CN107286104A - A kind of Sai Lexipa and pharmaceutic adjuvant solid dispersions and preparation method thereof - Google Patents
A kind of Sai Lexipa and pharmaceutic adjuvant solid dispersions and preparation method thereof Download PDFInfo
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- CN107286104A CN107286104A CN201610225862.3A CN201610225862A CN107286104A CN 107286104 A CN107286104 A CN 107286104A CN 201610225862 A CN201610225862 A CN 201610225862A CN 107286104 A CN107286104 A CN 107286104A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/20—Nitrogen atoms
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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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
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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
- A61K9/145—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 compounds
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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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Abstract
A kind of unformed Sai Lexipa, it is characterised in that the characteristic peak without Sai Lexipa in X ray Powder Diffraction patterns.The preparation method of unformed Sai Lexipa a kind of and its solid dispersions and its manufacture method with pharmaceutic adjuvant, it includes Sai Lexipa and pharmaceutic adjuvant, and both weight ratios are 1:0.1~100, wherein, Sai Lexipa is unformed shape, and the characteristic peak of the crystal without Sai Lexipa after the background peaks of pharmaceutic adjuvant is deducted in the X ray Powder Diffraction patterns of the solid dispersions.The Sai Lexipa of the present invention and the solid dispersions stability and favorable dispersibility of pharmaceutic adjuvant, add Sai Lexipa dissolution rate, it is more beneficial for improving the absorption of the bioavilability and body of pharmaceutical preparation to medicine, under the conditions of accelerated test, good physical stability and chemical stability can be kept.The preparation method of the unformed solid dispersions of the present invention is simple to operate, with low cost, favorable reproducibility, it is easy to accomplish, it is adapted to industrialized production.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular to a kind of unformed Sai Lexipa, further relate to one
Plant solid dispersions of unformed Sai Lexipa and pharmaceutic adjuvant and preparation method thereof.
Background technology
Sai Lexipa (Selexipag), chemical entitled 2- { 4- [(5,6- diphenyl -2- pyrazinyls) (isopropyl)
Amino] butoxy }-N- (methyl sulphonyl) acetamide, trade name Uptravi, its structure is as follows：
The medicine is a kind of selective non-prostanoid IP prostacyclins of Nippon Shinyaku Co., Ltd.'s research and development
Receptor stimulating agent, it is adaptable to treat pulmonary hypertension (PAH, WHO group I) and delay progression of disease and attenuating
The risk being in hospital for PAH.Compared with existing medicine, Sai Lexipa has more preferable security, is lung
Arterial hypertension patient provides an extra therapeutic choice.On December 21st, 2015, FDA approvals
Uptravi is listed in the U.S..
Although Sai Lexipa curative effect has been widely recognized as, but still there are some defects.Patent
CN102459198A discloses Sai Lexipa three kinds of crystal formations：Crystal formation I, crystal formation II and crystal formation III, its
Middle crystal formation I is thermodynamically stable crystal formation, and stable type is good, but solubility of the crystal formation in water is low,
It has impact on the bioavilability of medicine.
The solid forms of medicine directly affect the rate of dissolution of bulk drug, the dissolution rate of preparation and biology profit
Expenditure, in order to improve the bioavilability of medicine, reduction consumption, reduction toxic side effect, it will usually open
The new solid forms of dispensing thing, therefore, develop the drug solubility more preferably, bioavilability it is higher
Solid form just seem necessary.
The solid forms of medicine are in addition to crystalline state, also unformed state, the unformed state conduct of medicine
A kind of specific form of solid matter, there is important purposes in medicine preparation.Unformed shape medicine
It not only can be widely applied in pharmaceutical preparation, and can be improved by multiple technologies means and method
The stability of unformed shape medicine, makes the medicine being possessed of good qualities.
Due to Sai Lexipa good application of the unformed active constituents of medicine in terms of pharmaceutical preparation
Prospect, finds new unformed Sai Lexipa and preparation method thereof and just seems very necessary.
The content of the invention
It is an object of the invention to provide a kind of Sai Lexipa and the solid dispersions and its system of pharmaceutic adjuvant
Preparation Method, obtains the Sai Lexipa of the unformed shape of stability and favorable dispersibility and consolidating for pharmaceutic adjuvant
Body dispersion, adds Sai Lexipa dissolution rate, and the preparation method is not limited by drying process,
Also do not limited by solvent species and quantity of solvent, it is easy to operate, it is with low cost, it is easy to accomplish, can be real
Existing industrialized production.
