CN107184566B - Pharmaceutical composition containing lutein, preparation method and preparation thereof - Google Patents

Pharmaceutical composition containing lutein, preparation method and preparation thereof Download PDF

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CN107184566B
CN107184566B CN201710355210.6A CN201710355210A CN107184566B CN 107184566 B CN107184566 B CN 107184566B CN 201710355210 A CN201710355210 A CN 201710355210A CN 107184566 B CN107184566 B CN 107184566B
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lutein
cyclodextrin
pharmaceutical composition
tween
prescription
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CN107184566A (en
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欧阳德方
赵倩倩
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University of Macau
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

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Abstract

The invention discloses a pharmaceutical composition containing lutein, and a preparation method and a preparation thereof. The pharmaceutical composition comprises the following components in percentage by weight: 0.1% -10% of lutein crystal, 30% -70% of cyclodextrin, 10% -30% of surfactant and 10% -30% of hydrophilic carrier material. The quaternary system of the pharmaceutical composition containing lutein has high solubility, and a large number of in vitro characterization experiments show that the pharmaceutical composition improves the in vivo and in vitro bioavailability of the lutein, thereby improving the clinical curative effect.

Description

Pharmaceutical composition containing lutein, preparation method and preparation thereof
Technical Field
The invention relates to a pharmaceutical composition containing lutein, a preparation method and a preparation thereof, belonging to the technical field of pharmaceutical preparations and food science.
Background
Lutein is a carotenoid widely existing in the nature, and is a natural pigment with strong coloring capability and oxidation resistance. Scientific research reports that lutein is related to reducing the risk of age-related macular degeneration (AMD) caused by oxidative damage of macular areas, and effective administration of lutein can prevent and delay eye diseases such as vision loss, blindness or cataract caused by senile macular degeneration. Meanwhile, the lutein can also prevent cardiovascular sclerosis, tumors, coronary heart disease and the like caused by aging of organisms, prevent the aging of the organisms and improve the immunologic function of the bodies, and is widely applied to the fields of medicines, health-care foods and the like. But because the lutein has a unique conjugated polyene structure, the chemical stability of the lutein is poor, the lutein is easy to oxidize and degrade under the environment of illumination and oxygen to lose the original biological activity, and meanwhile, the solubility in water or fat is extremely low, so that the bioavailability of the lutein is very low, and the production and the application of the lutein are greatly limited by the characteristics.
Disclosure of Invention
In view of the above, the present invention provides a pharmaceutical composition containing lutein, and a preparation method and a preparation thereof, which are intended to solve at least some of the technical problems in the prior art.
In order to achieve the above object, the present invention provides the following technical solutions.
One aspect of the present invention provides a pharmaceutical composition containing lutein, which comprises the following components by weight: 0.1-10% of lutein crystal, 30-70% of cyclodextrin, 10-30% of surfactant and 10-30% of hydrophilic carrier material.
In another aspect, the present invention also provides a method for preparing the above pharmaceutical composition containing lutein, which comprises: dissolving the lutein crystal, hydrophilic carrier material, surfactant and cyclodextrin in solvent, mixing the components uniformly, reacting fully, and removing solvent to obtain dried product.
In still another aspect of the present invention, there is provided a pharmaceutical preparation containing lutein, which comprises the above pharmaceutical composition containing lutein and a pharmaceutically acceptable carrier.
In yet another aspect of the present invention there is provided a dietary supplement comprising the aforementioned pharmaceutical composition comprising lutein.
Compared with the prior art, the invention has the positive improvement effects that:
compared with the crude drugs and the secondary and tertiary systems in the prior patent documents, the quaternary system of the pharmaceutical composition containing lutein has high solubility, and a large number of in vitro characterization experiments show that the pharmaceutical composition improves the in vivo and in vitro bioavailability of the lutein, thereby improving the clinical curative effect.
Drawings
Figure 1 shows the phase solubility curve of the lutein-cyclodextrin system of example 1.
Fig. 2 shows the solubility diagram of the ternary system of lutein- γ -cyclodextrin-carrier material of example 2.
FIG. 3 shows the solubility diagram of the ternary system lutein-HP- β -cyclodextrin-carrier material of example 3.
FIG. 4 shows the solubility diagram of the ternary lutein- γ -cyclodextrin-Tween 80 system of example 4.
