CN105561329A - Cyclodextrin triad-supramolecular inclusion compound compounded by water-soluble coenzymes Q10 and alpha-lipoic acid and preparing method - Google Patents
Cyclodextrin triad-supramolecular inclusion compound compounded by water-soluble coenzymes Q10 and alpha-lipoic acid and preparing method Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
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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
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
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Abstract
The invention discloses a cyclodextrin triad-supramolecular inclusion compound compounded by water-soluble coenzymes Q10 and alpha-lipoic acid and a preparing method, and belongs to the technical field of medicines and health care products. The cyclodextrin triad-supramolecular inclusion compound compounded by the water-soluble coenzymes Q10 and the alpha-lipoic acid is prepared from the coenzymes Q10, the alpha-lipoic acid and cyclodextrin in the weight ratio of 1:(0.5-1):(5-20). According to the cyclodextrin triad-supramolecular inclusion compound, a compound of the coenzymes Q10 and the alpha-lipoic acid is subjected to polymolecular inclusion through the cyclodextrin, the cyclodextrin triad-supramolecular inclusion compound compounded by the coenzymes Q10 and the alpha-lipoic acid is formed, and the cyclodextrin triad-supramolecular inclusion compound has the advantages of being high in water solubility, high in bioavailability and good in stability.
Description
Technical field
The present invention relates to a kind of water-soluble coenzyme Q
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid and preparation method, this clathrate has better therapeutical effect to diseases such as cardiovascular disease, diabetes, hypoimmunities, and it belongs to medicine, health product technology field.
Background technology
Ubiquinone
10have another name called ubiquinone, also referred to as Ubiquinone, ubiquinol, CoenzymeQ10, Ubiquinone, English name is CoenzymeQ
10, Ubiquinone, molecular formula is C
59h
90o
4, chemical formula is 2-(3,7,11,15,19,23,27,31,35,39-methyl in the last of the ten Heavenly stems-2,6,10,14,18,22,26,30,34,38-40 decene base)-5,6-dimethoxy-3-methyl-p-benzoquinone, this material is the autologous material of human body, is also extensively present in the organs such as animal hearts, can extract and obtain, also can be obtained by chemosynthesis, biosynthesis from animal hearts.Ubiquinone
10it is indispensable important physiologically substance in human body, its chemical constitution feature determines it in human body, has many important physiological function, it is energy delivery material important in vital movement, be the critical substances of mitochondrial respiratory chain rate-limiting reaction, play a significant role in cellular energy generation, enhancing biologos.Containing ubiquinone in human body
10total amount is 500-1500mg, within about 20 years old, peaks, then reduces rapidly, and 70 years old reduces 57% than 20 years old youngster later.Research finds, in a lot of diseased patient, and ubiquinone
10physiological level declines obviously, as in Patients with Cardiac Failure (HF), and ubiquinone in patient's cardiac muscle and blood
10content obviously reduces, and supplements ubiquinone from external source
10after, obviously improve patient symptom.Research finds, the patient of a lot of hypoimmunity, its ubiquinone
10physiological level is lower, supplements ubiquinone
10after, symptom improves.Therefore, human body supplements ubiquinone from external source
10, treat various ubiquinone
10physiological level lowly becomes a kind of generally acknowledged clinical treatment.Alpha-lipoic acid (alphalipoicacid) is sulfur-bearing eight carbon fat acid, that one is present in mitochondrial enzyme, similar vitamin, can eliminate accelerated ageing and the free radical caused a disease, 6,8 have disulfide bond be connected (hydrogen atom on C6 and C8 is replaced by disulfide bond).Extensively be present in the prokaryotic cell of all kinds and eukaryotic cell with compound form and participate in energy metabolism, it is a kind of cofactors, be called as " universal antioxidant ", free radical hunter especially, be that body cell utilizes the restricted required nutrient substance of the one needed for saccharide equal energy source material produce power, be widely used in treatment and the various diseases such as prevention of cardiac, diabetes.It is generally acknowledged that it can preserve and regenerate other antioxidant, as vitamin C and E etc., and can balance blood sugar concentration.Effective enhancing vivo immuning system, from the destruction in free radical.
Medical research finds, ubiquinone
10(CoQ
10) with thioctic acid, there is good synergism, thioctic acid (ALA) is rapidly absorbed into after in body, can change into rapidly dihydrolipoic acid (DHLA) in cell, DHLA regenerates other endogenous antioxidant as vitamin E and vitamin C and ubiquinone by redox couple
10.Research display, conbined usage ALA and CoQ
10can obvious oxidation resistance and improve human body energy balance in lifting body.
