CN105708806B - A kind of ubiquinone for preparing the Yishui River and disperseing10The method of powder of nanometric particles preparation - Google Patents
A kind of ubiquinone for preparing the Yishui River and disperseing10The method of powder of nanometric particles preparation Download PDFInfo
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- CN105708806B CN105708806B CN201610074301.8A CN201610074301A CN105708806B CN 105708806 B CN105708806 B CN 105708806B CN 201610074301 A CN201610074301 A CN 201610074301A CN 105708806 B CN105708806 B CN 105708806B
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
Abstract
The invention discloses a kind of ubiquinone for preparing the Yishui River and disperseing10The method of powder of nanometric particles preparation.This method is by slightly water-soluble ubiquinone10Organic solvent solution and pH response polyelectrolyte class surfactants aqueous solution in mixer airtight cavity jet stream be blended；Wherein organic solvent be able to can dissolve each other with water；Collect from mixer outlet and flow out suspension, more than adjusting suspension pH to pH response polyelectrolyte class surfactant isoelectric points, suspension produces sedimentation of reuniting, then sediment is filtered and is dried in vacuo, and obtains the ubiquinone that the Yishui River disperses10Powder of nanometric particles.Preparation method of the present invention is quick, energy consumption is low, equipment volume is small.Prepared nanoparticle size is small, narrowly distributing and stability are good, while has the advantages that carrying drug ratio and granulating eduction rate are high.Powder of nanometric particles is indefiniteness state, this is beneficial to ubiquinone10Quick absorption in vivo.
Description
Technical field
The invention belongs to organic matter powder of nanometric particles preparation field, and in particular to a kind of ubiquinone for preparing the Yishui River and disperseing10
The method of powder of nanometric particles preparation.
Background technology
Ubiquinone10(coenzyme Q10), abbreviation CoQ10.Also known as ubiquinone, it is that all kinds of lifes are widely present in relatively low content
Fat-soluble quinones in object tissue, and a kind of biostearin material, are the required components of mitochondrial respiratory chain,
Important antioxidant and nonspecific immunity strengthening agent, have improve the immunity of the human body, strengthen it is anti-oxidant, slow down aging and
Strengthen the effect such as human activity, cardiovascular and cerebrovascular disease can be prevented, while more multi-energy is provided for cardiac muscle cell, strengthen heart work(
Energy.But CoQ10Hydrophobicity (ACDLogP=21) with superelevation, not soluble in water, this causes it to have after entering in organism
Extremely low effective haemoconcentration and bioavailability.Therefore, how ubiquinone is improved10Water dispersible and solubility become one
Key issue.Medicine generally can by chemical modification, or preparing medicament nano particle come by way of increasing its surface area come
Improve its water solubility.Meanwhile nano-particle is easier to when circulating in vivo by various organization barrier, or even fine and close blood brain screen
Barrier.
Chitosan is a kind of edible natural polysaccharide family macromolecule, be chitin it is deacetylated after product.And chitin is
It is the second largest natural reproducible height that cellulose is only second on the earth as the main ingredient of the shellfish crust such as shrimp, crab
Molecule.Chitosan contains compared with polyamino, is a kind of pH responses polyelectrolyte class surfactant, in pH>Do not dissolved in when~5
Water, in pH<Become positively charged lotus when~5 and be dissolved in water.And it can attract each other with the negative electrical charge of hydrophobic particle surfaces and be wrapped in its table
Face, with prevent between particle because hydrophobic effect is mutually reunited and size increase.
Polyvinylpyrrolidone has glue as a kind of water-soluble synthesis macromolecule good using extensive, physiological compatibility
Body protective effect, film forming, caking property, hygroscopicity, solubilising or cohesion, particularly medicine, food, cosmetics, wash agent,
Printing and dyeing, coating, pigment and catalyst preparation have a wide range of applications, and to contain tertiary amino be that a kind of pH responses gather electrolysis to its structure
Matter class surfactant.
