CN109453148A - A kind of curcumin eutectic composition and preparation method thereof - Google Patents
A kind of curcumin eutectic composition and preparation method thereof Download PDFInfo
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- CN109453148A CN109453148A CN201811519844.1A CN201811519844A CN109453148A CN 109453148 A CN109453148 A CN 109453148A CN 201811519844 A CN201811519844 A CN 201811519844A CN 109453148 A CN109453148 A CN 109453148A
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- 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
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
- A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- 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]
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- 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
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- 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
Abstract
The invention belongs to curcumin preparation fields, more particularly to a kind of curcumin eutectic composition and preparation method thereof, composition includes each substance of following parts by weight: 1 part of acarbose, 00-2500 parts of amino acid 1, curcumin -10-50 parts of 2,5-dihydroxybenzoic acid cocrystalization compound.The composition realizes the residence time improved curcumin in vivo and degree of absorption in a manner of coating, and improves the vivo biodistribution availability of curcumin.
Description
Technical field
The invention belongs to curcumin preparation fields, and in particular to a kind of curcumin eutectic composition and preparation method thereof.
Background technique
Curcumin is a kind of polyphenol compound extracted from the rhizome of herbaceos perennial turmeric, traditional
Curcumin is typically all to be used as food dye and additive.In recent years, largely research shows that curcumin has extensive physiology
Active function, such as it is reducing blood lipid, antitumor, anti-inflammatory, cholagogue, anti-oxidant.However curcumin category fat-soluble compound, it is insoluble in
Water is also oxidized easily in vitro, absorbs few, tachytrophism (elimination half-life period is only 7.4min in blood plasma) in vivo, stable
Property is poor, constrains extensive use of the curcumin in clinic.
In recent years, about the dosage form of curcumin mainly have micro emulsion, microballoon, solid dispersions, liposome, phosphatide complexes,
Micella, nanoparticle and cyclodextrin inclusion compound etc..Above method although there is certain improvement in terms of dissolution or oral absorption,
There is deficiency, if complex process, drugloading rate are low, obtained nano particles are inhomogenous, and using a large amount of organic in preparation process
Reagent has the problems such as genotoxic potential.To further increase the bioavilability and curative effect of curcumin in vivo, need in drug crystalline substance
Type, drug combination and dosage form etc. carry out further investigation.
Drug cocrystallization technology has caused academia, industry and the extensive concern for treating boundary, it passes through hydrogen bond, π-
Pi accumulation effect, Van der Waals force and halogen key make active pharmaceutical ingredient in conjunction with eutectic precursor, are not changing medicines structure and medicine itself
It manages in active situation, the new crystal of formation can be improved the stability of drug, change its fusing point, improve its dissolubility, reduce
It draws moist, slows down its release and dissolution rate, improve its bioavilability (Almarsson M., Zaworotko J.,
Chem.Commun.2004:1889)。
There is the enzyme that various digestive ferments and intestinal bacterium clump generate in gastrointestinal mucosal, they can be such that drug not yet absorbs
Metabolic response and loss of activity just occur in alimentary canal.Acarbose is effective alpha-glucosidase inhibitors, it can pass through
Increase membrane fluidity and change enzyme kinetics, inhibit P- glycoprotein and glucuronic acid enzymatic activity, adjusts the ways such as gastro-intestinal Fluid secretion
Diameter delays curcumin to be metabolized.Amino acid is the base substance of protein needed for constituting Animal nutrition.Come in research shows that amino acid
Treatment hepatopathy disease, disease of digestive tract, cardiovascular and cerebrovascular diseases and for improve in muscle vitality and treatment of cancer have it is obvious
Effect.
Summary of the invention
The application provides a kind of curcumin eutectic composition and preparation method thereof, improves curcumin in vivo stagnant to realize
Time and degree of absorption are stayed, the vivo biodistribution availability of curcumin is improved.
To realize the above-mentioned technical purpose, the technical solution that the application takes is a kind of curcumin eutectic composition, including such as
Each substance of lower parts by weight:
1 part of acarbose
00-2500 parts of amino acid 1
10-50 parts of dihydroxybenzoic acid cocrystal compound of curcumin -2,5-.