In order to achieve the above object, technical scheme is as follows：
A kind of unformed Sai Lexipa, preparation method comprises the following steps：
1) after Sai Lexipa solvents are dissolved, solution temperature is -50~150 DEG C, is formed and contains Sai Lexi
The solution of handkerchief, wherein, the weight ratio of Sai Lexipa and solvent is 0.001~100:1；
2) removing step 1) solvent in obtained solution, or by step 1) obtained solution is rapid
Cooling, or poor solvent is rapidly joined, crystallization is carried out, Sai Lexipa unformed form is obtained.
Also, step 1) solvent be selected from the alcohols containing less than 12 carbon atoms, phenols, ethers,
At least one of halogenated hydrocarbons, ketone, aldehydes, nitrile, acid amides, sulfone, sulfoxide, carboxylic acid and water,
Step 2) remove solvent method include：Evaporate, be evaporated in vacuo, being spray-dried, being freeze-dried,
Hot-melt extruded, filtering, centrifugation or agitated thin film.
A kind of Sai Lexipa and pharmaceutic adjuvant solid dispersions, the solid dispersions include Sai Lexipa
With pharmaceutic adjuvant, both weight ratios are 1:0.1~100, wherein, described Sai Lexipa is unformed
In state, the X-ray powder diffraction spectrum of the solid dispersions, after the background peaks for deducting pharmaceutic adjuvant
The characteristic peak of crystal without Sai Lexipa.
Further, the pharmaceutic adjuvant is selected from diluent, lubricant, adhesive, disintegrant, surface
At least one of activating agent, filmogen, coating material and capsule material.
Preferably, described pharmaceutic adjuvant is selected from HPMC, hydroxypropyl cellulose, poly- dimension
Ketone, polyethylene glycol, ethyl cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate,
The adjacent benzene two of carboxymethylethylcellulose, carboxymethyl cellulose phthalic acid ester, HPMC
Formic acid esters, HPMC acetate succinate, polyacrylic resin, carbopol, algae
Hydrochlorate, carragheen, caprolactone, natural gum, polyvinyl alcohol, pregelatinized starch, crosslinked starch,
Sodium carboxymethyl starch, dextrin, PEO, chitosan, chitosan, ion exchange resin and
At least one of collagen.
The present invention provides the preparation method of the solid dispersions of another Sai Lexipa and pharmaceutic adjuvant, bag
Include following steps：
1) Sai Lexipa and pharmaceutic adjuvant are mixed in a solvent, mixing temperature is -50~150 DEG C, is formed
Solution or suspension containing Sai Lexipa and pharmaceutic adjuvant, wherein, the weight ratio of Sai Lexipa and solvent
For 0.001~100:1, Sai Lexipa and pharmaceutic adjuvant weight ratio be 1:0.1~100；
2) removing step 1) solvent in obtained solution or suspension, obtain the match pleasure of unformed shape
The solid dispersions of western handkerchief and pharmaceutic adjuvant.
Further, the pharmaceutic adjuvant is selected from diluent, lubricant, adhesive, disintegrant, surface
At least one of activating agent, filmogen, coating material and capsule material.
Preferably, step 1) described in pharmaceutic adjuvant to be selected from HPMC, hydroxypropyl fine
Tie up element, PVP, microcrystalline cellulose, polyethylene glycol, ethyl cellulose, liposome, metering system
Acid copolymer, polyvinyl acetate, carboxymethylethylcellulose, carboxymethyl cellulose phthalic acid ester,
Hydroxypropyl methylcellulose phthalate, HPMC acetate succinate, polypropylene
Acid resin, carbopol, alginates, carragheen, caprolactone, natural gum, polyvinyl alcohol,
It is pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, PEO, chitosan, several
At least one of fourth glycan, ion exchange resin and collagen.
Also, step 1) solvent be selected from the alcohols containing less than 12 carbon atoms, phenols, ethers,
At least one of halogenated hydrocarbons, ketone, aldehydes, nitrile, acid amides, sulfone, sulfoxide, carboxylic acid and water,
Step 2) remove solvent method include：Evaporate, be evaporated in vacuo, being spray-dried, being freeze-dried,
Hot-melt extruded, filtering, centrifugation or agitated thin film.
Solid dispersions in the present invention refer to mixture, compound, copolymer, co-precipitate, altogether
Crystalline substance, solid dispersions, solvate and hydrate.
The Sai Lexipa of the present invention and the solid dispersions of pharmaceutic adjuvant, are radiated using Cu-K α, to spend
The background peaks that pharmaceutic adjuvant is deducted in the X-ray powder diffraction spectrum that 2 θ are represented are crystallized without Sai Lexipa
The characteristic peak of state, it is unformed state to show Sai Lexipa.Sai Lexipa is typically used in the prior art
Crystalline state, have no the report of its unformed shape.Normally due to the orderly and cycle of amorphous material molecule
Property arrangement, reduce the energy of intermolecular interaction, energy is relatively low, and the present invention Sai Lexipa be
Unformed shape, molecule is in height disordered state, and the surface free energy of material is bigger, in solid matter
Molecule has higher energy compared with the molecule in crystalline solid material, it is easier to scattered, increases its dissolution rate,
Improve Sai Lexipa bioavilability.