Ubiquinone
10are all liposoluble substances with alpha-lipoic acid, be insoluble in water, both are to light, heat, water unstable, and oral administration bioavailability is lower, and alpha-lipoic acid taste has pungent and sulfur stink, oral beyond affordability, stimulating gastrointestinal road.For this situation, develop the method for multiple raising oral administration bioavailability and taste masking in recent years, as inclusion technique, self emulsifying technology, liposome etc.Inclusion technique solves ubiquinone
10with a better method of alpha-lipoic acid dissolubility, existing patent and bibliographical information ubiquinone at present
10cyclodextrin clathrate and alpha-lipoic acid alpha-cyclodextrin clathrate, but there is no ubiquinone
10the cyclodextrin Ternary complex thing pertinent literature composite with alpha-lipoic acid or patent.Often ubiquinone is needed due to clinical
10with alpha-lipoic acid with the use of, and ubiquinone
10with alpha-lipoic acid because bioavailability and pungent flavour problems limit application, if used containing ubiquinone in the formulation simultaneously
10when cyclodextrin clathrate and alpha-lipoic acid cyclodextrin clathrate, or it is clinical when taking both clathrates simultaneously, likely there is molecule under appropriate conditions and again identify and to replace with enclose in both, and inclusion phenomenon again, cause part of compounds free out, cause product instability and absorb declining.If formation ubiquinone
10with the cyclodextrin Ternary complex thing of alpha-lipoic acid complex, it will be one of approach of addressing this problem.Ubiquinone
10larger difference is had, for this ubiquinone with alpha-lipoic acid chemical constitution
10this two kinds of independent enclose of compound will be different from completely with the enclose process of alpha-lipoic acid complex.The ubiquinone that possible enclose is formed
10with the composite cyclodextrin clathrate of alpha-lipoic acid by being a kind of new Ternary complex thing material, it is the better scheme that solves the problem.Do not retrieve the patent and the literature research report that both composite compounds are carried out to enclose at present.The document published at present, what associate with this patent through retrieval has following patent and document: 1. in document JournalActaPoloniaePharmaceutica (1995), vol.52, No.5, pp.379-386 and 1996, describe in vol.53, No.3, pp.193-196. and adopt stirring means to prepare ubiquinone
10gamma-cyclodextrin clathrate.2. United States Patent (USP) 6861447, which discloses the method preparing gamma-cyclodextrin clathrate.3. world patent WO2005/111224 discloses a kind of new ubiquinone
10benexate Hydrochloride preparation method, adopt paddling process preparation, the production time needs the time of 20 hours just can complete.4. Chinese patent CN200510048010.3 discloses a kind of water-soluble coenzyme Q
10the technology of preparing of compositions, relates to the technology of gamma-cyclodextrin and mannitol solid dispersion.5. Chinese patent CN200510100243 discloses clathrate compound of alpha-lipoic acid-cyclodextrin derivatives and preparation method thereof, and 6. Chinese patent ZL200610046307.0 discloses a kind of water-soluble coenzyme Q
10hydroxypropyl-beta-cyclodextrin inclusion and preparation method, above patent documentation does not all relate to the technology of the present invention.
Summary of the invention
The present invention is exactly to solve the problems of the technologies described above, and a kind of water-soluble coenzyme Q provided
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid and preparation method, the present invention adopts cyclodextrin to ubiquinone
10carry out polymolecular enclose with alpha-lipoic acid complex, define ubiquinone
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid, it has the feature of larger water solublity and higher bioavailability, clathrate good stability.
Water-soluble coenzyme Q
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid, it is prepared from by weight by following raw material: ubiquinone
10: alpha-lipoic acid: cyclodextrin=1: 0.5-1: 5-20.
Water-soluble coenzyme Q of the present invention
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid, preferred following raw material is prepared from by weight: ubiquinone
10: alpha-lipoic acid: cyclodextrin=1: 0.5-1: 10-15.
Above-mentioned cyclodextrin is gamma-cyclodextrin, beta-schardinger dextrin-or HP-β-CD.
A kind of above-mentioned water-soluble coenzyme Q
10the preparation method of the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid, its processing step is as follows: get cyclodextrin by described weight ratio, mix with the water being equivalent to cyclodextrin 3-5 times weight, be heated to 50 DEG C-60 DEG C, add the ubiquinone meeting above-mentioned weight ratio
10and alpha-lipoic acid, stir into pasty state, put into colloid mill, circular grinding 10-30 minute, release lapping liquid, add water to solid content and reach 15%, spraying dry obtains water-soluble coenzyme Q
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid.
Processing step is as follows: get cyclodextrin by described weight ratio, in high-shear homogenizer, is dissolved in the water being equivalent to cyclodextrin 50 times of weight, is heated to 50-60 DEG C, will meet the ubiquinone of above-mentioned weight ratio
10solution is become, by ubiquinone with alpha-lipoic acid dissolve with ethanol
10join in high-shear homogenizer with alpha-lipoic acid solution, turn with 10000-20000 and carry out high-speed stirred shearing 5-10 minute, blowing enters high pressure homogenizer, and with 60-100Mpa circulation 3-5 time, blowing, then carries out spraying dry, obtains ubiquinone
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid.
The consumption of above-mentioned ethanol is ubiquinone
10with alpha-lipoic acid gross weight 9-11 weight doubly.
Getting above-mentioned ternary super molecule inclusion compound adopts common process to be prepared into oral tablet or capsule.
Owing to adopting technique scheme, the present invention is made to have following features and effect:
The water-soluble coenzyme Q that the present invention obtains
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid has following feature: it is a kind of containing ubiquinone
10with the cyclodextrin ternary super molecule inclusion compound of thioctic acid, host and guest's molecule Inclusion ratio is ubiquinone
10: alpha-lipoic acid: cyclodextrin=1: 1: 7-8, color is faint yellow, has comparatively highly-water-soluble and stability, with ubiquinone
10compared with alpha-lipoic acid raw material, there is higher bioavailability.