The another object of the application is to provide a kind of preparation method of curcumin eutectic composition, includes the following steps:
It is passed through after the curcumin -2,5- dihydroxybenzoic acid cocrystal compound of proportional quantity is mixed with acarbose liquefied
CO2, and be uniformly dispersed to obtain mixture；
Mixture is pumped into high pressure crystal kettle, after adjusting temperature and pressure to preset value, is pumped into ammonia into high pressure crystal kettle
Base aqueous acid；
Continue to be passed through CO into high pressure crystal kettle2, and keep temperature and pressure in autoclave until water has been dried
Finish, stopping is pumped into CO2, dry sample is obtained after pressure is down to normal pressure.
As the improved technical solution of the application, the amino acid is glutamic acid, arginine, asparatate, Guang ammonia
One of acid, L-3,4 dihydroxyphenylalanine amino acid are a variety of.
As the improved technical solution of the application, the amino acid solution concentration is 50-100mg/ml.
As the improved technical solution of the application, autoclave preset temperature in reaction is 35-50 DEG C.
As the improved technical solution of the application, autoclave preset pressure in reaction is 10-20MPa.
As the improved technical solution of the application, the flow velocity that amino acid solution is pumped into autoclave is 2ml/min.
Beneficial effect
The application compounds acarbose, amino acid with curcumin cocrystalization compound, can both significantly improve curcumin and exist
Intracorporal residence time and degree of absorption improve the vivo biodistribution availability of curcumin, and can be played and be assisted by drug combination
With the effect for the treatment of, there is important clinical meaning.
The application uses supercritical anti-solvent crystallization technique, and curcumin eutectic and acarbose are dispersed in liquid under high pressure
Change CO2In, while CO2Effectively the amino acid solution sprayed from nozzle can be separated into rapidly as anti-solvent smaller
Drop contributes to form smaller nano particle.Curcumin nano particle (CN is prepared with existing super-critical crystallization technology
103705468 A, a method of nanocurcumin particle is prepared using ultrasonic wave auxiliary supercritical anti-solvent) compare, this Shen
Any organic solvent is not used during preparing curcumin eutectic composition please, avoids the problem that dissolvent residual.
To sum up, the present invention prepares curcumin cocrystalization compound using pharmaceutical co-crystals technology, in the medicine for inheriting curcumin itself
On the basis of reason activity, dissolubility, the stability of curcumin can obviously improve.
Curcumin eutectic composition nano particle, preparation method operation letter are prepared using supercritical anti-solvent crystallization technique
Single, treatment conditions are mildly controllable, and no solvent residue.
Specific embodiment
To keep purpose and the technical solution of the embodiment of the present invention clearer, below in conjunction with the embodiment of the present invention, to this
The technical solution of invention is clearly and completely described.Obviously, described embodiment is a part of the embodiments of the present invention,
Instead of all the embodiments.Based on described the embodiment of the present invention, those of ordinary skill in the art are without creativeness
Every other embodiment obtained, shall fall within the protection scope of the present invention under the premise of labour.
Chemical drug development of Chinese herb products direction all turns to compound preparation exploitation, such as hepatitis C (cure rate of lucky moral exploitation at present
99%) what is used is all the combination of several small molecule chemical drugs, and the cocktail therapy there are also AIDS is adopted by compound preparation
Coordinating effect between playing drug component with the mode of drug combination.
The object of the invention is to utilize pharmaceutical co-crystals skill to overcome defect present in prior art preparation curcumin
Art and supercritical carbon dioxide anti-solvent crystallization technique construct curcumin eutectic composition nano particle, are improving curcumin itself
While physicochemical property (dissolubility, stability and the bioavilability of curcumin), the respective curative effect of drug can be played even
Play the effect of synergistic treatment.
Curcumin cocrystalization compound is synthesized particular by pharmaceutical co-crystals technology, curcumin itself can be improved and be insoluble in water
The problem of；It is aided with acarbose and can be avoided curcumin and is destroyed and first pass effect by pipe intestinal digesting enzyme；The cladding of amino acid is made
It is protected with that can be formed to content, improves stability of the curcumin under illumination and high temperature；It will by super-critical crystallization technology
Three organically combines to form Nano composite granules, and the association of respective drug effect can also be realized while improving curcumin physicochemical property
With performance.
Curcumin eutectic composition involved in the application includes each substance of following parts by weight:
1 part of acarbose
00-2500 parts of amino acid 1
10-50 parts of dihydroxybenzoic acid cocrystal compound of curcumin -2,5-.
Curcumin eutectic composition described herein is prepared using following steps:
It is total according to the synthesis curcumin -2,5- dihydroxy-benzoic acid of preparation method disclosed in 107827724 A of Chinese patent CN
Brilliant compound.
