CN107308133A - Curcumin pharmaceutical preparation - Google Patents
Curcumin pharmaceutical preparation Download PDFInfo
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- CN107308133A CN107308133A CN201610267974.5A CN201610267974A CN107308133A CN 107308133 A CN107308133 A CN 107308133A CN 201610267974 A CN201610267974 A CN 201610267974A CN 107308133 A CN107308133 A CN 107308133A
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- drug delivery
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—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
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
-
- 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
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
Abstract
The invention belongs to drug field.In particular it relates to novel curcumin pharmaceutical preparation, including solid dispersions, micellar preparation, SMEDDS and nanoemulsions.By improving the solubility and bioavilability of curcumin, the present invention can more effectively utilize the pharmacological action such as anti-oxidant curcumin, anti-inflammatory, anticancer, inducing cell apoptosis, anti-angiogenesis, neuroprotection, antimicrobial, liver protection shield kidney, suppression vascularization, prevention heart infarction, hypoglycemic, antirheumatic.
Description
Technical field
The invention belongs to drug field.In particular it relates to novel curcumin pharmaceutical preparation.The new formulation can be more
Effectively utilize anti-oxidant curcumin, anti-inflammatory, anticancer, inducing cell apoptosis, anti-angiogenesis, neuroprotection, antimicrobial, guarantor
The pharmacological actions such as liver shield kidney, suppression vascularization, prevention heart infarction, hypoglycemic, antirheumatic.
Background technology
Curcumin (Curcumin), is undoubtedly one of molecule of most bioactivity that nature is found so far.Ginger
Flavine is interacted with the dose-dependent mode of two-phase and the extracellular target of substantial amounts of intracellular.It controls inflammatory, oxidative stress, cell to deposit
Living, cell secretion, homeostasis and propagation.Its mechanism of action is pointed generally in the exception for showing unordered physiology or being substantially mutated
The cell of state.It can easily cross all physiologic barriers, including blood-brain barrier.
In clinical test, oral 12g/ days, curcumin did not had any side effect.Curcumin and turmeric product are eaten by the U.S.
Product and FAD (FDA), Canadian natural health products office and FAO (Food and Agriculture Organization of the United Nation)/World Health Organization's joint specialist
The qualitative food additives for safety of the committee.
Curcumin is a kind of natural polyphenol class compound, is commercially separated from turmeric (Curcuma longa Linn)
The rhizome of (turmeric) (Zingiber), has long history in Ayurveda medicine.Many Asian countries, such as India and China,
Herbal medicine has been widely used as it thousands of years.The chemical name of curcumin is 1,7- couples-(4- hydroxy 3-methoxybenzenes base)-hept- 1,6- bis-
Alkene -3,5- diketone, chemical formula is C21H20O6.Curcuminoids are referred to as two asafoetide sulfonyl methanes (Diferuloyl Methane), are
The main component (77 weight %) of curcumin；Other two curcumins are desmethoxycurcumin (17 weight %) and double demethoxy ginger
Flavine (3 weight %).Curcumin is two ring first by being connected in diketone structure in a kind of fat-soluble polyphenolic substance, structure
Epoxide phenol is constituted.Ketoenol tautomerization allows curcumin to serve as Michael (Michael) acceptor 4.Phenolic group and diketone belong to
The characteristic of anti-oxidant compounds, and be the key structure of curcumin antioxidation.
Curcumin safety, tolerance are good.Due to its drug effect and security, curcumin is in extensive research field, body
Studied in outer and internal, animal and people.Low oral administration biaavailability (rat only 1%) and very short biology partly decline
Phase is the limiting factor of curcumin clinical development.But due to its lipophilicity, curcumin can be freely through cell membrane (log P
1/4 2.5).The low main cause of curcumin bioavilability be its in water (in pH 5.0 aqueous solution, only 11ng/
Ml), the solubility of acid and physiological ph is extremely low, and fast hydrolyzing under alkalescence condition.In the mankind, from pharmacokinetics
From the point of view of angle, after oral administration, the serum levels of curcumin reach peak value after 1-2 hours, when dosage is 4,000mg/ days, serum
Concentration range be 0.51 ± 0.11 μM, and dosage be 8,000mg/ days when, serum-concentration scope be 1.77 ± 1.87 μM.Environment because
Element, such as light, also can fast decoupled curcumin, cause it to be clinically difficult to handle.In order to realize the optimum of medicament administration, subtract
Hypopathia disease usually requires tailoring administration of drugs method, medicine is reached diseased region with therapeutic dose.Optimization prevention or it is therapeutic should
With needing to provide appropriate curcumin to impaired cell target.Finally, therapeutic effect can be with unexpected toxicity to around just
Chang Jiankang cell and tissue.The ideal characterisitics of bioactive compound is the solubility in aqueous body fluid.The parents such as curcumin
Lipid compound lacks water-soluble, but retains significant cell membrane or intracellular reactive.Its application is necessary to adopt new system
Agent.Therefore, one of significant challenge of medical industry is application strategy to develop problems compound, is changed into clinical suitable for reading
Clothes, bioavailable and therapeutically effective medicine.
In order to develop curcumin as clinical medicine, preferable preparation should solve following problem：The solubility of difference, chemistry are steady
Qualitative (hydrolysis, oxidation, light and heat) and pharmacokinetic properties, including absorb, be distributed, be metabolized and eliminate in vivo, biological utilisation
Spend low, poor permeability, half-life short, local delivery curcumin to therapeutic target potential difference.The trend of current curcumin research is exploitation
Potential delivery system, to improve its water solubility and bioavilability, because solubility act as the rate-limiting step absorbed.For
This purpose, new method is to use other delivery vectors, and as chelating strategy and the liposomal curcumin of bioconjugates, curcumin is received
Rice grain, phospholipid complexes of curcumin, nano liposomes, nanoemulsion, nano-lipid particle and micelle nano supensoid agent, glue
Beam, nano particle, nanoemulsions, with cyclodextrin formation inclusion compound, and curcumin analogue, are all confirmed.Use
Solubility can increase hundred times in these methods, water.But the method for most of reports only provides the bioavilability of curcumin
With limited improvement.Cyclodextrin is such as used, complexing process is slow, the HMW of cyclodextrin and the pH value of processing medium are all limited
Their actual utility.Most of delivery systems, such as microemulsion, liposome and micella act on limited to pulvis, because
Being converted into its stability during powder can be affected.Moreover, micella, microemulsion and liposome complex have before target position is arrived at
First it may degrade under one's belt, so as to damage the bioavilability of active component.Under the conditions of few researcher's concern physiological pHs
Stability, solubility and bioavilability, because curcumin is susceptible to hydrolysis, the biology of the stability of aqueous medium to curcumin
Availability is most important.Also a small amount of research is related to lucifuge, and the main of pharmaceutical business exploitation that be likely to become very sensitive to light is asked
One of topic.Effectively to treatment target position delivering medicine, the notice for not causing researcher too many, and target on cancer or brain
Relevant disease is necessary.So far, only a few studies personnel are conducted a research, and some of them are obtained using nanometer technology
Success is arrived.The potentiality of nano particle not only improve treatment or the imaging contrast of each dosage by increasing its bioavilability
Effect of preparation, and the targeting selectivity for tumour cell is also modified to, so as to increase image resolution ratio and/or reduction
The miss the target toxicity related to current chemotherapeutic.
This area still suffers from active demand, by selecting suitable formulation, improves effect of curcumin.
Summary of the invention
The present invention describes the curcumin new medicinal preparation based on Different Strategies, and the strategy includes：
1. nanometer technology drug delivery system
The drug delivery system includes micella, nano particle, nanofiber and nano suspending liquid etc..Nanometer technology is increasingly
It is considered as following technology.In the extensive use of nanometer technology, nano particle is used to improve lipophilic compound, such as ginger
Flavine, bioavilability and solubility in drug delivery system.Therefore, nano particle past 10 years by huge joyous
Meet, reason is to be degraded by protecting a drug from enzyme there is provided the blood circulation of medicine controlled releasing and extension, changes pharmacokinetics,
Drug toxicity is reduced, and limits the non-specific adsorption of medicine, so that potential improve the curative effect of encapsulated drug.
2. the drug delivery system of solid dispersions
Solid dispersions technique is one be dispersed in one or more active components in solids stages in inert base
Science, it is intended to by increasing solubility, dissolution rate, permeability, sustained release, the solid state properties and stability changed of medicine, enter
And realize improved bioavilability.