After Sai Lexipa and pharmaceutic adjuvant are well mixed by the present invention, " solid dispersion " method is used, is led to
The polymer network structure for crossing pharmaceutic adjuvant obstructs drug molecule, suppresses the generation of crystallization, protects it
Hold scattered and unformed state.It is medicinal that the present invention is using being widely used, cheap, dissolubility is good
Auxiliary material, these pharmaceutic adjuvants are mixed with Sai Lexipa, coordinate evaporation, spray drying, freeze-drying and
The technologies such as hot-melt extruded can obtain Sai Lexipa amorphous forms, increase Sai Lexipa's of the present invention
The stability of the unformed shape of Sai Lexipa in solid dispersions.
The present invention select pharmaceutically widely used, cheap auxiliary material, obtain Sai Lexipa with
The solid dispersions of pharmaceutic adjuvant, it is easy to develop pharmaceutical formulation, preparation method of the invention is not dried
The limitation of process, is not also limited by solvent species and quantity of solvent, easy to operate, with low cost, easily
In realization, industrialized production can be achieved.
Compared with prior art, the beneficial effects of the invention are as follows：
1) unformed Sai Lexipa prepared by the present invention has preferable stability, compared with crystal formation, tool
There are higher solubility and dissolution rate, be more beneficial for absorption of the body to medicine, improve the life of medicine
Thing availability, allows medicament to preferably play clinical disease treatment effect.
2) the unformed Sai Lexipa and the solid dispersions of pharmaceutic adjuvant that prepared by the present invention have height
Dispersiveness and stability, after solid pharmaceutical preparation is made, the degree of scatter of drug particle can be made by disintegration
More preferably, scattered and dissolution rate faster, is conducive to the absorption of medicine.Therefore, unformed state medicine
Dissolution rate substantially increase, be more beneficial for absorption of the body to medicine, improve the bioavilability of medicine,
Allow medicament to preferably play clinical disease treatment effect.
3) the preparation side of the solid dispersions of the Sai Lexipa of unformed state of the invention and pharmaceutic adjuvant
Method is not limited by drying process, is not also limited by solvent species and quantity of solvent, easy to operate, into
This is cheap, it is easy to accomplish, industrialized production can be achieved.
4) Sai Lexipa of unformed state and the solid dispersions of pharmaceutic adjuvant that prepared by the present invention exist
Under the conditions of accelerated test (40 ± 2 DEG C, humidity 75% ± 5%), can keep good physical stability and
Chemical stability.Therefore, the present invention will have broad application prospects.
Brief description of the drawings
Fig. 1 is the unformed Sai Lexipa of the embodiment of the present invention 1 X-ray powder diffraction figure.
Fig. 2 is that the unformed Sai Lexipa of the embodiment of the present invention 3 and the solid of PVP-K30 disperse
The X-ray powder diffraction figure of body.
Fig. 3 is the unformed Sai Lexipa and polyacrylic resin Eudragit of the embodiment of the present invention 12
The X-ray powder diffraction figure of L100 solid dispersions.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described, but protection scope of the present invention is not
It is limited by the following examples.
X-ray powder diffraction figure of the present invention is gathered on Ultima IV x-ray diffractometers.This
The method parameter of the described X-ray powder diffraction of invention is as follows：
X-ray powder parameter：Cu-Kα
1.5418
Voltage：40 kilovolts
Electric current：40 milliamperes
Divergent slit：Automatically
Scan pattern：Continuously
Scanning range：From 2.0 to 60.0 degree
Sampling step length：0.0200 degree
Sweep speed：60 degrees/min
Embodiment 1
Sai Lexipa (50 milligrams) is dissolved in isopropanol (600 microlitres) and water (900 microlitres),
It is heated to 60 DEG C of stirring dissolved clarifications.Above-mentioned solution is cooled to rapidly -10 DEG C, white solid, mistake is separated out
Filter, dries, obtains unformed Sai Lexipa, X-ray powder diffraction figure as shown in figure 1, X-ray
Characteristic peak without Sai Lexipa crystal formations in powder diagram.
Embodiment 2
Sai Lexipa (50 milligrams) is dissolved in ethanol (600 microlitres) and water (600 microlitres),
It is uniformly mixed at 40 DEG C.Above-mentioned solution is slowly concentrated to dryness in a rotary evaporator, obtained
White solid, obtains unformed Sai Lexipa, X-ray powder diffraction figure as shown in Fig. 2 X-ray
Characteristic peak without Sai Lexipa crystal formations in powder diagram.