Curcumin -2,5- dihydroxybenzoic acid cocrystal compound and acarbose are passed through liquefaction after mixing according to a certain percentage
CO2It is allowed to evenly dispersed.The mass ratio of the curcumin cocrystalization compound and acarbose is 50:1-10:1.
By liquefied CO2(containing curcumin cocrystalization compound and acarbose) is pumped into high pressure crystal kettle, adjust temperature and
After pressure to preset value (preset temperature is 35-50 DEG C, preset pressure 10-20MPa), and stablize a period of time, the time generally appoints
Meaning, but the following embodiments of the application mainly use and stablize 5min；The good amino sour water of configured in advance is pumped into the flow velocity of 2ml/min
Solution.Amino acid in the amino acid solution is glutamic acid, arginine, asparatate, cystine, L-3,4 dihydroxyphenylalanine amino
One of acid or any mass ratio it is a variety of.The mass ratio of the amino acid and curcumin cocrystalization compound is 10:1-50:
1.The amino acid solution concentration is 50-100mg/ml.
The flow velocity substantial scope that amino acid solution is pumped into high pressure crystal kettle is 1-3ml/min, and the application produces to control
Product encapsulation rate, is selected as 2ml/min.
After amino acid solution has pumped, continue to be passed through CO2, and keep temperature and pressure in autoclave until inciting somebody to action
Water drying finishes, and stopping is pumped into CO2, dry sample is obtained after pressure is down to normal pressure.
Embodiment 1
It is protected from light and lower curcumin cocrystalization compound (curcumin -2,5- dihydroxy-benzoic acid) and acarbose is distributed to liquefaction
CO2In, the mass ratio of curcumin cocrystalization compound and acarbose is 50:1.By CO2(containing curcumin and acarbose) pump
Enter in autoclave, after temperature of reaction kettle reaches 35 DEG C, pressure is 10MPa preset value and stabilization 5min, with 2ml/min
Flow velocity be pumped into the glutamic acid aqueous solution that concentration is 50mg/ml, the mass ratio of Glutamic Acid and curcumin cocrystalization compound is
10:1.After solution pump is complete, continue to be passed through CO2After 0.5h, stopping is passed through CO2, pressure release collects the particle in reaction kettle to get arriving
Curcumin eutectic composition nano particle.Its average grain diameter is 280nm, encapsulation rate 95%.
Embodiment 2
It is protected from light and lower curcumin cocrystalization compound and acarbose is distributed to liquefied CO2In, curcumin cocrystalization compound
Mass ratio with acarbose is 50:1.By CO2(containing curcumin and acarbose) is pumped into autoclave, to reaction kettle
After temperature reaches 35 DEG C, pressure is 10MPa preset value and stable 5min, concentration is pumped into as 100mg/ with the flow velocity of 2ml/min
The cystine and L-3,4 dihydroxyphenylalanine amino acid solution (cystine and L-3,4 dihydroxyphenylalanine amino acid masses ratio be 1:1) of ml, wherein amino acid and
The mass ratio of curcumin cocrystalization compound is 50:1.After solution pump is complete, continue to be passed through CO2After 0.5h, stopping is passed through CO2, pressure release,
The particle in reaction kettle is collected to get curcumin eutectic composition nano particle is arrived.Its average grain diameter is 350nm, and encapsulation rate is
93%.
Embodiment 3
It is protected from light and lower curcumin cocrystalization compound and acarbose is distributed to liquefied CO2In, curcumin cocrystalization compound
Mass ratio with acarbose is 30:1.By CO2(containing curcumin and acarbose) is pumped into autoclave, to reaction kettle
After temperature reaches 50 DEG C, pressure is 15MPa preset value and stable 5min, concentration is pumped into as 60mg/ml with the flow velocity of 2ml/min
Arginine aqueous solution, wherein the mass ratio of arginine and curcumin cocrystalization compound be 40:1.After solution pump is complete, continue to be passed through
CO2After 0.5h, stopping is passed through CO2, pressure release, collect reaction kettle in particle to get arrive curcumin eutectic composition nano particle.
Its average grain diameter is 170nm, encapsulation rate 96%.
Embodiment 4
It is protected from light and lower curcumin cocrystalization compound and acarbose is distributed to liquefied CO2In, curcumin cocrystalization compound
Mass ratio with acarbose is 10:1.By CO2(containing curcumin and acarbose) is pumped into autoclave, to reaction kettle
After temperature reaches 40 DEG C, pressure is 20MPa preset value and stable 5min, concentration is pumped into as 80mg/ml with the flow velocity of 2ml/min
Asparagine aqueous acid, wherein the mass ratio of asparatate and curcumin be 20:1.After solution pump is complete, continue to be passed through
CO2After 0.5h, stopping is passed through CO2, pressure release, collect reaction kettle in particle to get arrive curcumin eutectic composition nano particle.