3. the drug delivery system based on lipid
Drug delivery system based on lipid shows huge dive in terms of oral delivery is difficult to the candidate of patent medicine
Power, and the product for thering are several successes to list.Predissolve medicine is in the mixed of lipid, surfactant, or lipid and surfactant
Compound, eliminates dissolving/dissolution step, and dissolving/dissolution step is one and dived for the medicine of oral absorption poorly water-soluble
Rate-limiting factor, its result improves bioavilability, and it is malicious (through Lymphatic) that the liver that detours reduces liver, and can subtract
Few kidney poison (mechanism is failed to understand).The drug delivery system based on lipid includes lipid soln, lipid suspension, self-emulsifying drug
Delivery system, micella, nanoemulsion preparation.
The main object of the present invention is effectively to utilize curcumin, by solving following problems：The solubility of difference, chemistry
Stability (hydrolysis, oxidation, light and heat) and pharmacokinetic properties, including absorb, be distributed, be metabolized and eliminate in vivo, it is biological sharp
Expenditure is low, poor permeability, half-life short and poor to treatment target position local delivery curcumin, so as to obtain best result, realization
Such as anti-oxidant, anti-inflammatory, anticancer, inducing cell apoptosis, anti-angiogenesis, neuroprotection, antimicrobial, liver protection shield kidney, suppression
Thrombosis, heart infarction protection, the excellent pharmacological action such as hypoglycemic, antirheumatic is movable, effectively treat mammalian diseases.
Specifically, the present invention provides a kind of drug delivery system, its comprising active component curcumin or derivatives thereof or
Its pharmaceutically acceptable salt and polymer support Soluplus.
According to the present invention, curcumin and Soluplus weight ratio are 1:0.001-1:100.
According to the present invention, drug delivery system also includes other polymers carrier and/or surfactant.
According to the present invention, the other polymers carrier be water-soluble polymer, selected from N- vinyl lactam homopolymers,
N- vinyl lactams copolymer, cellulose esters, cellulose ether, polyalkylene oxides, polyacrylate, polymethylacrylic acid
Ester, the homopolymer of acrylic acid and copolymer, the homopolymer of methacrylic acid and copolymer, polyacrylamide, polyvinyl alcohol, acetic acid
Vinyl ester polymers, vinyl acetate copolymer, carboxy vinyl polymer, oligosaccharides, polysaccharide and its mixture.
According to the present invention, it is fine that the other polymers carrier is selected from alkylcellulose, hydroxy alkyl cellulose, hydroxyalkyl alkyl
Tie up element, methylcellulose (MC), ethyl cellulose (EC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl
Methylcellulose (HPMC), hydroxyethylmethylcellulose (HEMC), hydroxypropyl methyl cellulose succinate, hydroxypropyl methyl are fine
The plain acetate succinate of dimension, carboxymethylethylcellulose, sodium carboxymethylcellulose, potassium carboxymethylcellulose, cellulose acetate amber
Amber acid esters, cellulosic phthalic acetate, HPMCP, polyacrylic acid copolymerized compound,
Poly- (methyl) acrylate copolymer, poly- (hydroxyalkyl acrylates), poly- (hydroxyalkyl methacrylates), polyvinylpyrrolidone
(PVP), Kollidone 90F, vinylpyrrolidone copolymer, PVP, vinyl pyrrolidone-vinyl
Acetate copolymer (copolyvidone), the co-polymer of vinyl acetate, the copolymer of propionate, vinyl acetate and bar
Beans acid copolymer, polyethylene glycol, polyvinyl alcohol, the polyvinyl acetate of partial hydrolysis, gelatin, mosanom, soluble starch,
Arabic gum, dextrin, hyaluronic acid, sodium chondroitin sulfate, propylene glycol alginate, agar, tragacanth, xanthans, aminoalkyl
Methacrylate copolymer, polyvinyl acetate-diethyl amino yl acetate, methacrylate copolymer, metering system
It is acid copolymer L, Eudragit L100D55, Eudragit S100, polyethylene glycol (macrogol), polyoxyethylene, poly-
Oxypropylene, the copolymer of oxirane (EO) and expoxy propane (PO), carragheen, galactomannans and combinations thereof.
According to the present invention, the other polymers carrier is selected from hydroxypropyl methyl cellulose (HPMC), polyethylene glycol
(PEG), chitosan, PVP, PVP/VA, HPC, hydroxypropyl methyl cellulose acetate (HPMCAS), eudragit E100, be based on
The cation copolymer of dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate.
According to the present invention, the surfactant includes negative, positive or amphoteric surfactant, and selected from dodecane
Base sodium sulfonate, lauryl sodium sulfate (SDS), NaLS (SLS), polyoxyethylene sorbitol acid anhydride long-chain fatty acid ester,
D-ALPHA-tocopheryl polyethylene glycol 1000 succinate, cholate, NaTDC, sodium glycocholate, polyoxyethylene polyoxypropylene glycol and combinations thereof.
According to the present invention, drug delivery system be selected from the drug delivery system based on nanometer technology, solid solution system and
Emulsion system, to provide extra stability for possible precipitation.
According to the present invention, the drug delivery system based on nanometer technology be selected from micella, nano particle, nanofiber and
Nano suspending liquid, and the solid solution system that is based on is selected from solid dispersions, extrudate and solid carrier systems.
According to the present invention, drug delivery system is solid dispersion preparation, preferably also contains TPGS1000.
According to the present invention, drug delivery system is micellar preparation, preferably also contains TPGS 1000.
According to the present invention, the micellar preparation is further containing other polymers carrier and water/buffer, and wherein have
The curcumin of effect amount is included in micella.
According to the present invention, the micella is further comprising surfactant, solid-phase adsorbent, acidulant and/or anti-oxidant
Agent.
The present invention also provides a kind of preparation method of solid dispersion preparation, comprises the following steps：
Active component curcumin or derivatives thereof or its officinal salt are dispersed in polymer support and optional surface is lived
In property agent.
According to the present invention, the preparation method of solid dispersion preparation further comprises being selected from following step：Ice-melt bath is stirred
Mix, film cooling, liquid nitrogen, spraying condensation, hot-melt extruded, MeltrexTM, melting cohesion or solvent evaporation (drying, vacuum do
Dry, rotary evaporation, hot plate heating, spray drying, freeze-drying, supercritical anti-solvent, co-precipitation, electrostatic spinning, spray it is cold it is dry,
Ultrafast cold dry, liquid bed coating) and solvent melting.
The present invention also provides a kind of preparation method of micella, comprises the following steps：
By active component curcumin or derivatives thereof or its pharmaceutically acceptable salt, polymer support and surface-active
Agent, optional dissolved removes organic solvent in organic solvent by rotary evaporation, after film is formed, and vacuum drying adds buffer
Hydration, it is ultrasonically treated.
The present invention also provides a kind of drug delivery system based on lipid, and it includes active component curcumin or derivatives thereof
Or its pharmaceutically acceptable salt and lipid.
According to the present invention, the lipid is triglycerides, including long chain triglycerides (LCT), medium chain triglyceride (MCT)
With short chain triglycerides (SCT), wherein long chain triglycerides be selected from oil with hydrogenated soybean, hydrogenated vegetable oil, corn oil, olive oil,
Soya-bean oil, peanut oil and sesame oil, medium chain triglyceride are selected from the octanoic acid from cupu oil or palmit seed oil/certain herbaceous plants with big flowers acid glycerol three ester.
According to the present invention, the drug delivery system based on lipid also includes excipient, sweet selected from chemical triglycerides, part
Oily three esters, semi-synthetic oily ester and semi-synthetic nonionic surfactant ester.
According to the present invention, the drug delivery system based on lipid also include water-insoluble excipient (D), selected from beeswax, oleic acid,
Soya bean fatty acid, vitamin E ,-two-triglycerides of corn oil list, middle chain (C8/C10) monoglyceride and diglyceride, and fat
The propylene glycol ester of fat acid.
According to the present invention, the lipid is selected from Caproyl 90, Capmul MCM and CaproylTMOne kind in PGMC or
It is a variety of.
According to the present invention, the drug delivery system based on lipid also includes water-miscible organic solvent, surfactant, auxiliary
Surfactant, Polymer compatibilizers, phosphatide and/or additive.
