products Agency, and the Joint FAO/WHO Expert Committee.
  • Curcumin is a natural polyphenolic compound that is commercially isolated from the rhizome of Curcuma longa Linn (Curcuma) (Zingiberaceae) and has a long history in Ayurvedic medicine. Many Asian countries, such as India and China, have been widely used as herbs for thousands of years.
  • the chemical name of curcumin is 1,7-bis-(4-hydroxy-3-methoxyphenyl)-hepta-1,6-diene-3,5-dione, the chemical formula is C 21 H 20 O 6 .
  • Curcumin-like is called diferuloyl Methane and is the main component of curcumin (77% by weight); the other two curcumin are demethoxycurcumin (17% by weight) and bis-methoxycurcumin (3 wt%).
  • Curcumin is a fat-soluble polyphenolic compound consisting structurally of two cyclomethoxyphenols attached to a diketone structure. Keto-enol tautomerization allows curcumin to act as a Michael acceptor 4 . Phenol groups and diketones are characteristic of antioxidant compounds and are key structures for the antioxidant action of curcumin.
  • Curcumin is safe and well tolerated. Due to its efficacy and safety, curcumin has been studied in a wide range of research fields, in vitro and in vivo, in animals and in humans. Low oral bioavailability (only 1% in rats) and very short biological half-life are limiting factors in the clinical development of curcumin. However, due to its lipophilic nature, curcumin can pass freely through the cell membrane (log P 1/42.5). The main reason for the low bioavailability of curcumin is its very low solubility in water (only 11 ng/ml in an aqueous solution of pH 5.0), acidity and physiological pH, and rapid hydrolysis under alkaline conditions.
  • the serum level of curcumin peaked after 1-2 hours after oral administration, and the serum concentration ranged from 0.51 ⁇ 0.11 ⁇ M at a dose of 4,000 mg/day. At 8,000 mg/day, the serum concentration ranged from 1.77 ⁇ 1.87 uM.
  • alleviation of the condition usually requires a tailored method of administration in order for the drug to reach the lesion in a therapeutic amount.
  • Optimizing prophylactic or therapeutic applications requires the provision of an appropriate amount of curcumin to impaired cellular targets.
  • the therapeutic effect can be accompanied by accidental toxicity to surrounding normal healthy cells and tissues.
  • a biologically active compound is its solubility in aqueous body fluids.
  • Lipophilic compounds such as curcumin lack water solubility, but retain significant cell membrane or intracellular activity. It is necessary to use new formulations for its application. Therefore, one of the main challenges of the pharmaceutical industry is the application of strategies to develop such problematic compounds into clinically orally, bioavailable and therapeutically effective drugs.
  • curcumin In order to develop curcumin as a clinical drug, the ideal formulation should address the following problems: poor solubility, chemical stability (hydrolysis, oxidation, heat and light) and pharmacokinetic properties, including absorption, distribution, metabolism and elimination in vivo, bioavailability Low degree, poor permeability, short half-life, local delivery of curcumin to the treatment target.
  • the current trend in curcumin research is to develop potential delivery systems to increase their water solubility and bioavailability because solubility acts as a rate limiting step for absorption.
  • the new method is to use other delivery vehicles, such as chelating strategies and bioconjugates of liposomes curcumin, curcumin nanoparticles, curcumin phospholipid complexes, nanoliposomes, nanoemulsions, nanolipids Granules and micelle nanosuspensions, glue Beams, nanoparticles, nanoemulsions, inclusion complexes with cyclodextrins, and curcumin structural analogs have all been confirmed.
  • the solubility in water can be increased by a few hundred times.
  • most of the reported methods only provide limited improvement in the bioavailability of curcumin.
  • cyclodextrin is used, the complexation process is slow, and the high molecular weight of the cyclodextrin and the pH of the treatment medium limit their practical utility.
  • Most delivery systems such as microemulsions, liposomes, and micelles, have a limited effect on powders because their stability can be affected when converted to a powder.
  • micelles, microemulsions, and liposome complexes may degrade in the stomach prior to reaching the target site, thereby impairing the bioavailability of the active ingredient.
  • Few researchers have focused on stability, solubility, and bioavailability at physiological pH. Because curcumin is prone to hydrolysis, stability in aqueous media is critical to the bioavailability of curcumin.