Embodiment 3
(10 grams) of Sai Lexipa (5 grams) and PVP K30 are added in water (300 milliliters),
It is heated to 60 DEG C of stirring dissolved clarifications.Above-mentioned solution is dried with JISL mini spray dryers LSD-48,
60 DEG C of inlet temperature, 50 DEG C of outlet temperature are maintained, outlet material is collected, obtains white solid, enter
One step is dried in vacuo the solid dispersions for obtaining unformed Sai Lexipa and PVP-K30.X-ray powder
Last diffraction pattern is as shown in figure 3, in the X-ray powder diffraction figure of the solid dispersions, deduct medicinal auxiliary
Characteristic peak without Sai Lexipa crystal formations after the background peaks of material.
Embodiment 4
Sai Lexipa (1 gram) and HPMC E50 (0.2 gram) are added to water (10 milliliters)
In, it is heated to 40 DEG C of stirring dissolved clarifications.Above-mentioned solution is freeze-dried, white solid is obtained, i.e., without fixed
Type Sai Lexipa and HPMC E50 solid dispersions, the X-ray of the solid dispersions
In powder diagram, the characteristic peak without Sai Lexipa crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 5
Sai Lexipa (1 gram) and PEG 8000 (50 grams) are heated to melting, it is fast under stirring
Speed is cooled to room temperature, obtains white solid.Above-mentioned solid is crushed, white powdery solids are obtained,
I.e. unformed Sai Lexipa and PEG 8000 solid dispersions, the X- of the solid dispersions are penetrated
In line powder diagram, the characteristic peak without Sai Lexipa crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 6
Sai Lexipa (1 gram) and PEG20000 (100 grams) are heated to 240 DEG C, mixing
Uniformly, room temperature is quickly cooled to, white solid is obtained.Above-mentioned solid is crushed, white powder is obtained
Shape solid, i.e., unformed Sai Lexipa and PEG20000 solid dispersions, solid disperses
In the X-ray powder diffraction figure of body, the spy without Sai Lexipa crystal formations after the background peaks of pharmaceutic adjuvant is deducted
Levy peak.
Embodiment 7
Sai Lexipa (1 gram), isopropanol (20 grams) and liposome (4 grams) mixture are added
Heat is to 90 DEG C, and stirring is well mixed, and is evaporated in vacuo and is removed solvent, is cooled to room temperature and obtains white admittedly
Body, i.e., unformed Sai Lexipa and liposome solid dispersions, the X-ray powder of the solid dispersions
In last diffraction pattern, the characteristic peak without Sai Lexipa crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 8
By Sai Lexipa (1 gram), methanol (20 grams) and methacrylic acid copolymer A types (4 grams)
Mixture be heated to 50 DEG C, stirring, dissolved clarification is evaporated in vacuo and removes solvent, is cooled to room temperature and obtains
White solid, i.e., unformed Sai Lexipa and the solid dispersions of methacrylic acid copolymer A types, should
In the X-ray powder diffraction figure of solid dispersions, deduct after the background peaks of pharmaceutic adjuvant without Sai Lexipa
The characteristic peak of crystal formation.
Embodiment 9
By Sai Lexipa (1 gram), isopropanol (20 grams) and ethyl cellulose (2 grams) mixing
Thing is heated to 30 DEG C, stirs, and is well mixed, and is evaporated in vacuo and removes solvent, is cooled to room temperature and obtains white
Color solid, i.e., unformed Sai Lexipa and ethyl cellulose solid dispersions, the solid dispersions
In X-ray powder diffraction figure, the characteristic peak without Sai Lexipa crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 10
By Sai Lexipa (1 gram), methanol (20 grams) and hydroxypropyl cellulose SSL (4 grams)
Mixture is heated to 30 DEG C, stirs dissolved clarification, is evaporated in vacuo and removes solvent, is cooled to room temperature and obtains white
Solid, i.e., unformed Sai Lexipa and hydroxypropyl cellulose SSL solid dispersions, solid disperses
In the X-ray powder diffraction figure of body, the spy without Sai Lexipa crystal formations after the background peaks of pharmaceutic adjuvant is deducted
Levy peak.
Embodiment 11
By Sai Lexipa (1 gram), methanol (20 grams), water (10 grams) and polyvinyl acetate (4
Gram) mixture be heated to 30 DEG C, stir dissolved clarification, be evaporated in vacuo and remove solvent, be cooled to room temperature and obtain
To white solid, i.e., unformed Sai Lexipa and polyvinyl acetate solid dispersions, the solid disperses
In the X-ray powder diffraction figure of body, the spy without Sai Lexipa crystal formations after the background peaks of pharmaceutic adjuvant is deducted
Levy peak.