Its average grain diameter is 130nm, encapsulation rate 97%.
Efficacy test verifying:
The application can be put down to Oral Administration in Rats curcumin suspension, curcumin commercial preparation rouge respectively and the ginger of the application preparation
Flavine composite nanometer particle carries out drug biologic test.
Test procedure: taking the male Wistar rat (free water during fasting and test) of 30 fasting 12h, random flat
Three groups are divided into, curcumin suspension (curcumin is directly dispersing in purified water), curcumin commercial preparation are given in stomach-filling respectively
Rouge can put down (Shijiazhuang martial prowess medicine company) and self-control curcumin eutectic composition nano particle.
Every rat dosage is 200mg/kg, respectively after administration 5,10,20,30,60,120,180,240,
300,360,480,600 and 720min eye socket takes blood about 0.3mL, sets in the centrifuge tube for be coated with heparin and is handled, and asks calculation
The blood concentration of drug.
Test result: after rat single dose stomach-filling 200mg/kg curcumin, the C of gained curcumin suspensionmaxFor 0.179 μ
G/mL, AUC(0-∞)For 0.28 μ g/mLh；Stomach-filling curcumin commercial preparation rouge can put down after CmaxFor 0.485 μ g/mL, AUC(0-∞)
For 0.716 μ g/mLh；And C after stomach-filling self-control curcumin eutectic composition nano particlemaxFor 1.241 μ g/mL, AUC(0-∞)For
1.67μg/mL·h。
Conclusion (of pressure testing): comparison is it is found that the curcumin eutectic composition nano particle of this patent preparation is mixed compared to curcumin
Suspension and commercial preparation can significantly improve the oral administration biaavailability of curcumin.
The above is only embodiments of the present invention, and the description thereof is more specific and detailed, and but it cannot be understood as right
The limitation of the invention patent range.It should be pointed out that for those of ordinary skill in the art, not departing from the present invention
Under the premise of design, various modifications and improvements can be made, these are all belonged to the scope of protection of the present invention.
Claims (7)
1. a kind of curcumin eutectic composition, which is characterized in that each substance including following parts by weight:
1 part of acarbose
00-2500 parts of amino acid 1
10-50 parts of dihydroxybenzoic acid cocrystal compound of curcumin -2,5-.
2. a kind of preparation method based on curcumin eutectic composition described in claim 1, which is characterized in that including walking as follows
It is rapid:
Liquefied CO is passed through after the curcumin -2,5- dihydroxybenzoic acid cocrystal compound of proportional quantity is mixed with acarbose2,
And it is uniformly dispersed to obtain mixture；
Mixture is pumped into high pressure crystal kettle, after adjusting temperature and pressure to preset value, is pumped into amino acid into high pressure crystal kettle
Aqueous solution；
Continue to be passed through CO into high pressure crystal kettle2, and temperature and pressure in autoclave is kept to finish up to water is dry, stop
Only it is pumped into CO2, dry sample is obtained after pressure is down to normal pressure.
3. the preparation method of curcumin eutectic composition according to claim 2, which is characterized in that the amino acid is
One of glutamic acid, arginine, asparatate, cystine, L-3,4 dihydroxyphenylalanine amino acid are a variety of.
4. the preparation method of curcumin eutectic composition according to claim 2, which is characterized in that the amino acid is water-soluble
Liquid concentration is 50-100mg/ml.
5. the preparation method of curcumin eutectic composition according to claim 2, which is characterized in that autoclave is anti-
Seasonable preset temperature is 35-50 DEG C.
6. the preparation method of curcumin eutectic composition according to claim 2, which is characterized in that autoclave is anti-
Seasonable preset pressure is 10-20MPa.
7. the preparation method of curcumin eutectic composition according to claim 2, which is characterized in that amino acid solution pump
The flow velocity for entering autoclave is 2ml/min.
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Cited By (1)
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| CN110668932A (en) * | 2019-09-10 | 2020-01-10 | 刘湖 | Co-crystal, preparation method thereof, pharmaceutical composition containing co-crystal and application thereof |
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| CN110668932B (en) * | 2019-09-10 | 2023-11-03 | 刘湖 | Co-crystal, preparation method, pharmaceutical composition containing co-crystal and application |
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