  • the present invention describes novel pharmaceutical formulations of curcumin based on different strategies, including:
  • the drug delivery system includes micelles, nanoparticles, nanofibers, nanosuspensions, and the like.
  • Nanotechnology is increasingly seen as a technology of the future.
  • nanoparticles are used to increase the bioavailability and solubility of lipophilic compounds, such as curcumin, in drug delivery systems.
  • lipophilic compounds such as curcumin
  • Solid dispersion technology is a science in which one or more active ingredients are dispersed in an inert matrix in a solid phase, intended to increase the solubility, dissolution rate, permeability, sustained release, altered solid state properties and stability of the drug. , thereby achieving improved bioavailability.
  • Lipid-based drug delivery systems have shown great potential for oral delivery of difficult-to-drug candidates, and there are several successfully marketed products.
  • the pre-dissolved drug is in a lipid, a surfactant, or a mixture of a lipid and a surfactant, omitting the dissolution/dissolution step, and the dissolution/dissolution step is a potential rate limiting factor for oral absorption of a poorly water-soluble drug.
  • the results improve bioavailability, bypassing the liver to reduce hepatotoxicity (via lymphatic absorption), and reducing nephrotoxicity (unknown mechanism).
  • the lipid-based drug delivery system includes a lipid solution, a lipid suspension, a self-emulsifying drug delivery system, a micelle, a nanoemulsion formulation.
  • the main object of the present invention is to effectively utilize curcumin by solving various problems such as poor solubility, chemical stability (hydrolysis, oxidation, heat and light) and pharmacokinetic properties including absorption, distribution, metabolism and elimination in vivo, and bioavailability.
  • curcumin Low degree, poor permeability, short half-life and local delivery of curcumin to the therapeutic target to achieve the best results, such as anti-oxidation, anti-inflammatory, anti-cancer, induced apoptosis, anti-angiogenesis, neuroprotection, anti- It has excellent pharmacological effects such as microbial agents, liver and kidney protection, inhibition of thrombosis, myocardial infarction, hypoglycemia and anti-rheumatic activities, and is effective in treating mammalian diseases.
  • the present invention provides a drug delivery system comprising the active ingredient curcumin or a derivative thereof or a pharmaceutically acceptable salt thereof and a polymer carrier Soluplus.
  • the weight ratio of curcumin to Soluplus is from 1:0.001 to 1:100.
  • the drug delivery system further comprises other polymeric carriers and/or surfactants.
  • the other 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 , polyacrylate, polymethacrylate, homopolymer and copolymer of acrylic acid, homopolymer and copolymer of methacrylic acid, polyacrylamide, polyvinyl alcohol, vinyl acetate polymer, vinyl acetate copolymerization , carboxyvinyl polymers, oligosaccharides, polysaccharides, and mixtures thereof.
  • the other polymeric carrier is selected from the group consisting of alkyl cellulose, hydroxyalkyl cellulose, hydroxyalkyl alkyl cellulose, methyl cellulose (MC), ethyl cellulose (EC), hydroxyethyl Cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxyethyl methylcellulose (HEMC), hydroxypropylmethylcellulose succinate, hydroxypropyl Methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, sodium carboxymethyl cellulose, potassium carboxymethyl cellulose, cellulose acetate succinate, cellulose acetate phthalate, hydroxyl Propyl methylcellulose phthalate, polyacrylic acid copolymer, poly(meth)acrylic acid polymer, poly(hydroxyalkyl acrylate), poly(hydroxyalkyl methacrylate), polyethylene Pyrrolidone (PVP), vinylpyrrolidone homopolymer,
  • PVP
  • the other polymeric carrier is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), chitosan, PVP, PVP/VA, HPC, hydroxypropyl methylcellulose acetate (HPMCAS), eudragit E100, based on dimethylaminoethyl methacrylate a cationic copolymer of an ester, butyl methacrylate and methyl methacrylate.