The ubiquinone that the present invention obtains
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid is not simple physical mixture, and it is a kind of ternary super molecule inclusion compound be grouped into by three kinds of one-tenth, has and is different from ubiquinone
10feature with alpha-lipoic acid, cyclodextrin physical mixture, is also different from ubiquinone
10cyclodextrin clathrate and alpha-lipoic acid cyclodextrin clathrate physical mixture are a kind of new clathrate materials.This proves mainly through following method, by clathrate of the present invention, and ubiquinone
10with alpha-lipoic acid cyclodextrin and their physical mixture, do thermal analyses (DSC) and high performance liquid chromatography, result shows, clathrate thing phase DSC collection of illustrative plates of the present invention is different from other several material thing phase collection of illustrative plates and physical mixture collection of illustrative plates, ubiquinone in new clathrate DSC collection of illustrative plates
10disappear with the fusing point peak of alpha-lipoic acid, prove ubiquinone of the present invention
10a kind of new clathrate thing phase is defined with alpha-lipoic acid clathrate.High performance liquid chromatography shows new clathrate and contains ubiquinone
10with alpha-lipoic acid composition.Through thermal analyses DSC and high-performance liquid chromatogram determination, clathrate host and guest molecule Inclusion ratio of the present invention is ubiquinone
10: alpha-lipoic acid: cyclodextrin=1: 1: 7-8, the clathrate of formation mainly by the cavity more than 7 cyclodextrin moleculars, by ubiquinone
10load with alpha-lipoic acid molecular moiety group, or to ubiquinone
10graviational interaction between molecule, forms ubiquinone
10with the cyclodextrin tri compound super molecule inclusion compound of alpha-lipoic acid.
Clathrate of the present invention due to water soluble group more, and present larger water solublity and higher bioavailability.Clathrate stability of the present invention is better than ubiquinone
10with alpha-lipoic acid monomer molecule, be also better than both clathrate stabilized with mixture.Clathrate of the present invention eliminates the pungent taste of thioctic acid.
Ubiquinone of the present invention
10adopt high performance liquid chromatography with the clathrate content assaying method of alpha-lipoic acid, method gets ubiquinone
10the Ternary complex thing composite with alpha-lipoic acid is appropriate, and a small amount of washed with diethylether, volatilizes ether, adds a small amount of water-soluble loose, ultrasonic with ethanol heating, lets cool after being settled to normal concentration, filters, get subsequent filtrate as need testing solution, sample introduction, chromatographic condition: ubiquinone
10: C18 post, mobile phase is acetonitrile: oxolane: water=55: 40: 5 (volume ratios), determined wavelength 275nm, and quantified by external standard method, to obtain final product; Alpha-lipoic acid: C18 post, mobile phase is acetonitrile: 0.1% phosphoric acid=40: 60 (volume ratios), and determined wavelength 220nm, quantified by external standard method, to obtain final product.
Thermal analyses (DSC) measures: get ubiquinone
10, alpha-lipoic acid, cyclodextrin and their mixture, ubiquinone
10cyclodextrin clathrate and alpha-lipoic acid cyclodextrin clathrate, ubiquinone of the present invention
10beta-schardinger dextrin-Ternary complex thing, the ubiquinone composite with alpha-lipoic acid
10the gamma-cyclodextrin Ternary complex thing composite with alpha-lipoic acid and ubiquinone
10the each 5mg of Ternary complex thing of the HP-β-CD composite with alpha-lipoic acid (clathrate is after wash by ether, dry, resampling), tabletting, carry out thermal analyses (DSC) and measure, the results are shown in Figure 1, Fig. 2, Fig. 3, Fig. 4, Fig. 5, Fig. 6, Fig. 7, Fig. 8, Fig. 9, Figure 10 and Figure 11, Figure 12, Figure 13.
Accompanying drawing explanation
Fig. 1 is Q
10raw material DSC spectrogram.
Fig. 2 is alpha-lipoic acid DSC spectrogram.
Fig. 3 is beta-schardinger dextrin-DSC spectrogram.
Fig. 4 is gamma-cyclodextrin DSC spectrogram.
Fig. 5 is hydroxypropyl
-beta-schardinger dextrin-DSC spectrogram.
Fig. 6 is beta-schardinger dextrin-, ubiquinone
10, alpha-lipoic acid-physical mixture DSC spectrogram.
Fig. 7 is gamma-cyclodextrin, Q
10, alpha-lipoic acid-physical mixture DSC spectrogram.
Fig. 8 is HP-β-CD, Q
10, alpha-lipoic acid physical mixture DSC spectrogram.
Fig. 9 is embodiment 1,2,3 ubiquinone
10with alpha-lipoic acid, beta-schardinger dextrin-ternary super molecule inclusion compound DSC spectrogram.
Figure 10 is embodiment 6,10,18 ubiquinone
10with alpha-lipoic acid, gamma-cyclodextrin ternary super molecule inclusion compound DSC spectrogram.
Figure 11 is embodiment 7,9,19 ubiquinone
10with alpha-lipoic acid, HP-β-CD ternary super molecule inclusion compound DSC spectrogram.
Figure 12 is ubiquinone
10benexate Hydrochloride DSC spectrogram.
Figure 13 is the Benexate Hydrochloride DSC spectrogram of alpha-lipoic acid.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described further.Following examples are only several specific embodiment of the present invention, but design concept of the present invention is not limited thereto, and all changes utilizing this design the present invention to be carried out to unsubstantiality, all should belong to the behavior of invading scope.
Method in following embodiment, if no special instructions, is conventional method.