FIG. 5 shows the solubility diagram of the ternary system lutein-HP- β -cyclodextrin-Tween 80 in example 5.
Fig. 6 shows the solubility map of the quaternary system of lutein-cyclodextrin-tween-hydrophilic carrier material in example 6.
FIG. 7 shows the solubility diagram of the quaternary xanthophyll-cyclodextrin-tween-poloxamer system of example 7.
Figure 8 shows the percentage in vitro cumulative release versus time curve for the highly soluble lutein formulation of the present invention in example 8.
Figure 9 shows DSC detection of highly soluble lutein prescription in example 8.
Figure 10 shows fourier transform infrared spectroscopy measurements of highly soluble lutein formulations in example 8.
Fig. 11 shows a molecular dynamics simulation of the highly soluble lutein prescription in example 8, wherein fig. 11a is the initial structure, fig. 11b is the initial structure of the aqueous box, and fig. 11c is the final structure.
FIG. 12 shows the results of cell absorption of the highly soluble lutein prescription Caco-2 of example 8, wherein the lutein bulk drug is 0.197ug/ml, the lutein prescription is 25ug/ml, and the lutein prescription is 50 ug/ml.
Figure 13 shows plasma drug concentration-time curves in rats for highly soluble lutein prescription in example 8, where (API) lutein bulk drug, (lutein-SDs) lutein highly soluble prescription.
Detailed Description
In recent years, many reports on xanthophylls have been made, and patent publication No. CN101507704 describes a xanthophyll solid dispersion and a preparation method thereof, which mainly consists of a binary system of xanthophyll crystals and carrier materials, and other additives. The prescription composition is relatively single, the solubility test result is not shown, and the solubility improvement result is not clear. Although the lutein solid dispersion is prepared by adopting a plurality of methods, dissolution comparison and in-vivo and in-vitro bioavailability research experiments are not carried out.
Patent publication No. CN103860476A describes a lutein water-soluble powder and its preparation method, the main components of which are lutein, water-soluble carrier material, surfactant ternary system and other additives, and the preparation is made by spray drying. The prescription is a ternary system, and an in vitro dissolution test is carried out, so that the result is improved to a certain extent, but the solubility and related in vivo test research are not seen, and the effectiveness of the prescription cannot be fully proved. And the solvent used in the preparation process contains ethyl acetate, dichloromethane and the like with more toxicity, so that potential safety hazards exist.
The patent publication No. CN104434814 describes a water-soluble xanthophyll granule, its preparation process and application, its main component is binary system of xanthophyll and water-soluble polymer adjuvant, adopting CO2The supercritical fluid recrystallization method. The water-soluble particles prepared by the method can cause the lutein to form crystals after long-term storage, and the production equipment is expensive, so that the industrial production cost is high.
Patent publication No. CN104095816 describes a lutein microcapsule and its preparation method, which comprises main components of lutein, core material and wall material, and is prepared into final product by spray drying method. However, the temperature control is high in the preparation process, the lutein is unstable in property and possibly goes bad due to high temperature, and the preparation is a microcapsule and has a complex preparation process.
The inventor of the invention creatively discovers that compared with a binary system and a ternary system, the solubility of a lutein-cyclodextrin-surfactant-hydrophilic carrier material quaternary system is greatly improved (specific data are shown in each embodiment of the invention), and the in vitro dissolution rate of the lutein is greatly improved by further improving the formulas of the binary system and the ternary system through a large number of research experiments aiming at the defects of the prior art. Compared with the traditional water-soluble lutein particles or powder, the high-solubility lutein prescription disclosed by the invention not only has higher solubility and in-vitro dissolution rate, but also can improve the membrane permeability of lutein, so that the absorption of lutein in Caco-2 cells and the bioavailability in rats are greatly improved. And the invention draws the advantages of the traditional water-soluble particles or powder and simplifies the traditional preparation process.
To this end, one aspect of the present invention provides a pharmaceutical composition containing lutein, which comprises the following components by weight: 0.1-10% of lutein crystal, 30-70% of cyclodextrin, 10-30% of surfactant and 10-30% of hydrophilic carrier material.
Preferably, the pharmaceutical composition containing lutein of the present invention comprises the following components by weight: 1% -3% of lutein crystal, 50% -70% of cyclodextrin, 10% -25% of surfactant and 10% -25% of hydrophilic carrier material.