  • HPMC hydroxypropyl methylcellulose
  • PEG polyethylene glycol
  • chitosan PVP
  • PVP/VA HPC
  • HPC hydroxypropyl methylcellulose acetate
  • HPC hydroxypropyl methylcellulose acetate
  • HPC hydroxypropyl methylcellulose acetate
  • HPC hydroxypropyl methylcellulose acetate
  • HPC hydroxypropyl methylcellulose acetate
  • HPC hydroxypropyl methylcellulose acetate
  • HPC hydroxypropy
  • the surfactant comprises a negative, positive or amphoteric surfactant and is selected from the group consisting of sodium dodecyl sulfate, sodium dodecyl sulfate (SDS), sodium lauryl sulfate (SLS), polyoxygen Ethylene sorbate long-chain fatty acid ester, vitamin E-TPGS, bile salt, sodium deoxycholate, sodium glycocholate, polyoxyethylene polyoxypropylene glycol, and combinations thereof.
  • SDS sodium dodecyl sulfate
  • SLS sodium lauryl sulfate
  • polyoxygen Ethylene sorbate long-chain fatty acid ester vitamin E-TPGS
  • bile salt sodium deoxycholate
  • sodium glycocholate sodium glycocholate
  • polyoxyethylene polyoxypropylene glycol polyoxyethylene polyoxypropylene glycol
  • the drug delivery system is selected from the group consisting of nanotechnology-based drug delivery systems, solid solution systems, and emulsion systems to provide additional stability for possible precipitation.
  • the nanotechnology-based drug delivery system is selected from the group consisting of micelles, nanoparticles, nanofibers, and nanosuspensions
  • the solid solution based system is selected from the group consisting of solid dispersions, extrudates, and solid support systems.
  • the drug delivery system is a solid dispersion formulation, preferably further comprising TPGS 1000.
  • the drug delivery system is a micelle formulation, preferably further comprising TPGS 1000.
  • the micelle formulation further comprises other polymeric carriers and water/buffering agents, and wherein an effective amount of curcumin is encapsulated in the micelles.
  • the micelles further comprise a surfactant, a solid phase adsorbent, an acidulant and/or an antioxidant.
  • the invention also provides a preparation method of a solid dispersion preparation, comprising the following steps:
  • the active ingredient curcumin or a derivative thereof, or a pharmaceutically acceptable salt thereof is dispersed in a polymeric carrier and optionally a surfactant.
  • a method of preparing a solid dispersion formulation comprising a further step selected from: melting ice bath with stirring, the film was cooled with liquid nitrogen, spray congealing, hot melt extrusion, Meltrex TM, melt agglomeration, or solvent evaporation (drying , vacuum drying, rotary evaporation, hot plate heating, spray drying, freeze drying, supercritical antisolvent, coprecipitation, electrospinning, spray lyophilization, ultra-fast lyophilization, fluid bed coating) and solvent melting.
  • the invention also provides a preparation method of micelles, comprising the following steps:
  • the active ingredient curcumin or a derivative thereof, or a pharmaceutically acceptable salt thereof, a polymer carrier and a surfactant are optionally dissolved in an organic solvent, and the organic solvent is removed by rotary evaporation. After the film is formed, it is vacuum dried and added to a buffer. The agent is hydrated and sonicated.
  • the present invention also provides a lipid-based drug delivery system comprising the active ingredient curcumin or a derivative thereof or a pharmaceutically acceptable salt thereof and a lipid.
  • the lipid is a triglyceride comprising long chain triglycerides (LCT), medium chain triglycerides (MCT) and short chain triglycerides (SCT), wherein the long chain triglycerides are selected from hydrogenation Soybean oil, hydrogenated vegetable oil, corn oil, olive oil, soybean oil, peanut oil and sesame oil, medium chain triglycerides are selected from caprylic/maronic acid triglycerides from cocoa butter or palm seed oil.
  • LCT long chain triglycerides
  • MCT medium chain triglycerides
  • SCT short chain triglycerides
  • the lipid-based drug delivery system further comprises an excipient selected from the group consisting of chemical triglycerides, partial triglycerides, semi-synthetic oily esters, and semi-synthetic nonionic surfactant esters.
  • the lipid-based drug delivery system further comprises a water-insoluble excipient selected from the group consisting of beeswax, oleic acid, soy fatty acid, vitamin E, corn oil mono-di-triglyceride, medium chain (C8/C10) glycerol Monoesters and diglycerides, as well as propylene glycol esters of fatty acids.