Embodiment 1
Water-soluble coenzyme Q of the present invention
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid, it is prepared from by weight by following raw material, ubiquinone
10: alpha-lipoic acid: beta-schardinger dextrin-=1: 0.5: 5.
Get beta-schardinger dextrin-50 mass parts, add the mixing of the water of 150 mass parts, be heated to 50 DEG C, then add 10 mass parts ubiquinones
10and 5 mass parts alpha-lipoic acids, stir into pasty state, put into colloid mill, circular grinding 10 minutes, blowing, carry out vacuum drying or spraying dry or lyophilization, obtain water-soluble coenzyme Q
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid.
Embodiment 2
Water-soluble coenzyme Q of the present invention
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid, it is prepared from by weight by following raw material, ubiquinone
10: alpha-lipoic acid: beta-schardinger dextrin-=1: 1: 10.
Get beta-schardinger dextrin-100 mass parts, add the mixing of the water of 300 mass parts, be heated to 50 DEG C, then add 10 mass parts ubiquinones
10and 10 mass parts alpha-lipoic acids, stir into pasty state, put into colloid mill, circular grinding 10 minutes, blowing, carry out vacuum drying or spraying dry or lyophilization, obtain water-soluble coenzyme Q
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid.
Embodiment 3
Water-soluble coenzyme Q of the present invention
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid, it is prepared from by weight by following raw material, ubiquinone
10: alpha-lipoic acid: beta-schardinger dextrin-=1: 1: 20.
Get beta-schardinger dextrin-200 mass parts, add the mixing of the water of 700 mass parts, be heated to 55 DEG C, then add 10 mass parts ubiquinones
10and 10 mass parts alpha-lipoic acids, stir into pasty state, put into colloid mill, circular grinding 20 minutes, blowing, carry out vacuum drying or spraying dry or lyophilization, obtain water-soluble coenzyme Q
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid.
Get clathrate 1000g, by every heavy 0.3g, record capsule, must capsule be recorded.
Embodiment 4
Water-soluble coenzyme Q of the present invention
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid, it is prepared from by weight by following raw material, ubiquinone
10: alpha-lipoic acid: beta-schardinger dextrin-=1: 1: 15.
Get beta-schardinger dextrin-150 mass parts, add the mixing of the water of 750 mass parts, be heated to 60 DEG C, then add 10 mass parts ubiquinones
10and 10 mass parts alpha-lipoic acid stir into pasty state, put into colloid mill, circular grinding 30 minutes, blowing, carry out vacuum drying or spraying dry or lyophilization, obtain water-soluble coenzyme Q
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid.
Embodiment 5
Water-soluble coenzyme Q of the present invention
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid, it is prepared from by weight by following raw material, ubiquinone
10: alpha-lipoic acid: gamma-cyclodextrin=1: 0.5: 10.
Get gamma-cyclodextrin 100 mass parts, add the mixing of the water of 500 mass parts, be heated to 53 DEG C, then add 10 mass parts ubiquinones
10and 5 mass parts alpha-lipoic acid stir into pasty state, put into colloid mill, circular grinding 15 minutes, blowing, carry out vacuum drying or spraying dry or lyophilization, obtain water-soluble coenzyme Q
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid.
Embodiment 6
Water-soluble coenzyme Q of the present invention
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid, it is prepared from by weight by following raw material, ubiquinone
10: alpha-lipoic acid: gamma-cyclodextrin=1: 0.5: 5.
Get gamma-cyclodextrin 50 mass parts, add the mixing of the water of 150 mass parts, be heated to 57 DEG C, then add 10 mass parts ubiquinones
10and 5 mass parts alpha-lipoic acids, stir into pasty state, put into colloid mill, circular grinding 25 minutes, blowing, carry out vacuum drying or spraying dry or lyophilization, obtain water-soluble coenzyme Q
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid.
Embodiment 7
Water-soluble coenzyme Q of the present invention
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid, it is prepared from by weight by following raw material, ubiquinone
10: alpha-lipoic acid: HP-β-CD=1: 0.5: 5.
Get HP-β-CD 50 mass parts, add water 200 mass parts, be heated to 50 DEG C, then add 10 mass parts ubiquinones
10and 5 mass parts alpha-lipoic acids, stir into pasty state, put into colloid mill, circular grinding 30 minutes, blowing, carry out vacuum drying or spraying dry or lyophilization, obtain water-soluble coenzyme Q
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid.
Get this clathrate 50mg tabletting, carry out thermal analyses DSC mensuration, result shows that this clathrate is different from ubiquinone
10with alpha-lipoic acid, HP-β-CD and their mixture D SC collection of illustrative plates, define new thing phase.
Embodiment 8
Water-soluble coenzyme Q of the present invention
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid, it is prepared from by weight by following raw material, ubiquinone
10: alpha-lipoic acid: HP-β-CD=1: 0.7: 12.
Get HP-β-CD 120 mass parts, add water 500 mass parts, be heated to 51 DEG C, then add 10 mass parts ubiquinones
10and 7 mass parts alpha-lipoic acids, stir into pasty state, put into colloid mill, circular grinding 20 minutes, blowing, carry out vacuum drying or spraying dry or lyophilization, obtain water-soluble coenzyme Q
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid.
Getting clathrate can direct pressing tablet, and technique is get the above-mentioned clathrate 1000g prepared, and by the heavy 0.3g of every sheet, direct compression, to obtain final product.