Embodiment 12
(100 milligrams) of Sai Lexipa (50 milligrams) and polyacrylic resin Eudragit L100 are added
Enter to methanol (750 microlitres), dissolved clarification is stirred at room temperature.Above-mentioned solution is fast in a rotary evaporator
Speed is concentrated to dryness, and obtains white solid, i.e., unformed Sai Lexipa and polyacrylic resin Eudragit
L100 solid dispersions, the X-ray powder diffraction figure of the solid dispersions is as shown in figure 3, X-
The characteristic peak without Sai Lexipa crystal formations after the background peaks of pharmaceutic adjuvant is deducted in ray powder diffraction pattern.
Embodiment 13
By (5 milligrams) additions of Sai Lexipa (50 milligrams) and polyacrylic resin Eudragit S100
To methanol (4 milliliters) and ethyl acetate (1 milliliter), dissolved clarification is stirred at -30 DEG C.By above-mentioned solution
It is concentrated to dryness rapidly in a rotary evaporator, obtains white solid, stirring is lower separates out white solid, i.e.,
Unformed Sai Lexipa and polyacrylic resin Eudragit S100 solid dispersions, the solid disperses
In the X-ray powder diffraction figure of body, the spy without Sai Lexipa crystal formations after the background peaks of pharmaceutic adjuvant is deducted
Levy peak.
Embodiment 14
Sai Lexipa (50 milligrams) and carbopol Carbomer 940 (50 milligrams) are added to
Methanol (4 milliliters) and tetrahydrofuran (1 milliliter), are uniformly mixed at -30 DEG C.Will be above-mentioned molten
Liquid is concentrated to dryness rapidly in a rotary evaporator, obtains white solid, and stirring is lower to separate out white solid,
I.e. unformed Sai Lexipa and carbopol Carbomer 940 solid dispersions, the solid dispersions
X-ray powder diffraction figure in, deduct pharmaceutic adjuvant background peaks after the feature without Sai Lexipa crystal formations
Peak.
Embodiment 15
Sai Lexipa (50 milligrams) and pregelatinized starch Pharma-Gel (100 milligrams) are added to
Methanol (4 milliliters) and water (1 milliliter), are well mixed at room temperature.Above-mentioned solution is steamed in rotation
It is concentrated to dryness rapidly in hair device, obtains white solid, stirring is lower separates out white solid, i.e., unformed match
Le Xipa and Pharma-Gel pregelatinized starch solid dispersions, the X-ray of the solid dispersions
In powder diagram, the characteristic peak without Sai Lexipa crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 16
Sai Lexipa (50 milligrams) and high side chain crosslinked starch (50 milligrams) are added to methanol (4
Milliliter) and water (1 milliliter), dissolved clarification is stirred at room temperature, above-mentioned solution is fast in a rotary evaporator
Speed is concentrated to dryness, and obtains white solid, and stirring is lower to separate out white solid, i.e., unformed Sai Lexipa with
In the solid dispersions of high side chain crosslinked starch, the X-ray powder diffraction figure of the solid dispersions, button
Except the characteristic peak without Sai Lexipa crystal formations after the background peaks of pharmaceutic adjuvant.
Embodiment 17
Sai Lexipa (50 milligrams) and sodium carboxymethylcellulose SCMC (500 milligrams) are added to
Dimethyl sulfoxide (DMSO) (5 milliliters), stirs dissolved clarification at room temperature.Above-mentioned solution is fast in a rotary evaporator
Speed is concentrated to dryness, and obtains white solid, i.e., unformed Sai Lexipa and sodium carboxymethylcellulose SCMC
Solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, deduct the back of the body of pharmaceutic adjuvant
Characteristic peaks of the Jing Fenghou without Sai Lexipa crystal formations.
Embodiment 18
Sai Lexipa (50 milligrams) and chitosan (500 milligrams) are added to ethanol (5 milliliters),
Dissolved clarification is stirred at room temperature, above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, obtains white solid
Body, i.e., unformed Sai Lexipa and chitosan solid dispersions, the X-ray of the solid dispersions
In powder diagram, the characteristic peak without Sai Lexipa crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 19
Sai Lexipa (50 milligrams) and sodium carboxymethyl starch Explotab (500 milligrams) are added to
Ethanol (5 milliliters), is uniformly mixed at room temperature, and above-mentioned solution is rapid in a rotary evaporator
Be concentrated to dryness, obtain white solid, i.e., unformed Sai Lexipa and sodium carboxymethyl starch Explotab's
In solid dispersions, the X-ray powder diffraction figure of the solid dispersions, the background of pharmaceutic adjuvant is deducted
Characteristic peak without Sai Lexipa crystal formations behind peak.