  • a water-insoluble excipient selected from the group consisting of beeswax, oleic acid, soy fatty acid, vitamin E, corn oil mono-di-triglyceride, medium chain (C8/C10) glycerol Monoesters and diglycerides, as well as propylene glycol esters of fatty acids.
  • the lipid is selected from Caproyl 90, Capmul MCM Caproyl TM and one or more of PGMC.
  • the lipid-based drug delivery system further comprises a water-soluble organic solvent, a surfactant, a co-surfactant, a polymer solubilizer, a phospholipid, and/or an additive.
  • the water-soluble organic solvent is selected from the group consisting of PEG 200-10,000, polyvinyl caprolactam (PCL), polyvinyl acetate (PVA) or a copolymer thereof, a water-soluble form of vitamin E and ethanol; and a surfactant in which the fatty acid is a derivative of an unsaturated or saturated dietary oil synthesized by reacting PEG with a hydrolyzed vegetable oil, reacting an alcohol with ethylene oxide to form an alkyl ether ethoxylate, or reacting a polysorbate-based vegetable oil with ethylene oxide;
  • the agent is based on polyethylene glycol, polypropylene glycol, ethanol and glycerin;
  • the polymer solubilizer is selected from the group consisting of Soluplus, chitosan, polyvinylpyrrolidone (PVP), PVP/VA, HPC, HPMC, HPMCAS, eudragit E100, based on methacrylic acid A cationic cop
  • PEG 200-10,000 is selected from the group consisting of PEG 300, PEG 400, PEG 1,000 and PEG 6,000; the surfactant is selected from the group consisting of Cremophor RH 40, Labrasol, TPGS 1000, Tween 20, Cremophor E1 and Tween 80; and co-surfactant selection From PEG 300, PEG 400, propylene glycol, glycerol, ethanol, Transcutol HP and Transcutol P.
  • the additive comprises a solid phase adsorbent, a water soluble and fat soluble antioxidant, an acidulant, a chelating agent, a preservative, a stabilizer and/or a buffer
  • the solid phase adsorbent comprises a silicon based adsorbent and a silicon-based adsorbent
  • the silicon-based adsorbent is selected from the group consisting of Aerosil 200 and magnesium aluminum metasilicate
  • the non-silicon-based adsorbent is selected from the group consisting of microcrystalline cellulose, talc, anhydrous dibasic calcium phosphate (DCPA), and alkyl cellulose.
  • DCPA dibasic calcium phosphate
  • a water-soluble polymer composed of a group such as a hydroxyalkyl cellulose or a hydroxyalkylalkyl cellulose sugar;
  • the chelating agent is selected from the group consisting of ethylenediamine, disodium edetate, and disodium edetate.
  • the acidifying agent is selected from the group consisting of citric acid, acetic acid, fumaric acid, hydrochloric acid and nitric acid
  • the buffering agent is selected from the group consisting of potassium metaphosphate, potassium dihydrogen phosphate, sodium acetate, sodium citrate
  • the water-soluble or fat-soluble antioxidant is selected from the group consisting of Ascorbic acid, ascorbyl palmitate, butylhydroxyanisole, butylhydroxytoluene, hypophosphorous acid, thioglycerol, propyl gallate, sodium ascorbate, sodium hydrogen sulfite, sodium formaldehyde sulfoxylate, sulfoxylate, sodium metabisulfite .
  • lipid-based drug delivery system further comprises Capryol TM PGMC, RH 40, Labrasol, TPGS 1000, Transcutol P and/or Aerosil 200.
  • the lipid-based drug delivery system is selected from the group consisting of a lipid solution, a liposome suspension, a surfactant or a polymer-lipid mixed micelle, a self-microemulsifying drug delivery system (SMEDDS) and a nanoemulsion formulation. .
  • the lipid based drug delivery system is a liquid phase or solid phase SMEDDS.
  • a solid phase adsorbent is also included, preferably Aerosil 200.
  • the lipid based drug delivery system is a nanoemulsion formulation which further comprises water and/or a buffer.
  • the invention also provides a method of preparing a lipid-based drug delivery system comprising the following steps:
  • the active ingredient curcumin or a pharmaceutically acceptable salt thereof is dissolved in a lipid, a surfactant, or a mixture of a lipid and a surfactant.