Embodiment 9
Water-soluble coenzyme Q of the present invention
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid, it is prepared from by weight by following raw material, ubiquinone
10: alpha-lipoic acid: HP-β-CD=1: 1: 20.
Get HP-β-CD 200 mass parts, add water 1000 mass parts, be heated to 56 DEG C, then add 10 mass parts ubiquinones
10and 10 mass parts alpha-lipoic acids, stir into pasty state, put into colloid mill, circular grinding 12 minutes, blowing, carry out vacuum drying or spraying dry or lyophilization, obtain water-soluble coenzyme Q
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid.
Embodiment 10
Water-soluble coenzyme Q of the present invention
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid, it is prepared from by weight by following raw material, ubiquinone
10: alpha-lipoic acid: gamma-cyclodextrin=1: 0.5: 20.
Get gamma-cyclodextrin 200 mass parts, add the mixing of the water of 900 mass parts, be heated to 54 DEG C, then add 10 mass parts ubiquinones
10and 5 mass parts alpha-lipoic acids, stir into pasty state, put into colloid mill, circular grinding 23 minutes, blowing, carry out vacuum drying or spraying dry or lyophilization, obtain water-soluble coenzyme Q
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid.
Getting clathrate can direct pressing tablet, and technique is get the above-mentioned clathrate 1000g prepared, and by the heavy 0.3g of every sheet, direct compression, to obtain final product.
Embodiment 11
Water-soluble coenzyme Q of the present invention
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid, it is prepared from by weight by following raw material, ubiquinone
10: alpha-lipoic acid: beta-schardinger dextrin-=1: 0.5: 20.
Get beta-schardinger dextrin-200 mass parts, add the mixing of the water of 780 mass parts, be heated to 58 DEG C, then add 10 mass parts ubiquinones
10and 5 mass parts alpha-lipoic acids, stir into pasty state, put into colloid mill, circular grinding 21 minutes, blowing, carry out vacuum drying or spraying dry or lyophilization, obtain water-soluble coenzyme Q
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid.
Embodiment 12
Water-soluble coenzyme Q of the present invention
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid, it is prepared from by weight by following raw material, ubiquinone
10: alpha-lipoic acid: beta-schardinger dextrin-=1: 0.6: 14.
Get beta-schardinger dextrin-140 mass parts, add the mixing of the water of 450 mass parts, be heated to 57 DEG C, then add 10 mass parts ubiquinones
10and 6 mass parts alpha-lipoic acid stir into pasty state, put into colloid mill, circular grinding 27 minutes, blowing, carry out vacuum drying or spraying dry or lyophilization, obtain water-soluble coenzyme Q
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid.
Embodiment 13
Water-soluble coenzyme Q of the present invention
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid, it is prepared from by weight by following raw material, ubiquinone
10: alpha-lipoic acid: gamma-cyclodextrin=1: 0.8: 11.
Get gamma-cyclodextrin 110 mass parts, add the mixing of the water of 400 mass parts, be heated to 59 DEG C, then add 10 mass parts ubiquinones
10and 8 mass parts alpha-lipoic acids, stir into pasty state, put into colloid mill, circular grinding 17 minutes, blowing, carry out vacuum drying or spraying dry or lyophilization, obtain water-soluble coenzyme Q
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid.
Embodiment 14
Water-soluble coenzyme Q of the present invention
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid, it is prepared from by weight by following raw material, ubiquinone
10: alpha-lipoic acid: HP-β-CD=1: 0.7: 17.
Get HP-β-CD 170 mass parts, add the mixing of the water of 600 mass parts, be heated to 50 DEG C, then add 10 mass parts ubiquinones
10and 7 mass parts alpha-lipoic acids, stir into pasty state, put into colloid mill, circular grinding 10 minutes, blowing, carry out vacuum drying or spraying dry or lyophilization, obtain water-soluble coenzyme Q
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid.
Get clathrate 1000g, by every heavy 0.3g, record capsule, must capsule be recorded.
Embodiment 15
Water-soluble coenzyme Q of the present invention
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid, it is prepared from by weight by following raw material, ubiquinone
10: alpha-lipoic acid: beta-schardinger dextrin-=1: 0.7: 11.
Get beta-schardinger dextrin-110 mass parts, in high-shear homogenizer, be dissolved in the water of 5500 mass parts, be heated to 52 DEG C, by the ubiquinone of 10 mass parts
10solution is become, by ubiquinone with the dissolve with ethanol of 170 mass parts with the alpha-lipoic acid of 7 mass parts
10join in high-shear homogenizer with alpha-lipoic acid solution, 10000 turns are carried out high-speed stirred and shear 8 minutes, and blowing enters high pressure homogenizer, circulate 5 times with 60Mpa, and blowing, then carries out spraying dry, obtains water-soluble coenzyme Q
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid.
Embodiment 16
Water-soluble coenzyme Q of the present invention
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid, it is prepared from by weight by following raw material, ubiquinone
10: alpha-lipoic acid: gamma-cyclodextrin=1: 0.8: 13.
Get gamma-cyclodextrin 130 mass parts, in high-shear homogenizer, be dissolved in the water of 6500 mass parts, be heated to 57 DEG C, by the ubiquinone of 10 mass parts
10solution is become, by ubiquinone with the dissolve with ethanol of 170 mass parts with the alpha-lipoic acid of 8 mass parts
10join in high-shear homogenizer with alpha-lipoic acid solution, 15000 turns are carried out high-speed stirred and shear 9 minutes, and blowing enters high pressure homogenizer, circulate 3 times with 60Mpa, and blowing, then carries out spraying dry, obtains water-soluble coenzyme Q
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid.