Wherein, the cyclodextrin preferably comprises α -cyclodextrin, β -cyclodextrin, gamma-cyclodextrin, hydroxypropyl- β -cyclodextrin, methyl- β -cyclodextrin and sulfobutyl- β -cyclodextrin or the combination of several of them.
Wherein, the surfactant preferably comprises one or the combination of more of lauryl sodium sulfate, hexadecyl sodium sulfate, Tween 40, Tween 60, Tween 80, span 60, span 80 and span 85.
Wherein, the hydrophilic carrier material preferably comprises one or a combination of more of polyethylene glycol, povidone, sodium carboxymethylcellulose, poloxamer and sodium alginate.
The invention provides a pharmaceutical composition containing lutein, which comprises the following components in percentage by weight: 1% -3% of lutein crystal, 50% -70% of cyclodextrin, 10% -25% of tween and 10% -25% of poloxamer.
In another aspect, the present invention also provides a method for preparing the above pharmaceutical composition containing lutein, which comprises: dissolving the lutein crystal, hydrophilic carrier material, surfactant and cyclodextrin in solvent, mixing the components uniformly, reacting fully, and removing solvent to obtain dried product.
Wherein, the solvent can be conventional in the field, and preferably comprises one or more of water, ethanol, glycol and acetone.
The solvent removal method can be conventional in the art, and preferably comprises one or more of spray drying method, freeze drying method, rotary evaporation method and fluidized bed drying method.
In a preferred embodiment of the present invention, there is provided a method for preparing the pharmaceutical composition containing lutein, which comprises the steps of:
a) dissolving a hydrophilic carrier material in a solvent, adding a surfactant, carrying out ultrasonic or magnetic stirring to obtain a uniform mixed solution, adding cyclodextrin, and carrying out ultrasonic or magnetic stirring to obtain a uniform mixed solution;
b) finally adding lutein crystals, and carrying out ultrasonic or magnetic stirring for full reaction to obtain a uniform lutein mixed solution;
c) and (4) obtaining a dried finished product by a solvent removal method.
Wherein, if the solvent removing method adopts a spray drying method, the uniform lutein mixed solution is subjected to spray drying, and the solvent is removed to obtain a final finished product; if the solvent removal method adopts a freeze-drying method, the uniform lutein mixed solution is subjected to freeze-drying, and the solvent is removed to obtain a final finished product; if the solvent removal method adopts a rotary evaporation method, the uniform lutein mixed solution is volatilized at 40 ℃ to remove the solvent, and a final finished product is obtained; if the solvent removal method adopts a fluidized bed drying method, the uniform lutein mixed solution is placed in a fluidized bed and dried under the conditions that the physical and chemical pressure is 15000-20000pa and the temperature of materials and air is 40-50 ℃ to obtain the final product.
The obtained high-solubility xanthophyll product can be mixed with various conventional carriers in pharmaceutical field, and made into capsule, tablet, dripping pill, granule, concentrated pill, aqueous or oily suspension, solution, emulsion, syrup, elixir, etc., or added with various nutrient elements to make dietary supplement.
In still another aspect of the present invention, there is provided a pharmaceutical preparation containing lutein, which comprises the above pharmaceutical composition containing lutein and a pharmaceutically acceptable carrier.
Wherein the pharmaceutically acceptable carrier comprises various diluents, excipients, fillers, emulsifiers, binders, lubricants, absorption promoters, disintegrants, antioxidants, etc. which are conventional in the pharmaceutical field.
The dosage form of the pharmaceutical preparation can be any of various conventional oral solid preparations or oral liquid preparations, preferably capsules, tablets, dripping pills, granules, concentrated pills, aqueous or oily suspensions, solutions, emulsions, syrups and elixirs.
In yet another aspect of the present invention there is provided a dietary supplement comprising the aforementioned pharmaceutical composition comprising lutein.
The dietary supplement may also include some dietary supplement elements conventional in the art, as is conventional in the art.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The following description of certain embodiments of the invention, together with the accompanying drawings, further illustrate the practice and technical effects of the invention.