According to the present invention, water-miscible organic solvent is selected from PEG 200-10,000, Polyvinylcaprolactame (PCL), poly- second
Vinyl acetate (PVA) or its copolymer, the vitamin E and ethanol of water-soluble form；Surfactant is wherein aliphatic acid for not
The derivative of the prandial oil of saturation or saturation, passes through PEG and the reaction of hydrolyzing plant oil, alcohol and ethylene oxide reaction generation alkyl ether
Ethoxylate or vegetable oil based on polysorbate react and synthesized with ethylene oxide；Cosurfactant is based on
Polyethylene glycol, polypropylene glycol, ethanol and glycerine；Polymer compatibilizers are selected from Soluplus, chitosan, polyvinylpyrrolidone
(PVP), PVP/VA, HPC, HPMC, HPMCAS, eudragit E100, based on dimethylaminoethyl methacrylate, methyl
The cation copolymer of butyl acrylate and methyl methacrylate.It is preferred that, PEG200-10,000 is selected from PEG 300, PEG
400, PEG 1,000 and PEG 6,000；Surfactant be selected from Cremophor RH 40, Labrasol, TPGS 1000,
Tween 20, Cremophor E1 and Tween 80；And cosurfactant be selected from PEG 300, PEG 400, propane diols,
Glycerine, ethanol, Transcutol HP and Transcutol P.
According to the present invention, the additive includes solid-phase adsorbent, water-soluble and fat-soluble antioxidant, acidulant, chela
Mixture, preservative, stabilizer and/or buffer, wherein solid-phase adsorbent include silica-based adsorbent and non-silicon base adsorbent, silicon substrate
Adsorbent is selected from Aerosil 200 and Neusilin US2, and non-silicon base adsorbent is selected from microcrystalline cellulose, talcum, anhydrous phosphoric acid hydrogen
Dicalcium (DCPA), the water-soluble polymeric being made up of groups such as alkylcellulose, hydroxy alkyl cellulose, hydroxyalkylalkylcellulose sugar
Thing；Chelating agent is at least one selected from ethylenediamine, calcium disodium chelate and disodium ethylene diamine tetraacetate；Acidulant is selected
From citric acid, acetic acid, fumaric acid, hydrochloric acid and nitric acid；Buffer is selected from potassium metaphosphate, potassium dihydrogen phosphate, sodium acetate, citric acid
Sodium；Water-soluble or fat-soluble antioxidant is selected from ascorbic acid, ascorbyl palmitate, butylated hydroxy anisole, butyl hydroxyl
Base toluene, hypophosphorous acid, thioglycerol, propylgallate, sodium ascorbate, sodium hydrogensulfite, rongalite, secondary sulphur
Hydrochlorate, sodium pyrosulfite.
According to the present invention, in addition to curcumin, the drug delivery system based on lipid also includes CapryolTM PGMC、RH 40, Labrasol, TPGS 1000, Transcutol P and/or Aerosil 200.
According to the present invention, the drug delivery system based on lipid is selected from lipid soln, liposome suspension, surfactant
Or the micella of polymer-lipid mixing, self-emulsifying microemulsion drug delivery system (SMEDDS) and nanoemulsions preparation.
According to the present invention, the drug delivery system based on lipid is liquid phase or solid phase SMEDDS.Solid phase, in addition to solid in this way
Phase adsorbent, preferably Aerosil 200.
According to the present invention, the drug delivery system based on lipid is nanoemulsions preparation, and it also includes water and/or buffering
Agent.
The present invention also provides the preparation method of the drug delivery system based on lipid, comprises the following steps：
Active component curcumin or its pharmaceutically acceptable salt are dissolved in lipid, surfactant, or lipid and table
In the mixture of face activating agent.
According to the present invention, drug delivery system is solid dosage forms, selected from tablet, ring agent, patch, capsule, pill, particle
Agent, granula subtilis or pulvis, powder or band (strip), by oral, parenteral, suction, part or percutaneous, nose, intraocular, ear,
Rectum, vaginal approach administration.
According to the present invention, drug delivery system is liquid dosage form, selected from solution, suspension, emulsion, based on cosolvent is
System, aerosol, are administered by oral, parenteral, suction, local or percutaneous, intranasal, intraocular, ear, rectum, vaginal approach.
According to the present invention, drug delivery system is semisolid dosage form, selected from selected from ointment, creme, gel, paste, is passed through
External application or percutaneous, rectum, vaginal approach administration, for locally or systemically purpose.
According to the present invention, drug delivery system also includes pharmaceutically acceptable excipient, and the excipient is selected from disintegrant, lubrication
Agent, glidant, antitack agent, inert filler, wetting agent, pH modifying agent, adhesive, solubility modifying agent, recrystallization inhibition agent,
Diluent and combinations thereof.
According to the present invention, in the liquid preparation of drug delivery system, the content of curcumin is 0.001-1000mg/ml,
Either 0.1-100mg/ml or 10-20mg/ml, and in the solid pharmaceutical preparation of drug delivery system, the dosage of curcumin is
0.001-1000mg/ units, either 0.1-100mg/ units or 10-20mg/ units.
The drug delivery system of the present invention can be used for treating a variety of diseases, and select the present invention suitable according to disease type
Method of administration and formulation.Therefore, the present invention also provides drug delivery system and is preparing for anti-oxidant, anti-inflammatory, anticancer, inducing thin
Born of the same parents' apoptosis, anti-angiogenesis, neuroprotection, antimicrobial, liver protection shield kidney, suppress vascularization, it is prevention heart infarction, hypoglycemic, anti-
Application in the medicine of rheumatism.
Brief description
In order to more clearly describe technical scheme, briefly introduced below in conjunction with accompanying drawing.It is clear that this
A little accompanying drawings are only some embodiments that the application is recorded.The present invention includes but is not limited to these accompanying drawings.
Fig. 1 shows solubility (average value ± S.D., N=of the embodiment 1-2 curcumin in pH 1.2 buffer solution
3)。
Fig. 2 shows solubility (average value ± S.D., N=of the embodiment 3-10 curcumin in pH 1.2 buffer solution
3)。
Fig. 3 show curcumin in A buffer solutions and B buffer solutions containing solid dispersions chemical stability (average value ±
S.D., N=3).
Fig. 4 shows the DSC thermograms of curcumin, physical mixture (PM) and solid dispersions (embodiment 1).
Fig. 5 shows the X-ray diffraction of curcumin, Soluplus, physical mixture (PM) and solid dispersions (embodiment 1)
Figure.
Fig. 6 shows the SEM micrograph of curcumin, Soluplus and solid dispersions (embodiment 1).
Fig. 7 shows the Size Distribution by dynamic light scattering determination curcumin micella (embodiment 3).
Fig. 8 shows the physical stability (average value ± S.D., N=3) that NCF preparations (embodiment 3) are compared with curcumin, its
Middle Fig. 8 A-8D show hydrolytic stability, oxidation stability, heat endurance and light of the curcumin in micellar preparation of the present invention respectively
Stability.
Fig. 9 shows the influence (average value of curcumin, Soluplus and NCF (embodiment 1) to SH-SY5Y cell survivals
± S.D., N=3).
Figure 10 shows undressed curcumin and NCF (embodiment 1) to by CuSO4And H2O2The overexpression APP's of induction
The influence (average value ± S.D., N=3) of SH-SY5Y-APP695 cytotoxicities.
Figure 11 shows that curcumin and NCF (embodiment 1) take the photograph to the quantitative cell for over-expressing APP SH-SY5Y-APP695
Take research (average value ± S.D., N=3).
Figure 12 shows the SH-SY5Y-APP695 cells of the overexpression APP with curcumin and NCF (embodiment 1) processing
Fluorescence micrograph, wherein A are Natural Curcumin, and B is NCF.
Figure 13 shows that the Dissolution behaviours of curcumin, physical mixture (PM) and solid dispersions (SD) (embodiment 1) are (average
Value ± S.D., N=3).
Figure 14 shows pure curcumin and the NCF (embodiment 1) of optimization blood plasma distribution (average value ± S.D., N=3).
Embodiment
For a further understanding of the present invention, the preferred scheme of the present invention is described below in conjunction with embodiment.These
Description is merely illustrative the feature and advantage of curcumin new medicinal preparation of the present invention, the protection model being not intended to limit the present invention
Enclose.