Embodiment 17
Water-soluble coenzyme Q of the present invention
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid, it is prepared from by weight by following raw material, ubiquinone
10: alpha-lipoic acid: HP-β-CD=1: 0.9: 15.
Get HP-β-CD 150 mass parts, in high-shear homogenizer, be dissolved in the water of 7500 mass parts, be heated to 55 DEG C, by the ubiquinone of 10 mass parts
10solution is become, by ubiquinone with the dissolve with ethanol of 180 mass parts with the alpha-lipoic acid of 9 mass parts
10join in high-shear homogenizer with alpha-lipoic acid solution, 17000 turns are carried out high-speed stirred and shear 6 minutes, and blowing enters high pressure homogenizer, circulate 4 times with 60Mpa, and blowing, then carries out spraying dry, obtains water-soluble coenzyme Q
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid.
Embodiment 18
Water-soluble coenzyme Q of the present invention
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid, it is prepared from by weight by following raw material, ubiquinone
10: alpha-lipoic acid: gamma-cyclodextrin=1: 1: 10.
Get gamma-cyclodextrin 100 mass parts, in high-shear homogenizer, be dissolved in the water of 5000 mass parts, be heated to 60 DEG C, by the ubiquinone of 10 mass parts
10solution is become, by ubiquinone with the dissolve with ethanol of 180 mass parts with the alpha-lipoic acid of 10 mass parts
10join in high-shear homogenizer with alpha-lipoic acid solution, 20000 turns are carried out high-speed stirred and shear 10 minutes, and blowing enters high pressure homogenizer, circulate 5 times with 80Mpa, and blowing, then carries out spraying dry, obtains water-soluble coenzyme Q
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid.
Getting clathrate can direct pressing tablet, and technique is get the above-mentioned clathrate 1000g prepared, and by the heavy 0.3g of every sheet, direct compression, to obtain final product.
Embodiment 19
Water-soluble coenzyme Q of the present invention
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid, it is prepared from by weight by following raw material, ubiquinone
10: alpha-lipoic acid: HP-β-CD=1: 1: 15.
Get HP-β-CD 150g, in high-shear homogenizer, be dissolved in the water of 7500 mass parts, be heated to 50 DEG C, by the ubiquinone of 10 mass parts
10solution is become, by ubiquinone with the dissolve with ethanol of 220 mass parts with the alpha-lipoic acid of 10 mass parts
10join in high-shear homogenizer with alpha-lipoic acid solution, 15000 turns are carried out high-speed stirred and shear 5 minutes, and blowing enters high pressure homogenizer, circulate 4 times with 100Mpa, and blowing, then carries out spraying dry, obtains water-soluble coenzyme Q
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid.
Get clathrate 1000g, by every heavy 0.3g, record capsule, must capsule be recorded.
Below by way of experiment, the present invention is further described:
One, solubility test experiment: get ubiquinone prepared by the embodiment of the present invention 1 ~ 19 respectively
10with alpha-lipoic acid clathrate, ubiquinone
10appropriate with alpha-lipoic acid physical mixture, join in the pure water of 10ml respectively, make into supersaturated solution, sonic oscillation 10 minutes, filter, get filtrate as test liquid, adopt Syrups by HPLC, the results are shown in Table 1, table 2.Result shows, ubiquinone in clathrate prepared by the embodiment of the present invention 1 ~ 19
10dissolubility is 244-312 μ g/ml, and alpha-lipoic acid dissolubility is 611-678 μ g/ml; Ubiquinone
10with ubiquinone in alpha-lipoic acid physical mixture
10raw material is not measured, and alpha-lipoic acid raw material is 370 μ g/ml.
Two, dissolution determination: take ubiquinone prepared by the embodiment of the present invention 1 ~ 19 respectively
10with alpha-lipoic acid clathrate, ubiquinone
10appropriate with alpha-lipoic acid physical mixture, measure different time drug-eluting with digestion instrument.Medium is 500ml distilled water, temperature (37 DEG C ± 0.5), timing sampling 10ml, adopts Syrups by HPLC, the results are shown in Table 1, table 2.Table 1 ubiquinone
10dissolubility and relative dissolution
Dissolubility and the relative dissolution of table 2 alpha-lipoic acid
Table 1, table 2 show, present composition stripping sooner, more.
Three, ubiquinone in high effective liquid chromatography for measuring clathrate
10and alpha-lipoic acid
Get water-soluble coenzyme Q prepared by the embodiment of the present invention 1 ~ 19
10the cyclodextrin Ternary complex thing composite with alpha-lipoic acid is appropriate, and washed with diethylether, is vaporized ether, adds a small amount of water-soluble loose, ultrasonic with ethanol heating, lets cool after being settled to normal concentration, filters, get subsequent filtrate as need testing solution, sample introduction, chromatographic condition: ubiquinone
10: C18 post, mobile phase is acetonitrile: oxolane: water=55: 40: 5 (volume ratios), determined wavelength 275nm, and quantified by external standard method, to obtain final product; Alpha-lipoic acid: C18 post, mobile phase is acetonitrile: 0.1% phosphoric acid=40: 60 (volume ratios), determined wavelength 220nm, and quantified by external standard method, to obtain final product, and result chromatograms shows, all containing ubiquinone in clathrate prepared by embodiment 1 ~ 19
10with alpha-lipoic acid composition.