Example 1 phase solubility test of lutein with four different cyclodextrins (α -cyclodextrin, β -cyclodextrin, gamma-cyclodextrin, hydroxypropyl- β -cyclodextrin)
α -cyclodextrin with different molar concentrations of 0mmol/ml, 0.0025mmol/ml, 0.005mmol/ml, 0.01mmol/ml, 0.02mmol/ml and 0.03mmol/ml is used for carrying out a phase solubility test on lutein under certain conditions, and after the reaction is finished, the concentration of the lutein dissolved in the solution is determined, and a phase solubility curve is drawn by taking the molar concentration of α -cyclodextrin as a horizontal coordinate and the water solubility of the lutein as a vertical coordinate.
β -cyclodextrin with different molar concentrations of 0mmol/ml, 0.0025mmol/ml, 0.005mmol/ml, 0.01mmol/ml, 0.02mmol/ml and 0.03mmol/ml is used for carrying out a phase solubility test on lutein under certain conditions, and after the reaction is finished, the concentration of the lutein dissolved in the solution is determined, and a phase solubility curve is drawn by taking the molar concentration of β -cyclodextrin as a horizontal coordinate and the water solubility of the lutein as a vertical coordinate.
A series of different molarity: 0mmol/ml, 0.0025mmol/ml, 0.005mmol/ml, 0.01mmol/ml, 0.02mmol/ml and 0.03mmol/ml of gamma-cyclodextrin are used for carrying out a phase solubility test on the lutein under certain conditions, and after the reaction is finished, the concentration of the lutein dissolved in the solution is determined, and a phase solubility curve is drawn by taking the molar concentration of the gamma-cyclodextrin as an abscissa and the water solubility of the lutein as an ordinate.
Carrying out a phase solubility test on lutein by using hydroxypropyl- β -cyclodextrin with different molar concentrations of 0mmol/ml, 0.0025mmol/ml, 0.005mmol/ml, 0.01mmol/ml, 0.02mmol/ml and 0.03mmol/ml under a certain condition, determining the concentration of the lutein dissolved in a solution after the reaction is finished, and drawing a phase solubility curve by using the molar concentration of HP- β -cyclodextrin as a horizontal coordinate and the water solubility of the lutein as a vertical coordinate.
The detection method comprises the following steps: detecting by adopting a high performance liquid chromatography, wherein the chromatographic conditions are as follows: eclipse XDB C18 column (250 mm. times.4.6 mm, 5 μm); protection of the column: eclipse XDB C18 column (12.5 mm. times.4.6 mm, 5 μm); mobile phase: acetonitrile-methanol (1: 9); column temperature: 30 ℃; detection wavelength: 445 nm; flow rate: 1.0 mL/min -1; sample introduction amount: 20 μ L. The detection results are shown in FIG. 1, wherein CD is Cyclodextrin (Cyclodextrin).
Example 2 solubility test of the lutein- γ -cyclodextrin-hydrophilic Carrier Material (Tween 80, PEG1000, Poloxamer188, PVP) ternary System
Prescription 1
Xanthophyll 1mg/ml
Tween 801% ml/ml
Prescription 2
Xanthophyll 1mg/ml
Gamma-cyclodextrin 0.03mmol/ml
Tween 801% ml/ml
Prescription 3
Xanthophyll 1mg/ml
Gamma-cyclodextrin 0.03mmol/ml
PEG1000 1％ml/ml
Prescription 4
Xanthophyll 1mg/ml
Gamma-cyclodextrin 0.03mmol/ml
Poloxamer188 1％mg/ml
Prescription 5
Xanthophyll 1mg/ml
Gamma-cyclodextrin 0.03mmol/ml
PVP 1％mg/ml
The operation method comprises the following steps:
the lutein in each prescription is fixed to 10mg, the volume of the solution is 10ml, the prescription 1 is a binary system only containing lutein and tween 80, the prescriptions 2, 3, 4 and 5 all contain gamma-cyclodextrin with a fixed molar concentration of 0.03mmol/ml, the influence of different carrier materials of tween 80, PEG1000, Poloxamer188 and PVP on the solubility of lutein is examined, and the result is shown in fig. 2.