  • the drug delivery system is in the form of a solid dosage form selected from the group consisting of tablets, rings, patches, capsules, pills, granules, fine granules or powders, powders or strips, by oral, parenteral, inhalation. , local or percutaneous, nasal, intraocular, ear, rectal, vaginal route.
  • the drug delivery system is in the form of a liquid, selected from the group consisting of solutions, suspensions, emulsions, cosolvent-based systems, aerosols, by oral, parenteral, inhalation, topical or transdermal, intranasal, intraocular, aural, Rectal, vaginal route of administration.
  • the drug delivery system is a semi-solid dosage form selected from the group consisting of ointments, creams, gels, pastes, for topical or systemic purposes by topical or transdermal, rectal, vaginal routes.
  • the drug delivery system further comprises a pharmaceutically acceptable excipient selected from the group consisting of a disintegrant, a lubricant, a glidant, an anti-adherent, an inert filler, a wetting agent, a pH modifier. , binders, solubility modifiers, recrystallization inhibitors, diluents, and combinations thereof.
  • curcumin is contained in a liquid preparation of a drug delivery system in an amount of 0.001 to 1000 mg/ml, or 0.1 to 100 mg/ml, or 10 to 20 mg/ml, and in a solid preparation of a drug delivery system, curcumin
  • the dose is from 0.001 to 1000 mg/unit, or from 0.1 to 100 mg/unit, or from 10 to 20 mg/unit.
  • the drug delivery system of the present invention can be used to treat a variety of diseases and to select a suitable route of administration and dosage form according to the type of disease. Therefore, the present invention also provides a drug delivery system for preparing for anti-oxidation, anti-inflammatory, anti-cancer, inducing apoptosis, anti-angiogenesis, neuroprotection, anti-microbial, liver and kidney protection, inhibiting blood vessel formation, preventing myocardial infarction, Application in blood sugar lowering and anti-rheumatic drugs.
  • Figure 4 shows the DSC thermogram of curcumin, physical mixture (PM) and solid dispersion (Example 1).
  • Figure 5 shows the X-ray diffraction pattern of curcumin, Soluplus, physical mixture (PM) and solid dispersion (Example 1).
  • Figure 6 shows SEM micrographs of curcumin, Soluplus and solid dispersion (Example 1).
  • Figure 7 shows the measurement of the size distribution of curcumin micelles (Example 3) by dynamic light scattering.
  • Figure 12 shows fluorescent micrographs of SH-SY5Y-APP695 cells overexpressing APP treated with curcumin and NCF (Example 1), where A is native curcumin and B is NCF.
  • Example 9 Lipid-based nanoemulsion formulation
  • Example 10 Lipid-based nanoemulsion formulation
  • the required amount of curcumin, Soluplus and optionally TPGS 1000 were dissolved in ethanol.
  • 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.
  • curcumin, Soluplus and optionally TPGS 1000 were dissolved in ethanol according to Examples 3 and 4.
  • 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).
  • Preparation 3 Preparation of liquid self-microemulsifying drug delivery system (SMEDDS) formulations (Examples 5 and 7)
  • 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 curcumin and vortex to mix until the curcumin is completely dissolved.
  • a liquid 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). Prior to lyophilization, the solution was frozen at -80 °C for at least 6 hours and then lyophilized for at least 24 hours at -45 ° C and 7102 mbar pressure in Novalyphe-NL 500 (Savant Instruments Corp., Holbrook, NY). Finally, the solid phase SMEDDS is stored in a desiccator.
  • PVDF 0.45 ⁇ m syringe filter
  • 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 curcumin and vortex to mix until the curcumin is completely dissolved. The required amount of miliQ water was added dropwise until a clear, clear formulation was obtained.
  • Examples 1-10 provide a variety of different curcumin formulation formulations, including solid dispersions, micelles, SMEDDS, and nanoemulsion formulations, 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 acetonitrile and 1% (w/v) citrate buffer at a ratio of 70:30 (v/v).
  • the injection volume was 20 ⁇ l, the flow rate was 1 ml/min, and the detection wavelength was 423 nm.
  • Simulated gastrointestinal fluid (no enzyme and bile components) was prepared according to the USP method.