Four, bioavailability study:
(1) blood specimen collection:
SD rat 12, is divided into two groups at random, often organizes 3 female 3 heros.Wherein one group orally gives the embodiment of the present invention 2 clathrate, and group is oral gives ubiquinone in proportion for another
10with alpha-lipoic acid physical mixture, dosage is 10mg/kg ubiquinone
10with 10mg/kg alpha-lipoic acid.Individual dosage is calculated by rat body weight.Get blood from rat orbital vein respectively after administration 0,1,2,4,5,6,7,8,10,12,24h and be about 0.5mL, be placed in the EP pipe of heparinization.In 4 DEG C, the centrifugal 10min of 5000rpm, is stored in-80 DEG C of refrigerators after being separated by the blood plasma on upper strata, until analyze.
(2) plasma sample processing method:
Get 95 μ L ubiquinones
10plasma sample is put in 1.5mL centrifuge tube, add vortex mixing after mark working solution in 5 μ L ethanol and 5 μ L, then 1mL Extraction solvent (normal hexane: dehydrated alcohol=8: 1) is added, extraction of ocean eddies 3min, get supernatant after the centrifugal 10min of 13000rpm in another centrifuge tube, vacuum volatilizes.Residue adds 50 μ L dehydrated alcohol and redissolves, and vortex mixes, and the centrifugal 10min of 13000rpm, gets supernatant and analyze for HPLC-MS/MS.
Getting 100 μ L alpha-lipoic acid plasma samples puts in 1.5mL centrifuge tube, add vortex mixing after mark working solution in 10 μ L, then add 300 μ L acetonitriles, extraction of ocean eddies 3min, supernatant 150 μ L is got in another centrifuge tube, in the centrifugal 10min of 13000rpm after the centrifugal 10min of 13000rpm.Point get supernatant and analyze for HPLC-MS/MS.
(3) chromatographic condition:
Ubiquinone
10: adopt C18 post, mobile phase: methanol: ethanol=1: 4, flow velocity 0.3mL/min.Alpha-lipoic acid: C18; Mobile phase is methanol (A): water (B), 0 ~ 2minA: B=20: 80,2 ~ 7minA: B=95: 5,7 ~ 9minA: B=20: 80; Flow velocity 1mL/min, 1: 2 shunting after post.
(4) Mass Spectrometry Conditions:
Ubiquinone
10: mass spectrum adopts Atmosphere Pressure Chemical Ionization (APCI) ion source; Dry gas temperature: 300 DEG C; Vapourizing temperature: 350 DEG C; Dry gas flow velocity: 4L/min; Atomization gas pressure: 30psi.Ubiquinone
10: m/z863.5 → 1972, cracked voltage and collision energy are respectively 80V and 20eV; Interior mark m/z833.5 → 167, cracked voltage and collision energy are respectively 100V and 35eV.
Alpha-lipoic acid: mass spectrum adopts electric spray ion source, negative ion mode scans; Taper hole voltage is 20V; Capillary voltage is 3.0kV; Ion source temperature is 120 DEG C; Desolventizing temperature is 350 DEG C; Desolventizing gas is nitrogen, and flow velocity is 800L/h; Collision gas is argon, 0.25Pa; Residence time 0.5s.Alpha-lipoic acid: m/z205 → 171, taper hole voltage and collision energy are respectively 25V and 8eV; Interior mark m/z205 → 161, taper hole voltage and collision energy are respectively 25V and 9eV.
(5) pharmacokinetic parameters in rat body
After Oral Administration in Rats administration 10mg/kg embodiment 2 clathrate or in proportion physical mixture, make blood concentration-time curve, after the blood drug level (if negative is then considered as 0ng/mL) when the blood drug level of each time point all being deducted 0h, ubiquinone
10blood concentration-time data input DAS2.0 software with alpha-lipoic acid, calculates pharmacokinetic parameter in table.
Ubiquinone after the administration of table 3SD rat
10main pharmacokinetic parameters
The main pharmacokinetic parameters of alpha-lipoic acid after the administration of table 4SD rat
Five, Benexate Hydrochloride Inclusion ratio measures
According to clathrate composition of the present invention, get the ubiquinone of different mol ratio example
10with alpha-lipoic acid and beta-schardinger dextrin-, molar ratio comprises ubiquinone
10with the ratio 1: 1: 5,1: 1: 6,1: 1: 7,1: 1: 8,1: 1: 9 of alpha-lipoic acid and beta-schardinger dextrin-, prepare according to the polishing of preparation method of the present invention, preparation makees DSC collection of illustrative plates respectively to aforementioned proportion clathrate, and molar ratio reaches after 1: 1: 8, ubiquinone
10disappear with alpha-lipoic acid fusing point peak, determine Benexate Hydrochloride Inclusion ratio ubiquinone of the present invention
10be 1: 1: 8 with alpha-lipoic acid and beta-schardinger dextrin-.
Six, hydroxypropyl-beta-cyclodextrin inclusion Inclusion ratio measures
According to clathrate composition of the present invention, get the ubiquinone of different mol ratio example
10with alpha-lipoic acid and HP-β-CD, molar ratio comprises ubiquinone
10with the ratio 1: 1: 5,1: 1: 6,1: 1: 7,1: 1: 8,1: 1: 9 of alpha-lipoic acid and HP-β-CD, prepare according to the polishing of preparation method of the present invention, preparation makees DSC collection of illustrative plates respectively to aforementioned proportion clathrate, and molar ratio reaches after 1: 1: 8, ubiquinone
10disappear with alpha-lipoic acid fusing point peak, determine hydroxypropyl-beta-cyclodextrin inclusion Inclusion ratio ubiquinone of the present invention
10be 1: 1: 8 with alpha-lipoic acid and beta-schardinger dextrin-.