Table 1：Component used of the invention and its chemical name
Embodiment 1：Solid dispersion preparation
| Composition | Quantity (mg) |
| Curcumin | 100 |
| Soluplus | 1000 |
Embodiment 2：Solid dispersion preparation
| Composition | Quantity (mg) |
| Curcumin | 100 |
| Soluplus:TPGS 1000 | 1000:200 |
Embodiment 3：Micellar preparation
| Composition | Quantity (mg) |
| Curcumin | 100 |
| Soluplus | 1000 |
| PBS(7.4pH) | 10mL |
Embodiment 4：Micellar preparation
| Composition | Quantity (mg) |
| Curcumin | 100 |
| Soluplus:TPGS 1000 | 1000:200 |
| PBS(7.4pH) | 10mL |
Embodiment 5：SMEDDS preparations based on lipid
| Composition | Quantity |
| Curcumin | 50mg/mL |
| Caproyl PGMC | 20% |
| Cremophor RH 40 | 25% |
| Labrasol:TPGS 1000(4:1) | 25% |
| Transcutol P | 30% |
Embodiment 6：SMEDDS preparations based on lipid
| Composition | Quantity |
| Curcumin | 50mg/mL |
| Caproyl PGMC | 20% |
| Cremophor RH 40 | 25% |
| Labrasol:TPGS 1000(4:1) | 25% |
| Transcutol P | 30% |
| Aerosil 200 (adsorbent) | 5%w/v |
Embodiment 7：SMEDDS preparations based on lipid
| Composition | Quantity |
| Curcumin | 50mg/mL |
| Caproyl PGMC | 20% |
| Cremophor RH 40 | 25% |
| Labrasol | 25% |
| Transcutol P | 30% |
Embodiment 8：SMEDDS preparations based on lipid
| Composition | Quantity |
| Curcumin | 50mg/mL |
| Caproyl PGMC | 20% |
| Cremophor RH 40 | 25% |
| Labrasol | 25% |
| Aerosil 200 (adsorbent) | 5%w/v |
Embodiment 9：Nanoemulsions preparation based on lipid
| Composition | Quantity |
| Curcumin | 50mg/mL |
| Caproyl PGMC | 20% |
| Cremophor RH 40 | 25% |
| Labrasol:TPGS 1000(4:1) | 25% |
| Transcutol P | 30% |
| Water | It is enough |
Embodiment 10：Nanoemulsion preparation based on lipid
| Composition | Quantity |
| Curcumin | 50mg/mL |
| Caproyl PGMC | 20% |
| Cremophor RH 40 | 25% |
| Labrasol | 25% |
| Transcutol P | 30% |
| Water | It is enough |
Preparation example 1：The preparation of solid dispersion preparation (Examples 1 and 2)
According to Examples 1 and 2, the desired amount of curcumin, Soluplus and optional TPGS1000 are dissolved in ethanol.
Organic solvent is removed by Buchi Rotary Evaporators II.The film of formation is dried overnight in vacuum desiccator.Drying sample is from burning
Bottle is scraped, and is collected in mortar.Powder is crushed with pestle, and homogeneous form is made.
Preparation example 2：The preparation of micellar preparation (embodiment 3 and 4)
According to embodiment 3 and 4, the desired amount of curcumin, Soluplus and optional TPGS1000 are dissolved in ethanol.
Organic solvent is removed by Buchi Rotary Evaporators II.The film of formation is dried overnight in vacuum desiccator, then with 10ml 1
× PBS buffers (pH 7.4) are hydrated, and are incubated 30 minutes at 37 DEG C, are subsequently ultrasonicated for a few minutes.Gained mixture passes through
0.45 μm of syringe filters (PVDF) filtering.
Preparation example 3：The preparation of liquid self-emulsifying microemulsion drug delivery system (SMEDDS) preparation (embodiment 5 and 7)
According to embodiment 5 and 7, by the desired amount of oily (Capmul PGMC), surfactant (Cremophor RH 40,
Labrasol and TPGS 1000) and cosurfactant (Transcutol P) correct amount into vial.Then,
Mixed by being gently mixed with vortex, said components are mixed, and heated in incubator at 37 DEG C.Add the desired amount of turmeric
Element, vortex mixing, until curcumin is completely dissolved.
Preparation example 4：The preparation of the preparation (embodiment 6 and 8) of Solid Self-microemulsion drug delivery system
Liquid SMEDDS preparations produced above.Add after the desired amount of Aerosil 200, with minimal amount of miliQ water
Dilution, is stirred at room temperature 2 hours.Gained mixture is placed 15 minutes, is filtered after balance by 0.45 μm of syringe filters (PVDF).
Before freeze-drying, solution is freezed at least 6 hours at -80 DEG C, (the Savant of Novalyphe-NL 500 are subsequently placed in
Instruments Corp., Holbrook, NY) in freeze at least 24 hours under -45 DEG C and 7102mbar pressure.Finally, will be solid
Phase SMEDDS is stored in drier.
Preparation example 5：The preparation of system (embodiment 9 and 10) based on nanoemulsions
According to embodiment 9 and 10, by the desired amount of oily (Capmul PGMC), surfactant (Cremophor RH 40,
Labrasol and TPGS 1000) and cosurfactant (Transcutol P) correct amount into vial.Then,
Mixed by being gently mixed with vortex, said components are mixed, and heated in incubator at 37 DEG C.Add the desired amount of turmeric
Element, vortex mixing, until curcumin is completely dissolved.The desired amount of miliQ water is added dropwise, until obtaining limpid transparent preparation.
Embodiment 1-10 provide a variety of different curcumin preparation formulas, respectively including based on solid dispersions, micella,
SMEDDS and nanoemulsions preparation.Hereafter describe the advantage of these preparations in detail by effect example.
Effect example 1
Solubility of the curcumin in different types of preparation
Due to curcumin in low pH it is more stable, selection buffer solution (pH 1.2) be used for solubility studies.
The solubility studies of embodiment 1-2 solid dispersion preparations
It is each to add 1ml miliQ water in separated vial.Excessive curcumin is separately added into above-mentioned solution and solid
Phase dispersion.Then, it is whole in test, using mechanical vibrator (Axyos Technologies, Brisbane,
Australia it is) continuous at room temperature to rotate 24 hours.Reach after balance, each bottle is centrifuged 5 minutes with 3000rpm, passes through 0.45 μm
PVDF syringe filters are filtered, and abandon excessive insoluble curcumin.Then, filtrate is with methanol dilution.Using previous exploitation and
The HPLC methods of checking, carry out triple solubility analyses.
Sample analysis is operated in HPLC (Shimadzu, Kyoto, Japan) system, and the system is equipped with UV-VIS detections
Device [SPD-20A], DGU-20A3 on-line degassing devices, CBM-20A system controllers, SIL-20AHT autopipettes, and LC
Chromopac data processor solutions.Using Zorbax Eclipse XDB-C18 (4.6*150*3.5mm3) analytical column.
The mobile phase of sample analysis is made up of acetonitrile and 1% (w/v) citrate buffer solution, and ratio is 70:30(v/v).The μ of volume injected 20
L, flow velocity 1ml/min, Detection wavelength 423nm.
As a result find (referring to Fig. 1), compared with crystal curcumin and amorphous curcumin, curcumin is in solid dispersions system
Solubility in agent (embodiment 1 and embodiment 2) is significantly improved.
The solubility studies of embodiment 3-4 micellar preparations
Excessive curcumin and the desired amount of Soluplus and optional TPGS 1000 are dissolved in ethanol.Pass through
Buchi Rotary Evaporators II removes organic solvent.The film of formation is dried overnight in vacuum desiccator, then with 10ml 1 ×
PBS buffers (pH 7.4) are hydrated, and are incubated 30 minutes at 37 DEG C, are subsequently ultrasonicated for a few minutes.Each sample is centrifuged with 3000rpm
5 minutes.Gained mixture is filtered by 0.45 μm of syringe filters (PVDF).Using the previous HPLC methods developed and verified,
Carry out triple solubility analyses.
The solubility studies of embodiment 5-8 liquid or solid SMEDDS preparations and embodiment 9-10 nanoemulsions preparations
It is each to add preparation described in 1ml in separated vial.Excessive curcumin is added to above-mentioned solution, is then existed
Test is whole, utilizes mechanical vibrator (Axyos Technologies, Brisbane, Australia) continuous rotation at room temperature
24 hours.Reach after balance, each bottle is centrifuged 5 minutes with 3000rpm, filtered by 0.45 μm of PVDF syringe filters, abandoned
Excessive insoluble curcumin.Then, filtrate is with methanol dilution.Using the previous HPLC methods developed and verified, carry out triple
Solubility is analyzed.
As a result find (referring to Fig. 2), compared with crystal curcumin and amorphous curcumin, curcumin is in all new formulations
Solubility in (embodiment 3-10) is significantly improved.
Effect example 2
Curcumin and its stability in solid dispersions
Simulation gastro-intestinal Fluid (no enzyme and bile component) is prepared according to USP methods.In order to determine the chemical stability of curcumin,
Prepare and using curcumin (100 μ g/mL) and the solution of solid dispersions (100 μ g/mL equivalent curcumins).Between the scheduled time
Filtered every collection sample, and by 0.45 μm of PVDF syringe filters.All samples carry out triple points by HPLC methods
Analysis.