Embodiment 20
Sai Lexipa (50 milligrams) and alginates E401 (500 milligrams) are added to ethanol (5 millis
Rise), it is uniformly mixed at room temperature.Above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator,
Obtain white solid, i.e., unformed Sai Lexipa and alginates E401 solid dispersions, the solid
In the X-ray powder diffraction figure of dispersion, deduct after the background peaks of pharmaceutic adjuvant without Sai Lexipa crystal formations
Characteristic peak.
Embodiment 21
By Sai Lexipa (50 milligrams) and carboxymethyl cellulose phthalic acid ester Agucoat CPD (5
Gram) methanol (30 milliliters) is suspended in, it is heated to 50 DEG C and is uniformly mixed.Above-mentioned solution is existed
Rapid concentration removes most of solvent in rotary evaporator, filters, and dries, obtains white solid, i.e.,
Unformed Sai Lexipa and carboxymethyl cellulose phthalic acid ester Agucoat CPD solid disperses
In body, the X-ray powder diffraction figure of the solid dispersions, deduct after the background peaks of pharmaceutic adjuvant without match
The characteristic peak of Le Xipa crystal formations.
Embodiment 22
Sai Lexipa (50 milligrams) and carragheen E407 (500 milligrams) are suspended in methanol (30
Milliliter), it is heated to 50 DEG C and is uniformly mixed, above-mentioned solution is concentrated rapidly in a rotary evaporator
Most of solvent is removed, is filtered, dries, obtains white solid, i.e., unformed Sai Lexipa and OK a karaoke club
In glue E407 solid dispersions, the X-ray powder diffraction figure of the solid dispersions, deduct medicinal
Characteristic peak without Sai Lexipa crystal formations after the background peaks of auxiliary material.
Embodiment 23
Sai Lexipa (50 milligrams) and chitosan (5 grams) are suspended in methanol (50 milliliters), plus
Heat is uniformly mixed to 50 DEG C.By above-mentioned solution, concentration removes major part rapidly in a rotary evaporator
Solvent, is filtered, and is dried, and obtains white solid, i.e., unformed Sai Lexipa and chitosan solid point
In granular media, the X-ray powder diffraction figure of the solid dispersions, nothing after the background peaks of pharmaceutic adjuvant is deducted
The characteristic peak of Sai Lexipa crystal formations.
Embodiment 24
Sai Lexipa (30 milligrams) and polyacrylic resin Eudragit E100 (30 milligrams) is molten
In isopropanol (600 microlitres) and DMF (600 microlitres), 50 DEG C are heated to
Dissolved clarification is stirred, above-mentioned solution is cooled to 10 DEG C, white solid is separated out, filtered, dries, obtains nothing
Sizing Sai Lexipa and polyacrylic resin Eudragit E100 solid dispersions, the solid disperses
In the X-ray powder diffraction figure of body, the spy without Sai Lexipa crystal formations after the background peaks of pharmaceutic adjuvant is deducted
Levy peak.
Embodiment 25
Sai Lexipa (30 milligrams) and collagen Peptan (300 milligrams) are dissolved in isopropanol (600
Microlitre) and acetonitrile (600 microlitres) in, be heated to 50 DEG C stirring dissolved clarifications.Above-mentioned solution is cooled to
10 DEG C, white solid is separated out, is filtered, dries, obtains unformed Sai Lexipa and collagen Peptan
Solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, deduct the back of the body of pharmaceutic adjuvant
Characteristic peaks of the Jing Fenghou without Sai Lexipa crystal formations.
Embodiment 26
Sai Lexipa (30 milligrams) and natural gum Galactosol (300 milligrams) are dissolved in isopropanol (600
Microlitre) and methanol (600 microlitres) in, be heated to 50 DEG C stirring dissolved clarifications.Above-mentioned solution is cooled to
10 DEG C, white solid is separated out, is filtered, dries, obtains unformed Sai Lexipa and natural gum Galactosol
Solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, deduct the back of the body of pharmaceutic adjuvant
Characteristic peaks of the Jing Fenghou without Sai Lexipa crystal formations.
Embodiment 27
By Sai Lexipa (30 milligrams) and hydroxypropyl methylcellulose phthalate HPMCP (30
Milligram) ethanol (750 microlitres) and water (750 microlitres) are added to, it is heated to 80 DEG C of stirring mixing
Uniformly.By above-mentioned solution, concentration removes solvent rapidly in a rotary evaporator, obtains white solid, i.e.,
Unformed Sai Lexipa and hydroxypropyl methylcellulose phthalate HPMCP solid dispersions,
In the X-ray powder diffraction figure of the solid dispersions, deduct after the background peaks of pharmaceutic adjuvant without Sai Lexi
The characteristic peak of handkerchief crystal formation.