Seven, gamma-cyclodextrin clathrate Inclusion ratio measures
According to clathrate composition of the present invention, get the ubiquinone of different mol ratio example
10with alpha-lipoic acid and gamma-cyclodextrin, molar ratio comprises ubiquinone
10with the ratio 1: 1: 5,1: 1: 6,1: 1: 7,1: 1: 8,1: 1: 9 of alpha-lipoic acid and gamma-cyclodextrin, prepare according to the polishing of preparation method of the present invention, preparation makees DSC collection of illustrative plates respectively to aforementioned proportion clathrate, and molar ratio reaches after 1: 1: 7, ubiquinone
10disappear with alpha-lipoic acid fusing point peak, determine gamma-cyclodextrin clathrate Inclusion ratio ubiquinone of the present invention
10be 1: 1: 7 with alpha-lipoic acid and beta-schardinger dextrin-.
Eight, clathrate Stability Determination
The stability test of the present composition:
Get ubiquinone
10raw material, alpha-lipoic acid raw material and the ubiquinone prepared by previous patent document
10benexate Hydrochloride and alpha-lipoic acid clathrate mixture, and clathrate prepared by the embodiment of the present invention 1 ~ 19 is appropriate, carries out influence factor's experiment investigation.
Get above-mentioned substance under 4000LX light, temperature 40 DEG C, relative humidity 92.5% placed 10 days, respectively at 0 day, 5 days, 10 days sampling and measuring ubiquinones
10, alpha-lipoic acid, the results are shown in Table 5.
Table 5 affects test
Table 5 shows that clathrate light stability of the present invention is better than ubiquinone
10benexate Hydrochloride and alpha-lipoic acid clathrate mixture and both raw materials, " * " sample detection is gone on a tour from ubiquinone
10with alpha-lipoic acid composition.
Claims (7)
1. water-soluble coenzyme Q
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid, is characterized in that it is prepared from by weight by following raw material: ubiquinone
10: alpha-lipoic acid: cyclodextrin=1:0.5-1:5-20.
2. water-soluble coenzyme Q according to claim 1
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid, is characterized in that it is prepared from by weight by following raw material: ubiquinone
10: alpha-lipoic acid: cyclodextrin=1:0.5-1:10-15.
3. water-soluble coenzyme Q according to claim 1 and 2
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid, is characterized in that described cyclodextrin is gamma-cyclodextrin, beta-schardinger dextrin-or HP-β-CD.
4. water-soluble coenzyme Q described in a claim 1
10the preparation method of the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid, it is characterized in that processing step is as follows: get cyclodextrin by described weight ratio, mix with the water being equivalent to cyclodextrin 3-5 times weight, be heated to 50 DEG C-60 DEG C, add the ubiquinone meeting above-mentioned weight ratio
10and alpha-lipoic acid, stir into pasty state, put into colloid mill, circular grinding 10-30 minute, release lapping liquid, add water to solid content and reach 15%, spraying dry obtains water-soluble coenzyme Q
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid.
5. water-soluble coenzyme Q described in a claim 1
10the preparation method of the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid, it is characterized in that processing step is as follows: get cyclodextrin by described weight ratio, in high-shear homogenizer, be dissolved in the water being equivalent to cyclodextrin 50 times of weight, be heated to 50-60 DEG C, will the ubiquinone of above-mentioned weight ratio be met
10solution is become, by ubiquinone with alpha-lipoic acid dissolve with ethanol
10join in high-shear homogenizer with alpha-lipoic acid solution, turn with 10000-20000 and carry out high-speed stirred shearing 5-10 minute, blowing enters high pressure homogenizer, and with 60-100Mpa circulation 3-5 time, blowing, then carries out spraying dry, obtains ubiquinone
10the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid.
6. water-soluble coenzyme Q according to claim 5
10the preparation method of the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid, is characterized in that the consumption of described ethanol is ubiquinone
10with alpha-lipoic acid gross weight 9-11 weight doubly.
7. water-soluble coenzyme Q according to claim 4 or 5
10the preparation method of the cyclodextrin ternary super molecule inclusion compound composite with alpha-lipoic acid, is characterized in that getting described ternary super molecule inclusion compound adopts common process to be prepared into oral tablet or capsule.
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| CN116350540A (en) * | 2023-03-28 | 2023-06-30 | 水羊化妆品制造有限公司 | Ternary supermolecule inclusion compound, preparation method and application thereof |
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| CN115429758B (en) * | 2022-09-06 | 2024-05-14 | 厦门金达威生物科技有限公司 | Coenzyme Q10-lipoic acid type phospholipid nano-composite micelle and preparation method and application thereof |
| CN115814106A (en) * | 2022-12-09 | 2023-03-21 | 东南大学 | High-affinity inclusion peptide preparation and preparation method thereof |
| CN115814106B (en) * | 2022-12-09 | 2024-03-22 | 东南大学 | High-affinity inclusion peptide preparation and preparation method thereof |
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Application publication date: 20160511 |