As shown in Figure 3A, curcumin is significantly degraded under neutrality to alkaline pH, and basic holding is steady at acidic
It is fixed.Compared with pH 6.8 and 7.4, curcumin is more stable in low pH 1.2.Curcumin is with the balance between diketone and keto-enol
Form is present, and easily forms intramolecular H- keys.Curcumin hydrolysis starts from nucleophilic OH-Carbonyl in ion pair keto-enol part
Attack.Therefore, observe that degradation rate is bigger under high pH.In contrast, solid dispersions of the invention (embodiment 1) are in difference
Curcumin can be protected in pH Biomedia from degraded.As shown in Figure 3 B, curcumin divides in pH 1.2,6.8 and 7.4 containing solid
Stablize relatively in the buffer solution of granular media.The results verification, polymer micelle encapsulating curcumin prevention hydrolysis, reason is curcumin
Keto-enol part exempts from nucleophilic OH-The attack of ion.The chemical stability of curcumin infers that the degraded of curcumin is multiple
Miscellaneous mechanism, involves a variety of latencies.
Fig. 3 shows chemical stability (average value ± S.D., N=3) of the curcumin in A buffer solutions and B buffer solutions, wherein
A is the plain buffer without polymer, and B is the buffer solution containing solid dispersion preparation.
Table 2 shows that solid dispersions and Natural Curcumin of the present invention are at various ph values, different according to second-order kinetics
The total degradation rate of curcumin in sample.
Table 2：Speed constant and half-life period (average value ± S.D., N=3)
Effect example 3
The property research of solid dispersions
(1) the DSC thermograms of curcumin, physical mixture and solid dispersions are obtained
Differential scanning calorimetry (DSC) is carried out using TA Instruments Discovery DSC (model 2920) to survey
Amount.Before experiment operation, baseline and cell constancy calibration to instrument.Curcumin, Soluplus and solid dispersions (embodiment
Etc. 1) sample is enclosed in sealed aluminum pan, and for DSC experiments, blank panel is used as reference.The temperature range of experiment is from room temperature to 250
DEG C, 10 DEG C/minute of the rate of heat addition, 50ml/ points of controlled nitrogen flow rate.
The composition of physical mixture (PM) is identical with solid dispersions (SD), simply by medicine (curcumin) and polymer
(Soluplus) in ceramic mortar simple pestle and prepare.The mixture and then screening (250 μm), and it is stored in amber glass
In the container of lid.
Referring to Fig. 4, the change of solid-state in solid dispersion preparation is determined by DSC.In the thermogram of curcumin, see
Observe 183 DEG C of sharp melting peak.In physical mixture PM samples, compared with crystal curcumin, it was observed that the less peak of intensity,
Prompting crystal is partially converted into amorphous state.In the case of solid dispersions, the melting behaviors with curcumin are not observed
Corresponding endothermic thermal event, it is partial amorphism in solid dispersions to show curcumin.
(2) x-ray diffraction pattern of curcumin, Soluplus and solid dispersions (embodiment 1) sample is obtained
Utilize the CuK α radiation on PANalytical (Pa Nake), Empyrean (sharp shadow) X-ray diffractometerOperating parameter：40kV and 40mA, 2-50 ° of 2 θ, 0.013 ° of step-length, fixed 0.25 ° of divergent slit and
0.50 ° of antiscatter slits.
Referring to Fig. 5, X-ray diffraction (XRD) confirms the solid state characterization of sample.As expected, the crystal shape of curcumin
Formula shows diffractive features peak full to the brim, it was demonstrated that the crystallinity of original form.In physical mixture PM samples, with crystal curcumin
Compare, it was observed that the less peak of intensity, points out crystal to be partially converted into amorphous state.In Soluplus, it is not observed
Any peak, shows amorphous property.The XRD of solid dispersions does not show crystallinity, DSC results is confirmed, without note
Record endothermic thermal event corresponding with the melting behaviors of curcumin.
(3) SEM micrograph of curcumin, Soluplus and solid dispersions (embodiment 1) is obtained
Ultrahigh resolution secondary electron microscope (Zeiss Microscopy Merlin with GEMINI II
Column) equipped with Flied emission rifle, 0.7kV operations obtain secondary electron imaging.Curcumin, Soluplus and solid dispersions
(embodiment 1) sample is arranged on SEM object slands (stub) with conductive double sided adhesive tape.
Referring to Fig. 6, sem analysis research morphological feature.Curcumin shows needle-shaped crystals.Soluplus polymer show it is big and
Irregular shape.And in the imaging of solid dispersion powder, surface characteristics is varied considerably.The SEM results of solid dispersions show
Show, with Soluplus polymer phases ratio, surface area is dramatically increased, this contributes to solid dispersions in an aqueous medium fast instant
Go out.The crystal curcumin of trace is not observed in solid dispersions.
Effect example 4
The size distribution of micellar preparation
The novel curcumin preparation (NCF) (embodiment 3) prepared is measured using Malvern Zeta Sizer Nano ZS
Particle diameter, polydispersity index (PDI) and Zeta potential.In order to test, 1mg/ml solution is prepared, then with 25 DEG C of MiliQ water
Lower dilution (100 μ l, until 1ml).Then, by such scheme, three remeasurement particle diameters, PDI and Zeta potential.Load capacity is determined
Justice for curcumin and Soluplus weight ratio, and load efficiency be defined as load curcumin and primary quantity curcumin it
Than.Stability assessment is to prepare rear different time points to check turbidity, transparency and precipitation.Curcumin is fixed by the weight analysis of HPLC tri-
It is fixed to measure.All tests are all in triplicate, as a result to be represented with average and standard deviation.
It was observed that particle diameter is 63nm, and potentiality of the display as nanoengineered systems, PDI is 0.09, shows different particles
Size changes smaller, and Zeta potential is -8.65, shows that its long-time maintains stable potentiality.NCF shows high load energy
Power (9.15%) and load efficiency (98.23%).The application is assessed by turbidity, transparency and precipitation, has further acknowledged stability.
Referring to Fig. 7 and table 3, pass through the Size Distribution of dynamic light scattering determination micellar preparation of the present invention (embodiment 3).
Table 3：The physico-chemical parameter of curcumin micellar preparation (embodiment 3)
* stability is determined by turbidity, transparency and precipitation verification
Effect example 5
Stability study, including hydrolytic stability, oxidation stability, heat endurance and photostability
(1) Generic buffer is prepared from composition for the solution of boric acid, citric acid and phosphoric acid (each 0.04M).Add 0.2M hydrogen
The pH of the whole solution of sodium oxide molybdena regulation.Novel curcumin preparation (NCF) (embodiment 3) is in different cushioning liquid (pH 1.8-8)
Concentration is 100 μ g/mL.Incubation solution at room temperature in dark, to avoid photodissociation.Predetermined time interval gathers sample, and passes through
0.45 μm of PVDF syringe filters filtering.All samples carry out three weight analysis by HPLC methods.
Referring to Fig. 8 A, stability of the curcumin in micellar preparation (embodiment 3) is not by from acidity to alkaline all pH models
The influence enclosed.The results verification encapsulates curcumin by polymer micelle can prevent hydrolysis.
(2) 0.02%H of the concentration for 100 μ g/mL novel curcumin preparation (NCF) (embodiment 3) is prepared2O2With 3%
H2O2Solution.Incubation solution at room temperature in dark, to avoid photodissociation.Predetermined time interval gathers sample, and passes through 0.45 μm
PVDF syringe filters are filtered.All samples carry out three weight analysis by HPLC methods.
Referring to Fig. 8 B, stability of the curcumin in micellar preparation (embodiment 3) is not influenceed by hydrogenperoxide steam generator.Should
Results verification encapsulates curcumin by polymer micelle can prevent oxidative degradation.
(3) solution of the concentration for 100 μ g/mL novel curcumin preparation (NCF) (embodiment 3) is prepared.4 DEG C, 25 DEG C and
Incubation solution in 40 DEG C of equalization chamber.Predetermined time interval gathers sample, and is filtered by 0.45 μm of PVDF syringe filters.
All samples carry out three weight analysis by HPLC methods.
Referring to Fig. 8 C, stability of the curcumin in micellar preparation (embodiment 3), not by shadow under the conditions of different heat stresses
Ring.The results verification encapsulates curcumin by polymer micelle can prevent thermal degradation.
(4) solution of the concentration for 100 μ g/mL novel curcumin preparation (NCF) (embodiment 3) is prepared.According to world association
Adjust meeting (ICH) guide, the Incubation solution in light equalization chamber.Predetermined time interval gathers sample, and passes through 0.45 μm of PVDF
Syringe filters are filtered.All samples carry out three weight analysis by HPLC methods.