There are shortcomings in practice for several customary preparation methods of nano particle.For example, ball milling and high pressure are equal
The methods of matter, needs of a relatively high energy input, and hangover is distributed with now on large scale direction in caused particle
As.And for example, often Size Distribution is wide for the particle that anti-solvent stirring deposition method is prepared, and the more difficult stability contorting of granular size,
The uniformity of particle size is also poor between each batch.
The content of the invention
The object of the present invention is to provide a kind of ubiquinone for preparing the Yishui River and disperseing10The method of powder of nanometric particles preparation.
The present invention is achieved through the following technical solutions：A kind of ubiquinone for preparing the Yishui River and disperseing10Powder of nanometric particles preparation
Method, is by slightly water-soluble ubiquinone10The aqueous solution of organic solvent solution and pH response polyelectrolyte class surfactants exist
Jet stream is blended in mixer airtight cavity, wherein the organic solvent can be miscible with water；Collect from mixer outlet outflow
Suspension, is adjusted more than pH of suspension to pH response polyelectrolyte class surfactant isoelectric points, and suspension, which produces to reunite, to sink
Drop, then sediment is filtered and is dried in vacuo, obtain the ubiquinone that the Yishui River disperses10Powder of nanometric particles.
Comprise the concrete steps that：
(1) respectively by ubiquinone10It is dissolved in organic solvent that can be miscible with water, pH response polyelectrolyte class surfactants
It is dissolved in the water of appropriate pH.
(2) as shown in Figure 1, jet stream is blended in mixer airtight cavity by above-mentioned two solution.Wherein organic solvent can be with
Water dissolves each other, and organic solvent shifts to water phase, the molten ubiquinone of shipwreck10Therefore solubility instantaneously declines and separates out.The mixing has high Reynolds
Number, though process only needs low energy to input, dissipates for high-energy-density, for causing particle to overcome large surface to form nano-grade size
Grain.Meanwhile SURFACTANT ADSORPTION limits the further growth of particle, and effectively stable and discrete particles in particle surface.Shape
Into stabilization nano suspending liquid from mixer outlet flow out.
(3) suspension is collected, adjusts pH of suspension, the electric charge of pH response surfactants is neutralized and is changed into water not
Molten, nano particle loses protection reunion precipitation, is filtered via filter membrane, vacuum drying can obtain ubiquinone10Powder.The powder passes through
PH and stirring are adjusted back, can be dispersed in water to form stable nano suspending liquid again.
In the above method, mixed process is blended for high reynolds number turbulent flow, and mixing chamber single entry injection speed is 0.1m/s
More than.
Mixer described in the above method contains at least two fluids note using non-open closed mixer, mixing chamber
Entrance and a flow export.
Heretofore described pH responses polyelectrolyte class surfactant, can be chitosan or polyvinylpyrrolidine
Ketone.By adjusting pH, surfactant can between water-soluble and water-insoluble reversible transition, such as pH<5, chitosan is water solubility；
pH>5, chitosan is insoluble for water.pH<7, polyvinylpyrrolidone is water-soluble higher；pH>7, polyvinylpyrrolidone is water-soluble
Reduce.
Ubiquinone is dissolved in the method for the present invention10Organic solvent can it is miscible with water, selected from acetone, tetrahydrofuran, DMF, DMA,
Ethanol, propyl alcohol or their arbitrary mixtures.
Compared with conventional method, the method for the present invention preparation speed is fast, and energy consumption is low, and equipment volume is small and easily operated.Prepare
Grain diameter it is small, average about 120nm；Carrying drug ratio is up to 93%；Ubiquinone10Granulating eduction rate is up to 86%.
Brief description of the drawings
Nanometers of suspensions of Fig. 1 prepare and the dry schematic diagram of separation.
The ubiquinone that Fig. 2 chitosans are stablized10The particle size distribution figure of nano particle.
The ubiquinone that Fig. 3 chitosans are stablized10The particle diameter transmission electron microscope picture of nano particle.