  • curcumin significantly degrades under neutral to alkaline pH conditions and remains substantially stable at acidic pH. Curcumin is more stable at low pH 1.2 compared to pH 6.8 and 7.4. Curcumin exists in an equilibrium form between diketone and keto-enol, and easily forms intramolecular H-bonds. Curcumin hydrolysis begins with the attack of a nucleophilic OH - ion on the carbonyl group in the keto-enol moiety. Therefore, the greater the rate of degradation observed at high pH. In contrast, the solid dispersion of the invention (Example 1) protects curcumin from degradation in biological media of different pH.
  • curcumin was relatively stable in buffers containing solid dispersions at pH 1.2, 6.8 and 7.4. This was confirmed, encapsulated polymer micelle hydrolysis prevention curcumin, curcumin because keto - enol portion from nucleophilic OH - ions attack. Studies on the chemical stability of curcumin have inferred that the degradation of curcumin is a complex mechanism involving a variety of potential factors.
  • Table 2 shows the total degradation rate of curcumin in different samples according to the second-order kinetics of the solid dispersion of the present invention and natural curcumin at different pH values.
  • DSC Differential Scanning Calorimetry
  • the composition of the physical mixture (PM) was the same as that of the solid dispersion (SD) except that the drug (curcumin) and the polymer (Soluplus) were simply prepared in a ceramic mortar. The mixture was then sieved (250 ⁇ m) and stored in a container of amber glass lid.
  • X-ray diffraction confirmed the solid state characteristics of the sample.
  • the crystalline form of curcumin showed a sharp diffractive characteristic peak confirming the crystal form of the initial form.
  • a less intense peak was observed compared to the crystalline curcumin, suggesting that the crystal was partially converted to an amorphous state.
  • Soluplus no peaks were observed, indicating amorphous nature.
  • the XRD pattern of the solid dispersion did not show crystallinity, confirming the DSC results, in which no endothermic phenomenon corresponding to the melting of curcumin was recorded.
  • the Zeiss Microscopy Merlin with GEMINI II column is equipped with a field emission gun and operates at 0.7kV for secondary electron imaging.
  • Samples of curcumin, Soluplus, and solid dispersion (Example 1) were mounted on SEM scaffolds with conductive double-sided tape.
  • the particle size, polydispersity index (PDI) and zeta potential of the novel curcumin preparation (NCF) (Example 3) prepared were measured using a Malvern Zeta Sizer Nano ZS. For the test, a 1 mg/ml solution was prepared, followed by dilution with MiliQ water at 25 ° C (100 ⁇ l, up to 1 ml). Then, the particle size, PDI, and Zeta potential were triple measured by the above scheme.
  • the load capacity is defined as the weight ratio of curcumin to Soluplus, and the loading efficiency is defined as the ratio of the loaded curcumin to the initial amount of curcumin. Stability assessment was performed to check for turbidity, clarity, and precipitation at various time points after preparation. Curcumin was quantitatively determined by HPLC triple analysis. All tests were repeated three times and the results were expressed as mean and standard deviation.
  • a particle size of 63 nm was observed, indicating potential for use as a nanotechnology system with a PDI of 0.09, indicating a small variation in the size of the different particles, and a zeta potential of -8.65, indicating its potential to remain stable over time.
  • NCF showed high load capacity (9.15%) and load efficiency (98.23%).
  • the present application also confirmed stability by turbidity, transparency, and precipitation evaluation.
  • the size distribution of the micelle preparation of the present invention was determined by dynamic light scattering.
  • a universal buffer was prepared from a solution having a composition of boric acid, citric acid, and phosphoric acid (0.04 M each). The pH of the final solution was adjusted by the addition of 0.2 M sodium hydroxide. The concentration of the novel curcumin preparation (NCF) (Example 3) in different buffer solutions (pH 1.8-8) was 100 ⁇ g/mL. The solution was incubated at room temperature in the dark to avoid photolysis. Samples were taken at predetermined time intervals and filtered through a 0.45 ⁇ m PVDF syringe filter. All samples were subjected to triple analysis by HPLC method.