Referring to Fig. 8 D, stability of the curcumin in micellar preparation (embodiment 3) is uninfluenced under light stressed condition.
The results verification encapsulates curcumin by polymer micelle can prevent photodissociation.
Effect example 6
External safety research
(1) born of the same parents' poison of invention formulation is studied using SH-5Y5Y cell lines
Cell culture analytical
Cell culture is operated using SH-SY5Y cell lines.DMEM culture mediums (Dulbecco ' s Modified Eagle
Medium)：Nutritional blend F12 is with 1:The ratio between 1 is used to cultivate cell in 25ml cell culture flasks, and the nutritional blend is mended
Filled with 10% hyclone (FBS) and 1% Pen .- Strep solution.Cell is in incubator in 5%CO2Under the conditions of 37 DEG C
Cultivated.
MTT analyzes SH-SY5Y cells viability
In 96 orifice plates, with 5 × 103The density inoculation SH-5YSY cells of cells/well.After 24 hours, with containing 10 μ g/
The undressed curcumin of mL equivalent or novel curcumin preparation (NCF) (embodiment 1) and Soluplus culture medium replace former training
Support base.The preparation of preparation uses sterilized water.Cells viability passes through MTT ([3- (4,5- dimethylthiazole -2- bases) -2,5- hexichol
Base tetrazole bromide], tetrazolium bromide) method measurement.After 20 hours, 20 μ L MTT of every hole addition (Sigma-Aldrich, USA,
5mg/ml PBS), incubate 1 hour.Add 150 μ L DMSO and dissolve insoluble purple formazan products, it is coloured molten to generate
Liquid.Optical density (OD) is read with 600nm wavelength on porous scanning spectrophotometer (BIO-RAD model 2550EIA readout meters)
Number.
Referring to Fig. 9, compared with blank Soluplus and curcumin, safety research is carried out to novel curcumin preparation, with
Evaluate preliminary safety characteristic.Any Difference In Toxicity is not observed to cell, confirmation is non-born of the same parents' poison.
(2) born of the same parents' poison of invention formulation is studied using SH-5Y5Y-APP695 cell lines
Cell culture analytical
Cell culture is operated using SH-SY5Y-APP695 cell lines.DMEM culture mediums (Dulbecco ' s Modified
Eagle Medium)：Nutritional blend F12 is with 1:The ratio between 1 is used to cultivate cell in 25ml cell culture flasks, and the nutrition is mixed
Compound is supplemented with 10% hyclone (FBS) and 1% Pen .- Strep solution.Cell is in incubator in 5%CO2Condition
Lower 37 DEG C are cultivated.
MTT analyzes SH-SY5Y-APP695 cells viability
In 96 orifice plates, with 5 × 103The density inoculation SH-5YSY-695 cells of cells/well.After 24 hours, with containing 10
The undressed curcumin of μ g/mL equivalent or the culture medium of novel curcumin preparation (NCF) (embodiment 1), CuSO4And H2O2Replace
Former culture medium, to induce the cytotoxicity for representing Alzheimer disease.The preparation of preparation uses sterilized water.Cells viability passes through
MTT ([3- (4,5- dimethylthiazole -2- bases) -2,5- diphenyltetrazolium bromide bromides], tetrazolium bromide) method is measured.After 20 hours,
20 μ L MTT (Sigma-Aldrich, USA, 5mg/ml PBS) are added per hole, are incubated 1 hour.Add 150 μ L DMSO dissolvings not
Dissolubility purple formazan products, to generate colored solutions.In porous scanning spectrophotometer, (BIO-RAD models 2550EIA is read
Go out instrument) on 600nm wavelength to optical density (OD) reading.
Referring to Figure 10, SH-SY5Y-APP695 cells are via CuSO4And H2O2The viability after born of the same parents' poison is induced, passes through MTT
Analysis is evaluated.Compared to the anti-Alzheimer disease effect of undressed curcumin, novel curcumin preparation (NCF) (embodiment
1) show that there is provided excellent neuroprotection for significantly more preferable effect.
Effect example 7
(1) cellular uptake is studied
Taken the photograph with the cell that SH-SY5Y-APP695 cells evaluate curcumin and novel curcumin preparation (NCF) (embodiment 1)
Take.In short, by SH-SY5Y-APP695 cells using density as 5 × 104Cells/well be seeded in 24 orifice plates (Corning, NY,
USA).After 37 DEG C incubate 24 hours, attached cell is 10 μ g/ml Natural Curcumin and the NCF of isoconcentration with or without concentration
Processing, and maintained at 37 DEG C in cell culture apparatus (Hera Cell, Thermo Scientific, Waltham, MA).6 is small
Shi Hou, cell is washed twice with PBS (0.01M, pH 7.4), and adds methanol decomposition.Cell pyrolysis liquid with 10,000rpm, 4 DEG C from
The heart 10 minutes.By LC/MS/MS, the concentration of curcumin in the supernatant collected is measured.It is each to measure in triplicate, the number of acquisition
The average value of three experiments is represented according to this.
LC/MS/MS methods：
Sample analysis is operated in Quadrapole LC/MS/MS (Shimadzu, Kyoto, Japan) system, the system
It is equipped with the mass spectrographs of API 3000, Shimadzu SIL 20A autopipettes, Shimadzu LC20AD pumps and analysis 1.6.2
Data processor.Using newly developed and checking LC/MS/MS methods, to the concentration quantitative of curcumin in blood plasma.Extract redissolves
In methanol/water (50:50) in, Shimadzu Nexera HPLC systems are injected to, Kinetex C18 2.6mm × 50mm ×
3mm posts (Phenomenex) are parsed, mobile phase flow velocity 0.2ml/min, the μ l of volume injected 15.Mobile phase A (MPA) is 5% methanol
With the aqueous solution of 0.1% formic acid, and mobile phase B (MPB) is the aqueous solution of 95% methanol and 0.1% formic acid.Mobile phase timetable
The gradient set as：10%MPB is originated, to 100%MPB at the 1.5th minute, 95%MPB6 minutes are maintained, then 10%MPB
30 seconds, prepare next sample.The total run time of each sample analysis is 10 minutes.Post eluent is introduced into negative ion mode EFI
Mist (ESI) mass spectral analysis.The operating parameter of ion gun includes analyte dependence parameter and source dependence parameter, and optimization obtains matter
The optimum performance of spectrometer analysis.MRM analyses are carried out by monitoring precursor ion, mass-to-charge ratio (m/z) are produced as follows：Curcumin
367.0/134.20 with Fa Hualin 307.2/161.2.Using 0 air as source gas, and nitrogen both also serves as collision gas as gas curtain gas.
Peak area, calibration of the caliberator as structure compound/IS area ratios of internal standard (IS) and concentration known are obtained from compound
Curve.Quantitatively it is limited to 5ng/ml.The in a few days and in the daytime variability of each compound is in 15%.
Cellular uptake is important parameter, it is necessary to which the parameter explains how invention formulation is successfully delivered into cancerous tissue.
Referring to Figure 11, when concentration is 10 μ g/mL, NCF cellular uptake compares Natural Curcumin, improves 87%.Therefore, cell is taken the photograph
Research is taken to confirm NCF intakes more more preferable than Natural Curcumin.The result that the research is obtained is supported compared to undressed curcumin,
NCF has more excellent neuroprotection to cell.
(2) fluorescence microscopy is observed
In order to which quantitative cellular uptake is studied, by SH-SY5Y-APP695 cells using density as 15 × 104Cells/well is seeded in
35mm culture plates (Corning, NY, USA), for for fluorescence microscope studies.After 37 DEG C incubate 24 hours, attached cell is used
In cell culture apparatus (Hera at the Natural Curcumin of constant density (10 μ g/ml) and 37 DEG C of the NCF (embodiment 1) of isoconcentration
Cell, Thermo Scientific, Waltham, MA) in processing 2 hours.After incubation, cell monolayer with 1ml PBS (0.01M,
PH 7.4) flush three times, to remove excessive solid dispersions (SD) or Natural Curcumin.Added in plate fresh PBS (0.01M,
PH 7.4), cell is observed, with blue light microscopic by exciting curcumin to take pictures.
Using the photochemical properties of curcumin, by fluophotometer, by NCF intracellular intake and Natural Curcumin ratio
Compared with.Referring to Figure 12, by measuring the fluorescence intensity of curcumin, compared with Natural Curcumin, NCF shows that significantly higher cell is taken the photograph
Take.