Example 3 solubility test of the lutein-HP- β -Cyclodextrin-hydrophilic Carrier Material (Tween 80, PEG1000, Poloxamer188, PVP) ternary System
Prescription 1
Xanthophyll 1mg/ml
Tween 801% ml/ml
Prescription 2
Xanthophyll 1mg/ml
HP- β -Cyclodextrin 0.03mmol/ml
Tween 801% ml/ml
Prescription 3
Xanthophyll 1mg/ml
HP- β -Cyclodextrin 0.03mmol/ml
PEG1000 1％ml/ml
Prescription 4
Xanthophyll 1mg/ml
HP- β -Cyclodextrin 0.03mmol/ml
Poloxamer188 1％mg/ml
Prescription 5
Xanthophyll 1mg/ml
HP- β -Cyclodextrin 0.03mmol/ml
PVP 1％mg/ml
The operation method comprises the following steps:
the lutein in each prescription is fixed to be 10mg, the volume of the solution is 10ml, the prescription 1 is a binary system only containing lutein and Tween 80, the prescriptions 2, 3, 4 and 5 respectively contain HP- β -cyclodextrin with a certain molar concentration of 0.03mmol/ml, the influence of different carrier materials of Tween 80, PEG1000, Poloxamer188 and PVP on the solubility of the lutein is examined, and the result is shown in figure 3.
Example 4 Effect of concentration in lutein- γ -Cyclodextrin-Tween 80 ternary System on lutein solubility
Prescription 1
Xanthophyll 1mg/ml
Gamma-cyclodextrin 0.01mmol/ml
Tween 801% ml/ml
Prescription 2
Xanthophyll 1mg/ml
Gamma-cyclodextrin 0.01mmol/ml
Tween 802% ml/ml
Prescription 3
Xanthophyll 1mg/ml
Gamma-cyclodextrin 0.01mmol/ml
Tween 803% ml/ml
Prescription 4
Xanthophyll 1mg/ml
Gamma-cyclodextrin 0.02mmol/ml
Tween 801% ml/ml
Prescription 5
Xanthophyll 1mg/ml
Gamma-cyclodextrin 0.02mmol/ml
Tween 802% ml/ml
Prescription 6
Xanthophyll 1mg/ml
Gamma-cyclodextrin 0.02mmol/ml
Tween 803% ml/ml
Prescription 7
Xanthophyll 1mg/ml
Gamma-cyclodextrin 0.03mmol/ml
Tween 801% ml/ml
Prescription 8
Xanthophyll 1mg/ml
Gamma-cyclodextrin 0.03mmol/ml
Tween 802% ml/ml
Prescription 9
Xanthophyll 1mg/ml
Gamma-cyclodextrin 0.03mmol/ml
Tween 803% ml/ml
The operation method comprises the following steps:
in each prescription, lutein was fixed at 10mg and the solution volume was 10ml, and nine sets of experiments were performed in parallel: when the concentration of the gamma-cyclodextrin in the solution is 0.01mmol/ml, adding 1%, 2% and 3% of Tween 80 respectively, and measuring the solubility of lutein in different formulas after full reaction; when the concentration of the gamma-cyclodextrin in the solution is 0.02mmol/ml, adding 1%, 2% and 3% of Tween 80 respectively, and measuring the solubility of lutein in different formulas after full reaction; when the concentration of gamma-cyclodextrin in the solution is 0.03mmol/ml, adding 1%, 2% and 3% tween 80 respectively, after full reaction, measuring the solubility of lutein in different formulas, and examining the influence of the concentration of gamma-cyclodextrin and the volume percentage of tween 80 on the solubility of lutein, see fig. 4 for the result.