The ubiquinone that Fig. 4 chitosans are stablized10Nano particle again disperse after particle size distribution figure.
The ubiquinone that Fig. 5 are protected without chitosan10The particle size distribution figure of nano particle.
Fig. 6 material powders and the ubiquinone of chitosan protection10Nano particle after distinct methods separation drying respectively by obtaining
The XRD diagram of the powder arrived.
Embodiment
Embodiment one：In model experiment, 3mL 10mg/mLCoQ are prepared10Acetone soln and 3mL 10mg/mL chitosans
Aqueous hydrochloric acid solution (pH<5) two solution, are entered into mixer from two entrance of mixer with identical speed injection at the same time.Two fluids exists
Abundant turbulent closure scheme is carried out in mixer cavity, the suspension of preparation is flowed out from mixer outlet.Injection takes about 5s altogether, with Sheng
The container for having 24mL water is received in mixer outlet.With its particle size (average diameter about 110nm) of dynamic light scattering determination
With distribution (such as Fig. 2), morphology characterization (such as Fig. 3) is carried out with transmission electron microscope.Rise suspension is adjusted to pH>5, nano particle occurs
Reunite and settle, via suction filtration, obtain sediment powder, powder can be dried in vacuo.Powder is agitated can be scattered in pH again<5 water
Solution, average diameter about 110nm (such as Fig. 4) is with disperseing preceding particle diameter no significant difference again.
Embodiment two：In contrast experiment, pH response surfactant chitosans are not added.Prepare 3mL 10mg/
mLCoQ10Acetone soln, with 3mL water at the same time with identical speed from two entrance injecting mixer cavitys.Two fluids is in mixer chamber
Abundant turbulent closure scheme is carried out in body, obtained suspension is flowed out from mixer outlet.Injection time-consuming about 5s altogether, with filling 24mL water
Container mixer outlet receive, characterize its particle size and distribution with dynamic light scattering, as shown in Figure 5.Particle diameter is relatively implemented
Example one is big, average diameter about 800nm.
Embodiment three：In carrying drug ratio and eduction rate measure, the nanometer suspension 12mL prepared in example one is taken, adjusts rise
Suspension is to pH>5, sedimentation of reuniting occurs for nano particle, via suction filtration, obtains sediment powder, immediately that filter membrane and powder is cold
It is lyophilized dry.According to the nanoparticle mass of poor quality of obtaining before and after membrane filtration it is 11.1mg after drying.Nano particle after drying
Acetone is dissolved in, ubiquinone is measured by HPLC10And calculate to obtain ubiquinone10Quality is 10.4mg.Carrying drug ratio (drug quality/nanometer
Grain quality)=93.3%, ubiquinone10Granulating eduction rate (granulating drug quality/feed intake drug quality)=10.4/12=86.4%.
Example IV：Powder of nanometric particles crystalline state measure in, by embodiment one nanometer suspension readjustment pH, sedimentation,
Filter and be dried in vacuo, and measure XRD.The results show powder of nanometric particles is in XRD without sharp peak (as shown in fig 6d), table
Bright is unformed shape, this is readily able to it and is absorbed by the body.And the spray-dried obtained powder of nanometric particles of nanometer suspension exists
Occur sharp peak (such as Fig. 6 c) on XRD, show to be recrystallized, this will reduce human body to its infiltration rate.
Embodiment five：Respectively using tetrahydrofuran, DMF, DMA, propyl alcohol, other organic solvents of ethanol instead of in embodiment one
Acetone, prepares 3mL 10mg/mLCoQ10Organic solution and 3mL 10mg/mL chitosan aqueous solutions (pH<5), by two solution at the same time
Enter mixer from two entrance of mixer with identical speed injection.Two fluids carries out abundant turbulent closure scheme in mixer cavity,
The suspension of preparation is flowed out from mixer outlet.Injection takes about 5s altogether, is connect with the container for filling 24mL water in mixer outlet
Receive.With dynamic light scattering determination, its average grain diameter is as shown in table 1.Rise suspension is adjusted to pH>5, group occurs for nano particle
Coagulation drops, and via suction filtration, obtains sediment powder, powder can be dried in vacuo.Powder is agitated can be scattered in pH again<5 is water-soluble
Liquid, average diameter is with disperseing preceding particle diameter no significant difference again.