Effect example 8
Dissolution is studied
Pure curcumin, physical mixed are carried out using USP II type oars device (AT 7Smart, Sotax GmbH, Germany)
The dissolution of thing (PM) and the curcumin of solid dispersions (SD) (embodiment 1) form.Operating parameter：50rpm rotating speeds, 37 ± 0.5
DEG C temperature, SIF (simulated intestinal fluid) pH 6.8 (USP).The preparation of 20mg curcumin equivalent is inserted into " 2 " number hard gelatin capsule.Glue
Capsule is placed in sinker, and is put into dissolution container.Different time interval gathers sample, and uses the fresh dissolution medium of equivalent every time
Replace.Sample is filtered by 0.45 μm of PVDF syringe filters, and is analyzed by the HPLC methods developed previously.
As shown in figure 13, undressed curcumin substantially maintains insoluble 2h in dissolution medium.With undressed curcumin phase
Than causing the curcumin dissolution in medicament solubilization, PM slightly higher due to micellization.Compared to PM, solid dispersions (SD) (embodiment 1)
Show significantly high rate of release.This implies that curcumin mainly exists in SD with amorphous state, thus with higher dissolving
Degree.In 120 minutes, it was observed that SD dissolution rate is 100%.
Effect example 9
Pharmacokinetic
Male SD rat (250 ± 10g) is obtained within least 1 week before on-test, to be its adjusting ambient in laboratory, to eat
Thing and water.Preoperative anesthetized rat.Make longitudinal cut in neck and closer to jugular vein region.Then, given birth to 20 units/ml heparin
Salt solution filling conduit is managed, and inserts jugular vein, until the first silica gel plug.Suture plug and muscle are fixed in there.Conduit
The other end it is subcutaneous through neck, closer to ears.Finally, with 500 units/ml heparin-salines filling conduit, and fill in
The free-end of conduit.After the completion of operation, rat is placed in different cages and recovered.Second day, medicine is carried out to every rat for power
Learn research.Before administration, animal fasting 12 hours, random drinking water.
The preparation of curcumin suspension (CS) is that curcumin is added into 0.5% sodium carboxymethylcellulose (CMC-Na) solution,
Then ultrasonically treated a few minutes, unit for uniform suspension is obtained.Novel curcumin preparation (NCF) (embodiment 1) is dissolved in mili Q water
In.Two groups of Oral Administration in Rats administration curcumin suspension and NCF, dosage are equal to 50mg/kg curcumin.Oral raise applies medicine
After preparation, in the time interval of 0,15,30,45,60,90,120,180,240,300,360,420,480 and 720 minute,
Gather 0.2ml blood samples.During each blood specimen collection, conduit is all rinsed with same amount of heparin-saline.After blood specimen collection,
5000rpm, 4 DEG C centrifuge 5 minutes, blood plasma is separated with blood.- 20 DEG C are stored in after blood plasma separation, until analysis.900 μ l contain
There is warfarin (warfarin) ice cold methanol, 100 μ L plasma samples are added to as internal standard (400ng/ml), then rotation concussion
10 minutes, 13,000rpm centrifugations 5 minutes, then nitrogen drying.Before LC/MS/MS is injected to, extract is with methanol/water (50:
50) redissolve, and filtered by 0.22 μm of film filter.Using Phoenix WinNonlin (Pharsight, St.Louis, MO)
Non- chamber pharmacokinetic analysis (noncompartmental pharmacokinetics are carried out to each Concentration-time characteristic
analysis)。
Referring to Figure 14 and table 4, the Cmax of pure curcumin suspension (CS) and novel curcumin preparation (NCF) (embodiment 1)
There is significant difference between value.Compared with pure curcumin, NCF bioavilability improves nearly 123 times.Curcumin is in intestines and stomach
In effective solubilized and anti-degraded be bioavilability improvement possible cause.Moreover, carrier S oluplus is polymer, also lure
Intestinal epithelial permeability increase is led.
Table 4：The pharmacokinetic parameter (mean+SD) (N=3) of curcumin and NCF (50mg/kg)
| Parameter | Curcumin suspension | NCF |
| Cmax(ng/mL) | 38.75612 | 3657.552 |
| Tmax(mins) | 60 | 180 |
| AUC0-t(ng·min/mL) | 6511.4531 | 801873.35 |
| AUC0-∞(ng·min/mL) | 6607.5779 | 806448.55 |
| F0-t (%) | - | 123.1481418 |
| F0- ∞ (%) | - | 122.0490416 |
Claims (39)
1. drug delivery system, it includes active component curcumin or derivatives thereof or its pharmaceutically acceptable salt and polymer
Carrier S oluplus.
2. the weight ratio of the drug delivery system of claim 1, wherein curcumin and Soluplus is 1:0.001-1:100.
3. the drug delivery system of claim 1, it also includes other polymers carrier and/or surfactant.
4. the drug delivery system of claim 3, wherein the other polymers carrier is water-soluble polymer, selected from N- ethene
Base lactams homopolymer, N- vinyl lactams copolymer, cellulose esters, cellulose ether, polyalkylene oxides, polyacrylic acid
Ester, polymethacrylates, the homopolymer of acrylic acid and copolymer, the homopolymer of methacrylic acid and copolymer, polyacrylamide
Amine, polyvinyl alcohol, vinyl acetate polymer, vinyl acetate copolymer, carboxy vinyl polymer, oligosaccharides, polysaccharide and its mixed
Compound.
5. the drug delivery system of claim 3, wherein the other polymers carrier is selected from alkylcellulose, hydroxylalkyl
Element, hydroxyalkylalkylcellulose, methylcellulose (MC), ethyl cellulose (EC), hydroxyethyl cellulose (HEC), hydroxypropyl are fine
Dimension plain (HPC), hydroxypropyl methyl cellulose (HPMC), hydroxyethylmethylcellulose (HEMC), hydroxypropyl methyl cellulose amber
Acid esters, HPMCAS, carboxymethylethylcellulose, sodium carboxymethylcellulose, carboxymethyl cellulose
Plain potassium, cellulose acetate succinate, cellulosic phthalic acetate, HPMCP,
Polyacrylic acid copolymerized compound, poly- (methyl) acrylate copolymer, poly- (hydroxyalkyl acrylates), poly- (hydroxyalky methyl acrylic acid
Ester), polyvinylpyrrolidone (PVP), Kollidone 90F, vinylpyrrolidone copolymer, PVP, ethene
Base pyrrolidone/vinyl acetate copolymers (copolyvidone), the co-polymer of vinyl acetate, the copolymerization of propionate
Thing, the copolymer of vinyl acetate and crotonic acid, polyethylene glycol, polyvinyl alcohol, the polyvinyl acetate of partial hydrolysis, gelatin,
Mosanom, soluble starch, Arabic gum, dextrin, hyaluronic acid, sodium chondroitin sulfate, propylene glycol alginate, agar, the Radix Astragali
Glue, xanthans, Eudragit E100, polyvinyl acetate-diethyl amino yl acetate, methacrylic acid
Ester copolymer, Eudragit L100, Eudragit L100D55, Eudragit S100, polyethylene glycol
(macrogol), copolymer, carragheen, the gala of polyoxyethylene, polyoxypropylene, oxirane (EO) and expoxy propane (PO) are sweet
Reveal glycan and combinations thereof.
6. the drug delivery system of claim 3, wherein the other polymers carrier is selected from hydroxypropyl methyl cellulose
(HPMC), polyethylene glycol (PEG), chitosan, PVP, PVP/VA, HPC, hydroxypropyl methyl cellulose acetate (HPMCAS),
Eudragit E100, the sun based on dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate
Ionic copolymer.
7. the drug delivery system of claim 3, wherein the surfactant includes negative, positive or amophoteric surface active
Agent, and selected from dodecyl sodium sulfate, lauryl sodium sulfate (SDS), NaLS (SLS), polyoxyethylene
Alcohol acid anhydride long-chain fatty acid ester, D-ALPHA-tocopheryl polyethylene glycol 1000 succinate, cholate, NaTDC, sodium glycocholate, polyoxyethylene polyoxypropylene glycol and
It is combined.
8. the drug delivery system of claim 1, it is selected from the drug delivery system based on nanometer technology, solid solution system and
Emulsion system.
9. the drug delivery system of claim 8, wherein the drug delivery system based on nanometer technology is selected from micella, nanometer
Particle, nanofiber and nano suspending liquid, and the solid solution system that is based on is selected from solid dispersions, extrudate and solid carrier
System.
10. the drug delivery system of claim 1, it is solid dispersion preparation.
11. the drug delivery system of claim 10, wherein the solid dispersions also contain TPGS 1000.
12. the drug delivery system of claim 1, it is micellar preparation.