  • NCF novel curcumin preparation
  • Example 3 A solution of 0.02% H 2 O 2 and 3% H 2 O 2 of a novel curcumin preparation (NCF) (Example 3) at a concentration of 100 ⁇ g/mL was prepared. The solution was incubated at room temperature in the dark to avoid photolysis. Samples were taken at predetermined time intervals and filtered through a 0.45 ⁇ m PVDF syringe filter. All samples were subjected to triple analysis by HPLC method.
  • NCF novel curcumin preparation
  • Example 3 A solution of a novel curcumin preparation (NCF) (Example 3) at a concentration of 100 ⁇ g/mL was prepared. The solution was incubated in a stable chamber at 4 ° C, 25 ° C and 40 ° C. Samples were taken at predetermined time intervals and filtered through a 0.45 ⁇ m PVDF syringe filter. All samples were subjected to triple analysis by HPLC method.
  • NCF novel curcumin preparation
  • NCF novel curcumin preparation
  • Example 3 A solution of a novel curcumin preparation (NCF) (Example 3) at a concentration of 100 ⁇ g/mL was prepared. The solution was incubated in a light stable chamber according to the International Conference on Harmonization (ICH) guidelines. Samples were taken at predetermined time intervals and filtered through a 0.45 ⁇ m PVDF syringe filter. All samples were subjected to triple analysis by HPLC method.
  • ICH International Conference on Harmonization
  • 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 a medium containing 10 ⁇ g/mL equivalent of unprocessed curcumin or a novel curcumin preparation (NCF) (Example 1) and Soluplus. 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.
  • MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]
  • DMSO dimethyl methacrylate
  • 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-695 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 a medium containing 10 ⁇ g/mL of unprocessed curcumin or a novel curcumin preparation (NCF) (Example 1), CuSO 4 and H 2 O 2 to induce the representative of Alz. Cytotoxicity of Haimer's disease. 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.
  • MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]
  • MTT Sigma-Aldrich, USA, 5 mg/ml PBS
  • 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).
  • SH-SY5Y-APP695 cells were seeded at a density of 5 x 10 4 cells/well in 24-well plates (Corning, NY, USA). After 24 hours of incubation at 37 ° C, adherent cells were treated with or without natural curcumin at a concentration of 10 ⁇ g/ml and at an equal concentration of NCF and maintained at 37 ° C in a cell culture device (Hera Cell, Thermo Scientific, Waltham, MA). in. After 6 hours, the cells were washed twice with PBS (0.01 M, pH 7.4) and methanol was added for lysis.
  • PBS 0.01 M, pH 7.4
  • the cell lysate was centrifuged at 10,000 rpm for 10 minutes at 4 °C.
  • the concentration of curcumin in the collected supernatant was measured by LC/MS/MS. Each measurement was repeated three times and the obtained data was expressed as the average of three experiments.
  • 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 10% MPB, 100% MPB at 1.5 minutes, maintaining 95% MPB for 6 minutes, then 10% MPB for 30 seconds, preparing the next sample.
  • the total run time for each sample 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.
  • the mass-to-charge ratio (m/z) was generated by monitoring the precursor ions for MRM analysis as follows: curcumin 367.6/132.20 and Fahualin 307.2/161.2. Zero air is used as the source gas, and nitrogen is used as both the curtain gas and the collision gas.
  • the peak area was obtained from the compound, and the internal standard (IS) and the calibrant of known concentration were used as a calibration curve for constructing the ratio of compound/IS area.
  • the limit of quantification is 5 ng/ml.
  • the intra- and inter-day variability of each compound was within 15%.
  • the SH-SY5Y-APP695 cells at a density of 15 ⁇ 10 4 cells / well were seeded in 35mm culture plates (Corning, NY, USA), for, for fluorescence microscopy. After incubation for 24 hours at 37 ° C, adherent cells were incubated with a constant concentration (10 ⁇ g/ml) of natural curcumin and an equal concentration of NCF (Example 1) at 37 ° C in a cell culture device (Hera Cell, Thermo Scientific, Waltham, MA). Processing in 2 hours. After the incubation, the cell monolayer was washed three times with 1 ml of PBS (0.01 M, pH 7.4) to remove excess solid dispersion (SD) or natural curcumin. Fresh PBS (0.01 M, pH 7.4) was added to the plate, and the cells were observed, and photos were photographed by exciting the curcumin with a blue light microscope.
  • PBS 0.01 M, pH 7.4
  • the unprocessed curcumin remained substantially insoluble for 2 h in the dissolution medium.