Table 1
Embodiment six：Chitosan in embodiment one is replaced using polyvinylpyrrolidone, prepares 3mL 10mg/mLCoQ10Third
Ketone solution and 3mL 10mg/mL polyvinylpyrrolidones (pH<7), by two solution at the same time from two entrance of mixer with identical speed
It is injected into mixer.Two fluids carries out abundant turbulent closure scheme in mixer cavity, and the suspension of preparation is from mixer outlet
Outflow.Injection takes about 5s altogether, is received with the container for filling 24mL water in mixer outlet.With dynamic light scattering determination, it is flat
Equal diameter about 234nm.Rise suspension is adjusted to pH>7, sedimentation of reuniting occurs for nano particle, via suction filtration, obtains sediment powder
End, powder can be dried in vacuo.Powder is agitated can be scattered in pH again<7 aqueous solutions, average diameter is with disperseing preceding particle diameter without bright again
Significant difference is different.
Claims (6)
- A kind of 1. ubiquinone for preparing the Yishui River and disperseing10The method of powder of nanometric particles preparation, it is characterised in that：Slightly water-soluble is auxiliary Enzyme Q10The aqueous solution of organic solvent solution and pH response polyelectrolyte class surfactants penetrated in mixer airtight cavity Stream blending, wherein the organic solvent can be miscible with water；The suspension from mixer outlet outflow is collected, adjusts pH of suspension To more than pH response polyelectrolyte class surfactant isoelectric points, suspension produces sedimentation of reuniting, then sediment is taken out Filter and vacuum drying, obtain the ubiquinone that the Yishui River disperses10Powder of nanometric particles.
- 2. the ubiquinone according to claim 1 for preparing the Yishui River and disperseing10The method of powder of nanometric particles preparation, its feature exist In：Mixed process is blended for high reynolds number turbulent flow, and mixing chamber single entry injection speed is more than 0.1m/s.
- 3. the ubiquinone according to claim 1 for preparing the Yishui River and disperseing10The method of powder of nanometric particles preparation, its feature exist In：Using non-open closed mixer, mixing chamber contains at least two fluid-infusing ports and a flow export.
- 4. the ubiquinone according to claim 1 for preparing the Yishui River and disperseing10The method of powder of nanometric particles preparation, its feature exist In：The pH responses polyelectrolyte class surfactant is chitosan or polyvinylpyrrolidone.
- 5. the ubiquinone according to claim 4 for preparing the Yishui River and disperseing10The method of powder of nanometric particles preparation, its feature exist In：By adjusting pH, surfactant can between water-soluble and water-insoluble reversible transition.
- 6. the ubiquinone according to claim 1 for preparing the Yishui River and disperseing10The method of powder of nanometric particles preparation, its feature exist In：Dissolve ubiquinone10Organic solvent can it is miscible with water, selected from acetone, tetrahydrofuran, DMF, DMA, methanol, ethanol or they appoint The mixture of meaning.
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| AU2007261943B2 (en) * | 2006-06-22 | 2012-11-01 | Kaneka Corporation | Reduced coenzyme Q10-containing composition and method for producing the same |
| KR101066197B1 (en) * | 2009-04-06 | 2011-09-20 | 한국생명공학연구원 | Coenzyme Q10 nanoparticles, method for preparing the same, and composition comprising the same |
| CN101530394B (en) * | 2009-04-17 | 2011-06-29 | 上海应用技术学院 | Preparation method of polypeptide-chitosan composite nanoparticles loaded with coenzyme Q10 |
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