13. the drug delivery system of claim 12, wherein the micellar preparation also contains TPGS1000.
14. the drug delivery system of claim 12 or 13, wherein the micella further containing other polymers carrier and water/
Buffer, and wherein the curcumin of effective dose is included in micella.
15. the drug delivery system of claim 12 or 13, wherein the micella further includes surfactant, solid phase adsorption
Agent, acidulant and/or antioxidant.
16. the preparation method of solid dispersion preparation, comprises the following steps：
Active component curcumin or derivatives thereof or its officinal salt are dispersed in polymer support and optional surfactant
In.
17. the preparation method of claim 16, it further comprises being selected from following step：Ice-melt bath stirring, film cooling, liquid
Nitrogen, spraying condensation, hot-melt extruded, MeltrexTM, melting cohesion or solvent evaporation (drying, vacuum drying, rotary evaporation, hot plate
Heating, spray drying, freeze-drying, supercritical anti-solvent, co-precipitation, electrostatic spinning, cold dry, ultrafast cold dry, liquid bed of spraying
Coating) and solvent melting.
18. the preparation method of micella, comprises the following steps：
By active component curcumin or derivatives thereof or its pharmaceutically acceptable salt, polymer support and surfactant, appoint
Choosing is dissolved in organic solvent, and organic solvent is removed by rotary evaporation, after film is formed, vacuum drying, adds buffer hydration,
It is ultrasonically treated.
19. the drug delivery system based on lipid, it includes active component curcumin or derivatives thereof or its is pharmaceutically acceptable
Salt and lipid.
20. the drug delivery system based on lipid of claim 19, wherein the lipid is triglycerides, including long-chain glycerine
Three esters (LCT), medium chain triglyceride (MCT) and short chain triglycerides (SCT), wherein long chain triglycerides are selected from hydrogenated soybean
Oil, hydrogenated vegetable oil, corn oil, olive oil, soya-bean oil, peanut oil and sesame oil, medium chain triglyceride be selected from from cupu oil or
The octanoic acid of palmit seed oil/certain herbaceous plants with big flowers acid glycerol three ester.
21. the drug delivery system based on lipid of claim 19, it also includes excipient, selected from chemical triglycerides, portion
Divide triglycerides, semi-synthetic oily ester and semi-synthetic nonionic surfactant ester.
22. the drug delivery system based on lipid of claim 19, it also includes water-insoluble excipient (D), selected from beeswax, oil
Acid, soya bean fatty acid, vitamin E ,-two-triglycerides of corn oil list, middle chain (C8/C10) monoglyceride and diglyceride, with
And the propylene glycol ester of aliphatic acid.
23. the drug delivery system based on lipid of claim 19, wherein the lipid is selected from Caproyl 90, Capmul
MCM and CaproylTMOne or more in PGMC.
24. the drug delivery system based on lipid of claim 19, its also include water-miscible organic solvent, surfactant,
Cosurfactant, Polymer compatibilizers, phosphatide and/or one or more additives.
25. the drug delivery system based on lipid of claim 24, wherein water-miscible organic solvent are selected from PEG 200-10,
000th, Polyvinylcaprolactame (PCL), polyvinyl acetate (PVA) or its copolymer, the vitamin E of water-soluble form and second
Alcohol；Surfactant be wherein aliphatic acid be insatiable hunger and/or saturation prandial oil derivative, it is anti-by PEG and hydrolyzing plant oil
Answer, alcohol and ethylene oxide reaction generate alkyl ether ethoxylate or vegetable oil and ethylene oxide based on polysorbate
React and synthesize；Cosurfactant is based on polyethylene glycol, polypropylene glycol, ethanol and glycerine；Polymer compatibilizers are selected from
Soluplus, chitosan, polyvinylpyrrolidone (PVP), PVP/VA, HPC, HPMC, HPMCAS, eudragit E100, it is based on
The cation copolymer of dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate.
26. the drug delivery system based on lipid of claim 25, wherein PEG 200-10,000 is selected from PEG 300, PEG
400, PEG 1,000 and PEG 6,000；Surfactant be selected from Cremophor RH 40, Labrasol, TPGS 1000,
Tween 20, Cremophor E1 and Tween 80；And cosurfactant be selected from PEG 300, PEG 400, propane diols,
Glycerine, ethanol, Transcutol HP and Transcutol P.
27. the drug delivery system based on lipid of claim 24, wherein the additive includes solid-phase adsorbent, water solubility
With fat-soluble antioxidant, acidulant, chelating agent, preservative, stabilizer and/or buffer, wherein solid-phase adsorbent includes silicon
Base adsorbent and non-silicon base adsorbent, silica-based adsorbent are selected from Aerosil 200 and Neusilin US2, and non-silicon base adsorbent is selected from
Microcrystalline cellulose, talcum, anhydrous phosphoric acid hydrogen dicalcium (DCPA), by alkylcellulose, hydroxy alkyl cellulose, hydroxyalkyl alkylcellulose
The water-soluble polymer of the groups such as plain sugar composition；Chelating agent is selected from ethylenediamine, calcium disodium chelate and ethylenediamine tetraacetic
At least one of acetic acid disodium；Acidulant is selected from citric acid, acetic acid, fumaric acid, hydrochloric acid and nitric acid；Buffer is selected from metaphosphoric acid
Potassium, potassium dihydrogen phosphate, sodium acetate, sodium citrate；Water-soluble or fat-soluble antioxidant is selected from ascorbic acid, ascorbic acid palm
Acid esters, butylated hydroxy anisole, butylated hydroxytoluene, hypophosphorous acid, thioglycerol, propylgallate, sodium ascorbate, sulfurous
Sour hydrogen sodium, rongalite, sulfoxylate, sodium pyrosulfite.
28. the drug delivery system based on lipid of claim 19, in addition to curcumin, it also includes CapryolTM PGMC、RH 40, Labrasol, TPGS 1000, Transcutol P and/or Aerosil 200.
29. the drug delivery system based on lipid of claim 19, it is selected from lipid soln, liposome suspension, surface work
Property agent or polymer-lipid mixing micella, self-emulsifying microemulsion drug delivery system (SMEDDS) and nanoemulsions preparation.
30. the drug delivery system based on lipid of claim 29, wherein SMEDDS is solid phase, in addition to solid-phase adsorbent.
31. the drug delivery system based on lipid of claim 30, wherein the solid absorbent is Aerosil 200.
32. the drug delivery system based on lipid of claim 29, wherein nanoemulsions preparation also include water and/or buffering
Agent.
33. the preparation method of any one of the claim 19-32 drug delivery system based on lipid, comprises the following steps：
Active component curcumin or its pharmaceutically acceptable salt are dissolved in into lipid, surfactant, or lipid to live with surface
In the mixture of property agent.
34. any one of claim 1-15 and 19-32 drug delivery system, it is solid dosage forms, selected from tablet, ring agent, patch
Agent, capsule, pill, granule, granula subtilis or pulvis, powder or band (strip), pass through oral, parenteral, suction, part
Or percutaneous, nose, intraocular, ear, rectum, vaginal approach administration.
35. any one of claim 1-15 and 19-32 drug delivery system, it is liquid dosage form, selected from solution, suspension,
Emulsion, the system based on cosolvent, aerosol, by oral, parenteral, suction, local or percutaneous, intranasal, intraocular, ear, straight
Intestines, vaginal approach administration.
36. any one of claim 1-15 and 19-32 drug delivery system, it is semisolid dosage form, selected from selected from ointment, frost
Agent, gel, paste, are administered by external application or percutaneous, rectum, vaginal approach, for locally or systemically purpose.
37. any one of claim 1-15 and 19-32 drug delivery system, it also includes pharmaceutically acceptable excipient, the figuration
Agent is selected from disintegrant, lubricant, glidant, antitack agent, inert filler, wetting agent, pH modifying agent, adhesive, solubility and changed
Property agent, recrystallization inhibition agent, diluent and combinations thereof.
38. any one of claim 1-15 and 19-32 drug delivery system, wherein in liquid preparation, the content of curcumin
For 0.001-1000mg/ml, either 0.1-100mg/ml or 10-20mg/ml, and in solid pharmaceutical preparation, the dosage of curcumin
For 0.001-1000mg/ units, either 0.1-100mg/ units or 10-20mg/ units.
39. any one of claim 1-15,19-32 and 34-38 drug delivery system are being prepared for anti-oxidant, anti-inflammatory, resisted
Cancer, inducing cell apoptosis, anti-angiogenesis, neuroprotection, antimicrobial, liver protection shield kidney, suppress vascularization, prevention heart infarction,
Application in hypoglycemic, antirheumatic medicine.
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