Embodiment 28
By Sai Lexipa (30 milligrams) and ion exchange resin Amberlite IR-120 (300 milligrams)
Ethanol (750 microlitres) and water (750 microlitres) are added to, 80 DEG C is heated to and is uniformly mixed.
By above-mentioned solution, concentration removes solvent rapidly in a rotary evaporator, obtains brown solid, i.e., unformed
Sai Lexipa and ion exchange resin Amberlite IR-120 solid dispersions, the solid dispersions
X-ray powder diffraction figure in, deduct pharmaceutic adjuvant background peaks after the feature without Sai Lexipa crystal formations
Peak.
Embodiment 29
Sai Lexipa (30 milligrams) and caprolactone (300 milligrams) are added to ethanol (750
Microlitre) and water (750 microlitres), it is heated to 80 DEG C and is uniformly mixed.By above-mentioned solution in rotation
Rapid concentration removes solvent in evaporator, obtains brown solid, i.e., unformed Sai Lexipa and carboxyl second
In the solid dispersions of acid lactone, the X-ray powder diffraction figure of the solid dispersions, deduct medicinal auxiliary
Characteristic peak without Sai Lexipa crystal formations after the background peaks of material.
Embodiment 30
Sai Lexipa (30 milligrams) and dextrin Maltrin M100 (300 milligrams) are added to ethanol
(750 microlitres) and water (750 microlitres), is heated to 80 DEG C and is uniformly mixed.By above-mentioned solution
Rapid concentration removes solvent in a rotary evaporator, obtains brown solid, i.e., unformed Sai Lexipa with
In dextrin Maltrin M100 solid dispersions, the X-ray powder diffraction figure of the solid dispersions,
Deduct the characteristic peak without Sai Lexipa crystal formations after the background peaks of pharmaceutic adjuvant.
Embodiment 31
Sai Lexipa (30 milligrams) and sodium carboxymethylcellulose SCMS (3 milligrams) are added to water
(30 milliliters), are heated to 100 DEG C and are uniformly mixed.Above-mentioned solution is fast in a rotary evaporator
Speed concentration removes solvent, obtains white solid, i.e., unformed Sai Lexipa and sodium carboxymethylcellulose
In SCMC solid dispersions, the X-ray powder diffraction figure of the solid dispersions, deduct medicinal auxiliary
Characteristic peak without Sai Lexipa crystal formations after the background peaks of material.
Embodiment 32
Sai Lexipa (30 milligrams) and beta-schardinger dextrin (30 milligrams) are added to methanol (300 microlitres)
With water (300 microlitres), dissolved clarification is stirred at room temperature.Above-mentioned solution is rapid dense in a rotary evaporator
Contracting removes solvent, obtains white solid, i.e., unformed Sai Lexipa and beta-schardinger dextrin solid dispersions,
In the X-ray powder diffraction figure of the solid dispersions, deduct after the background peaks of pharmaceutic adjuvant without Sai Lexi
The characteristic peak of handkerchief crystal formation.
Embodiment 33
Sai Lexipa (30 milligrams) and sodium carboxymethylcellulose SCMC (30 milligrams) are added to first
Alcohol (300 microlitres) and water (60 microlitres), are uniformly mixed at 60 DEG C.By above-mentioned solution in rotation
Turn rapid concentration in evaporator and remove solvent, obtain white solid, i.e., unformed Sai Lexipa and carboxylic first
In base sodium cellulosate SCMC solid dispersions, the X-ray powder diffraction figure of the solid dispersions,
Deduct the characteristic peak without Sai Lexipa crystal formations after the background peaks of pharmaceutic adjuvant.
Embodiment 34
By (60 milligrams) additions of Sai Lexipa (5 milligrams) and PEO Polyox WSR301
To methanol (300 microlitres) and water (60 microlitres), it is uniformly mixed at 60 DEG C.Will be above-mentioned molten
Concentration removes solvent to liquid rapidly in a rotary evaporator, obtains white solid, i.e., unformed Sai Lexi
The solid dispersions of handkerchief and PEO Polyox WSR301, the X-ray of the solid dispersions
In powder diagram, the characteristic peak without Sai Lexipa crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 35
Sai Lexipa (30 milligrams) and polyvinyl alcohol EG-40 (60 milligrams) are added to methanol (300
Microlitre) and water (60 microlitres), dissolved clarification is stirred at 60 DEG C, by above-mentioned solution in a rotary evaporator
Rapid concentration removes solvent, obtains white solid, i.e., unformed Sai Lexipa and polyvinyl alcohol EG-40
Solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, deduct pharmaceutic adjuvant
Characteristic peak without Sai Lexipa crystal formations after background peaks.