Example 5 Effect of concentration in lutein-HP- β -Cyclodextrin-Tween 80 ternary System on lutein solubility
Prescription 1
Xanthophyll 1mg/ml
HP- β -Cyclodextrin 0.01mmol/ml
Tween 801% ml/ml
Prescription 2
Xanthophyll 1mg/ml
HP- β -Cyclodextrin 0.01mmol/ml
Tween 802% ml/ml
Prescription 3
Xanthophyll 1mg/ml
HP- β -Cyclodextrin 0.01mmol/ml
Tween 803% ml/ml
Prescription 4
Xanthophyll 1mg/ml
HP- β -Cyclodextrin 0.02mmol/ml
Tween 801% ml/ml
Prescription 5
Xanthophyll 1mg/ml
HP- β -Cyclodextrin 0.02mmol/ml
Tween 802% ml/ml
Prescription 6
Xanthophyll 1mg/ml
HP- β -Cyclodextrin 0.02mmol/ml
Tween 803% ml/ml
Prescription 7
Xanthophyll 1mg/ml
HP- β -Cyclodextrin 0.03mmol/ml
Tween 801% ml/ml
Prescription 8
Xanthophyll 1mg/ml
HP- β -Cyclodextrin 0.03mmol/ml
Tween 802% ml/ml
Prescription 9
Xanthophyll 1mg/ml
HP- β -Cyclodextrin 0.03mmol/ml
Tween 803% ml/ml
The operation method comprises the following steps:
fixing lutein in each prescription to 10mg, setting the volume of the solution to 10ml, carrying out nine groups of experiments in parallel, when the concentration of HP- β -cyclodextrin in the solution is 0.01mmol/ml, respectively adding 1%, 2% and 3% of Tween 80, fully reacting, and then measuring the solubility of lutein in different prescriptions, when the concentration of HP- β -cyclodextrin in the solution is 0.02mmol/ml, respectively adding 1%, 2% and 3% of Tween 80, fully reacting, then measuring the solubility of lutein in different prescriptions, when the concentration of HP- β -cyclodextrin in the solution is 0.03mmol/ml, respectively adding 1%, 2% and 3% of Tween 80, fully reacting, and then measuring the solubility of lutein in different prescriptions, and investigating the influence of the concentration of HP- β -cyclodextrin and the volume percentage of Tween 80 on the solubility of lutein, wherein the results are shown in FIG. 5.
Example 6 solubility testing of a Quaternary System of lutein-Cyclodextrin-Tween-hydrophilic Carrier Material (Poloxamer188, PEG1000, PVP, SDS, CMC)
Prescription 1
Figure BDA0001298900930000121
Prescription 2
Figure BDA0001298900930000122
Prescription 3
Figure BDA0001298900930000123
Prescription 4
Figure BDA0001298900930000124
Prescription 5
Figure BDA0001298900930000125
Figure BDA0001298900930000131
Prescription 6
Figure BDA0001298900930000132
Prescription 7
Figure BDA0001298900930000133
Prescription 8
Figure BDA0001298900930000134
Prescription 9
Figure BDA0001298900930000135
Prescription 10
Figure BDA0001298900930000136
The operation method comprises the following steps:
1) the lutein in each prescription is fixed to 10mg, the volume of the solution is 10ml, the volume percentage of tween 80 is 1%, when the cyclodextrin is gamma-cyclodextrin and the concentration is 0.03mmol/ml, hydrophilic carrier materials of Poloxamer188, PVP, PEG1000, SDS and CMC-Na with the mass percentage of 1% are respectively added, and after full reaction, the solubility of the lutein in different prescriptions is measured, and the result is shown in figure 6.
2) The lutein in each prescription is fixed to 10mg, the volume of the solution is 10ml, the volume percentage of tween 80 is 1%, when the cyclodextrin is HP- β -cyclodextrin, and the concentration is 0.03mmol/ml, hydrophilic carrier materials Poloxamer188, PVP, PEG1000, SDS and CMC-Na with the mass percentage of 1% are respectively added, and after full reaction, the solubility of the lutein in different prescriptions is measured, and the result is shown in FIG. 6.
Example 7 Effect of Cyclodextrin species on lutein solubility in Tetrakis-Cyclodextrin-Tween-Perosamer Quaternary System
Prescription 1
Figure BDA0001298900930000141
Prescription 2
Figure BDA0001298900930000142
Prescription 3
Figure BDA0001298900930000143
The lutein in each prescription is fixed to 10mg, the volume of the solution is 10ml, the volume percentage of tween 80 is 1 percent, the mass percentage of Poloxamer188 is 1 percent, gamma-cyclodextrin, HP- β -cyclodextrin and β -cyclodextrin with the molar concentration of 0.03mmol/ml are respectively added, after full reaction, the solubility of the lutein in different prescriptions is measured, and the result is shown in figure 7.
The preparation method comprises the following steps: dissolving poloxamer in appropriate amount of ethanol solution, adding tween 80, performing ultrasonic treatment to obtain uniform mixed solution, adding cyclodextrin, performing ultrasonic treatment to obtain uniform mixed solution, adding xanthophyll crystal, and performing ultrasonic treatment for 30min to obtain xanthophyll mixed solution. Volatilizing the organic solvent in the prepared lutein mixed solution at 40 ℃, and drying to obtain the final product.