  • the dissolution of the drug in the PM is slightly higher due to the solubilization of the drug due to micellization.
  • the solid dispersion (SD) (Example 1) showed a significantly higher release rate than PM. This suggests that curcumin exists mainly in amorphous form in SD and thus has higher solubility. Within 120 minutes, the dissolution rate of SD was observed to be 100%.
  • Rats Male Sprague-Dawley rats (250 ⁇ 10 g) were obtained at least 1 week prior to the start of the trial to regulate the environment, food and water in the laboratory. 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 curcumin suspension (CS) was prepared by adding curcumin to a 0.5% sodium carboxymethylcellulose (CMC-Na) solution and then sonicating for a few minutes to obtain a homogeneous suspension.
  • the new curcumin formulation (NCF) (Example 1) was dissolved in mili Q water. Two groups of rats were orally administered with curcumin suspension and NCF at a dose equivalent to 50 mg/kg of curcumin. 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, 120, 180, 240, 300, 360, 420, 480 and 720 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. 900 ⁇ l of ice-cold methanol containing warfarin was added as an internal standard (400 ng/ml) to 100 ⁇ L of plasma sample, followed by shaking for 10 minutes, centrifugation at 13,000 rpm for 5 minutes, and then drying with nitrogen. The extract was reconstituted with methanol/water (50:50) prior to injection into LC/MS/MS and filtered through a 0.22 [mu]m membrane filter. Using Phoenix WinNonlin (Pharsight, St. Louis, MO) Noncompartmental pharmacokinetics analysis of each concentration-time characteristic.

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Abstract

L'invention concerne des préparations pharmaceutiques à base de curcumine, comprenant une dispersion solide, une préparation de micelle, un SMEDDS et une nanoémulsion. L'augmentation de la solubilité et de la biodisponibilité de la curcumine permet de l'utiliser plus efficacement pour ses effets pharmacologiques tels que l'antioxydation, l'anti-inflammation, son action anti-cancéreuse induisant l'apoptose, l'anti-angiogenèse, la neuroprotection, son action antimicrobienne, la protection du foie et du rein, l'inhibition de la vascularisation, la prévention de l'infarctus du myocarde, la réduction de la glycémie, son action anti-rhumatismale et autres.
PCT/CN2017/094665 2017-07-27 2017-07-27 Préparations pharmaceutiques à base de curcumine WO2019019091A1 (fr)

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WO2020181256A1 (fr) * 2019-03-06 2020-09-10 Renibus Therapeutics, Inc. Nouvelles compositions de tétrahydrocurcumine, leurs procédés de fabrication et leurs procédés d'utilisation
CN111956713A (zh) * 2020-09-03 2020-11-20 华熙生物科技股份有限公司 含透明质酸的解酒护肝组合物及其应用
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CN113332250A (zh) * 2021-07-15 2021-09-03 诺言医药科技(上海)有限公司 一种谷氨酰胺酶抑制剂冻干粉及其制备方法和应用
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WO2020181256A1 (fr) * 2019-03-06 2020-09-10 Renibus Therapeutics, Inc. Nouvelles compositions de tétrahydrocurcumine, leurs procédés de fabrication et leurs procédés d'utilisation
CN111995307A (zh) * 2020-08-31 2020-11-27 湖北工业大学 一种用于海洋周边建筑防护涂层材料的制备方法
CN111956713A (zh) * 2020-09-03 2020-11-20 华熙生物科技股份有限公司 含透明质酸的解酒护肝组合物及其应用
CN111956713B (zh) * 2020-09-03 2021-10-15 华熙生物科技股份有限公司 含透明质酸的解酒护肝组合物及其应用
CN113332250A (zh) * 2021-07-15 2021-09-03 诺言医药科技(上海)有限公司 一种谷氨酰胺酶抑制剂冻干粉及其制备方法和应用
CN113332250B (zh) * 2021-07-15 2022-11-04 诺言医药科技(上海)有限公司 一种谷氨酰胺酶抑制剂冻干粉及其制备方法和应用
WO2023024185A1 (fr) * 2021-08-24 2023-03-02 江苏万邦生化医药集团有限责任公司 Comprimé en suspension

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