Dissolving the prepared xanthophyll finished product powder in 10ml deionized water, performing ultrasonic treatment for 10min, after complete dissolution, centrifuging to obtain supernatant, filtering with 0.45 μm microporous membrane, discarding primary filtrate, detecting the sample solution at wavelength of 445nm by high performance liquid chromatography, and calculating xanthophyll solubility by external standard method, wherein the result is shown in FIG. 7.
Example 8 in vitro characterization and in vivo and in vitro bioavailability assay of the Tetrakis System of lutein-Cyclodextrin-Tween-Perosamer
Prescription
Figure BDA0001298900930000151
The preparation method comprises the following steps: dissolving poloxamer188 in an appropriate amount of ethanol solution, adding tween 80, performing ultrasonic treatment to obtain a uniform mixed solution, adding cyclodextrin, performing ultrasonic treatment to obtain a uniform mixed solution, adding lutein crystal, and performing ultrasonic treatment for 30min to obtain lutein mixed solution. Volatilizing the organic solvent in the prepared lutein mixed solution at 40 ℃, and drying to obtain a final finished product (hereinafter called a high-solubility lutein prescription).
Operation 1: in vitro dissolution test of high-solubility lutein prescription
Bulk drugs and physical mixtures were prepared in parallel for in vitro dissolution studies. According to the second method of measuring the release rate in the four 0931 items of the pharmacopoeia 2015 edition, 900mL of distilled water is used as a release medium, the temperature is controlled to be (37 +/-0.5) DEG C, and the rotating speed is 100 r.min-1Taking 5mL of solution at 5min, 10min, 15 min, 20 min, 30min and 45min, filtering with 0.45 μm microporous membrane, discarding the primary filtrate, taking the secondary filtrate for use, and instantly supplementing 5mL of blank medium solution; the dissolution rates at different time points were calculated by high performance liquid chromatography at 445nm, and the results are shown in FIG. 8.
Operation 2: differential scanning calorimetry detection test for high-solubility lutein prescription
Preparing a physical mixture of raw material medicines, single auxiliary materials and a prescription in parallel, analyzing and measuring a sample by adopting a DSC-60 type differential scanning calorimeter, precisely weighing the sample (about 3mg), and setting DSC analysis conditions as follows: the scanning range is 20-200 ℃, and the heating rate is 10 ℃ per minute-1The scanning environment is N2The atmosphere and the results are shown in FIG. 9.
Operation 3: fourier transform infrared spectrum detection test for high-solubility lutein prescription
Preparing a physical mixture of the raw material medicine, the single auxiliary material and the prescription in parallel, analyzing a sample by adopting a Fourier infrared spectrometer, grinding and pressing sample powder and KBr together into a sheet, and then performing infrared scanning analysis. The scanning range is 400-4000 cm-1Scanning speed of 2cm-1The results are shown in FIG. 10.
And operation 4: molecular dynamics simulation test of high-solubility lutein prescription
The inventor also provides a molecular dynamics simulation method of the molecular interaction between lutein and each component, which intuitively presents the state and interaction of the high-solubility lutein prescription existing in each component molecule at the molecular level, and the result is shown in fig. 11.
Operation 5: caco-2 cell absorption experiment for high-solubility lutein prescription
Caco-2 cells were inoculated in 12-well plates in suspension at a density of 5X 104Per well, put 5% CO2Culturing in 37 deg.C incubator for 48 hr, adding 1ml serum-free xanthophyll raw material (0.197ug/ml) and high-solubility xanthophyll prescription (25ug/ml and 50ug/ml) DMEM culture solution, and incubating for 24 hr. Then immediately washing the cells with PBS solution three times, removing lutein on the cell surface, dissolving the cells with trypsin, centrifuging, removing the supernatant, and adding 500 μ L DMSO to extract lutein in the cells. The xanthophyll concentration in the cells was analyzed by high performance liquid chromatography, and the results are shown in FIG. 12.
Operation 6: high-solubility lutein prescription rat in vivo pharmacokinetic test
Bulk drug and commercial formulations were prepared in parallel as reference formulations. Healthy SD male rats, with a weight of about 200-. Fasted for 12h the day before the experiment and water was freely available. The test animals were randomly divided into 2 groups of 6 animals each, and the lutein drug substance and the test preparation T (highly soluble lutein prescription, i.e. the lutein pharmaceutical composition of the present invention) were administered separately in a single dose of 10mg/kg BW. The lutein raw material medicine and the tested preparation are respectively drenched, 0, 0.16, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 10 hours after administration, and 300 mu L of blood is taken from the orbit. The plasma was transferred to a heparin-coated tube, centrifuged at 3000rpm for 10min, separated and stored in a freezer at-80 ℃ until use. Plasma samples were processed and plasma concentrations were measured at various time points using high performance liquid chromatography and pharmacokinetic parameters were calculated as shown in table 1 and fig. 13.
Table 1 shows the pharmacokinetic parameters of the highly soluble xanthophyll pharmaceutical composition of the present invention in rats, wherein API is xanthophyll bulk drug and lutein-SDs is highly soluble xanthophyll prescription, i.e. finished xanthophyll pharmaceutical composition of the present invention.
TABLE 1 measurement of pharmacokinetic parameters
Parameter(s) Unit of API Lutein-SDs
Cmax ng·mL-1 20.417 135.812
Tmax h 2 2
AUC0-t ng·h·mL-1 95.742 633.042
AUC0-∞ ng·h·mL-1 173.559 861.538
The above-mentioned embodiments are intended to illustrate the objects, technical solutions and advantages of the present invention in further detail, and it should be understood that the above-mentioned embodiments are only exemplary embodiments of the present invention and are not intended to limit the present invention, and any modifications, equivalents, improvements and the like made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (11)

1. A pharmaceutical composition containing lutein comprises the following components in percentage by weight: 0.1% -10% of lutein crystal, 30% -70% of cyclodextrin, 10% -30% of surfactant and 10% -30% of hydrophilic carrier material;
the surfactant is one or a combination of more of Tween 40, Tween 60 and Tween 80;
the hydrophilic carrier material is poloxamer.
2. The lutein-containing pharmaceutical composition according to claim 1, which consists of the following components in percentage by weight: 1% -3% of lutein crystal, 50% -70% of cyclodextrin, 10% -25% of surfactant and 10% -25% of hydrophilic carrier material.
3. The pharmaceutical composition containing lutein according to claim 1 or 2, wherein the cyclodextrin comprises one or more of α -cyclodextrin, β -cyclodextrin, γ -cyclodextrin, hydroxypropyl- β -cyclodextrin, methyl- β -cyclodextrin and sulfobutyl- β -cyclodextrin.
4. A pharmaceutical composition containing lutein comprises the following components in percentage by weight: 1% -3% of lutein crystal, 50% -70% of cyclodextrin, 10% -25% of tween and 10% -25% of poloxamer.
5. A process for the preparation of a pharmaceutical composition containing lutein according to any of claims 1 to 4 comprising: dissolving the lutein crystal, hydrophilic carrier material, surfactant and cyclodextrin in solvent, mixing the components uniformly, reacting fully, and removing solvent to obtain dried product.
6. The method according to claim 5, wherein the solvent comprises one or more of water, ethanol, ethylene glycol and acetone.
7. The method of claim 5, wherein the solvent removal method comprises one or more of spray drying, freeze drying, rotary evaporation and fluidized bed drying.
8. A pharmaceutical preparation containing lutein, comprising the pharmaceutical composition containing lutein according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.
9. The pharmaceutical formulation containing xanthophyll of claim 8, wherein the pharmaceutical formulation is in a dosage form selected from any one of capsules, tablets, dripping pills, granules, pellets for concentration, aqueous or oily suspensions, solutions and emulsions.
10. The lutein-containing pharmaceutical formulation according to claim 9, wherein the solution is a syrup or elixir.
11. A dietary supplement comprising a pharmaceutical composition containing lutein according to any one of claims 1 to 4.
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WO2004026231A2 (en) * 2002-09-18 2004-04-01 Bone Care International, Inc. Formulation for lipophilic agents
CN103860476A (en) * 2014-02-28 2014-06-18 广州新济药业科技有限公司 Lutein water soluble powder and preparation method thereof

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Publication number Priority date Publication date Assignee Title
WO2004026231A2 (en) * 2002-09-18 2004-04-01 Bone Care International, Inc. Formulation for lipophilic agents
CN103860476A (en) * 2014-02-28 2014-06-18 广州新济药业科技有限公司 Lutein water soluble powder and preparation method thereof

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