Embodiment 36
By Sai Lexipa (50 milligrams) and HPMC acetate succinate Agoat MG
(2 grams) are added at ethanol (10 milliliters) and water (2 milliliters), 80 DEG C and are uniformly mixed,
Above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, white solid is obtained, i.e., unformed match pleasure
The solid dispersions of western handkerchief and HPMC acetate succinate Agoat MG, the solid
In the X-ray powder diffraction figure of dispersion, deduct after the background peaks of pharmaceutic adjuvant without Sai Lexipa crystal formations
Characteristic peak.
Embodiment 37
Sai Lexipa (50 milligrams) and carboxymethylethylcellulose (2 grams) are added to ethanol (10
Milliliter) and water (1 milliliter), it is uniformly mixed at 80 DEG C, by above-mentioned solution in rotary evaporator
In be concentrated to dryness rapidly, obtain white solid, i.e., unformed Sai Lexipa and carboxymethylethylcellulose
Solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, deduct the back of the body of pharmaceutic adjuvant
Characteristic peaks of the Jing Fenghou without Sai Lexipa crystal formations.
Embodiment 38
Sai Lexipa (50 milligrams) is dissolved in isopropanol (600 microlitres) and water (900 microlitres),
It is heated to 60 DEG C of stirring dissolved clarifications.Above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, obtains white
Color solid, obtains unformed Sai Lexipa free alkalis.It is brilliant without Sai Lexipa in X-ray powder diffraction figure
The characteristic peak of type.
Embodiment 39
Sai Lexipa (50 milligrams) is dissolved in isopropanol (600 microlitres) and water (900 microlitres),
It is heated to 60 DEG C of stirring dissolved clarifications.10 milliliters of toluene are added into above-mentioned solution, depressurized after filtering dry
It is dry, obtain unformed Sai Lexipa.Characteristic peak without Sai Lexipa crystal formations in X-ray powder diffraction figure.
Embodiment 40
Sai Lexipa (50 milligrams) is dissolved in isopropanol (600 microlitres) and water (900 microlitres),
It is heated to 60 DEG C of stirring dissolved clarifications.Above-mentioned solution is directly freeze-dried, unformed Sai Lexi is obtained
Handkerchief free alkali.Characteristic peak without Sai Lexipa crystal formations in X-ray powder diffraction figure.
Embodiment 41
Sai Lexipa (50 milligrams) is dissolved in isopropanol (600 microlitres) and water (900 microlitres),
It is heated to 60 DEG C of stirring dissolved clarifications.Above-mentioned solution is dried with JISL mini spray dryers LSD-48,
60 DEG C of inlet temperature, 50 DEG C of outlet temperature are maintained, outlet material is collected, obtains white solid, enter
The vacuum drying of one step obtains unformed Sai Lexipa free alkalis.Without Sai Lexi in X-ray powder diffraction figure
The characteristic peak of handkerchief crystal formation.
Embodiment 42
Sai Lexipa (50 milligrams) is dissolved in isopropanol (600 microlitres) and water (900 microlitres),
It is heated to 60 DEG C of stirring dissolved clarifications.Above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, obtains white
Color solid, obtains unformed Sai Lexipa.Spy without Sai Lexipa crystal formations in X-ray powder diffraction figure
Levy peak.
Embodiment 43
Sai Lexipa (50 milligrams) is dissolved in isopropanol (600 microlitres) and water (900 microlitres),
It is heated to 60 DEG C of stirring dissolved clarifications.10 milliliters of toluene are added into above-mentioned solution, depressurized after filtering dry
It is dry, obtain unformed Sai Lexipa.Characteristic peak without Sai Lexipa crystal formations in X-ray powder diffraction figure.
Embodiment 44
Sai Lexipa (50 milligrams) is dissolved in isopropanol (600 microlitres) and water (900 microlitres),
It is heated to 60 DEG C of stirring dissolved clarifications.Above-mentioned solution is directly freeze-dried, unformed Sai Lexi is obtained
Handkerchief.Characteristic peak without Sai Lexipa crystal formations in X-ray powder diffraction figure.
Embodiment 45
Sai Lexipa (50 milligrams) is dissolved in isopropanol (600 microlitres) and water (900 microlitres),
It is heated to 60 DEG C of stirring dissolved clarifications.Above-mentioned solution is directly done with JISL mini spray dryers LSD-48
It is dry, 60 DEG C of inlet temperature, 50 DEG C of outlet temperature are maintained, outlet material is collected, obtains white solid,
Further vacuum drying obtains unformed Sai Lexipa.Sai Lexipa crystal formations in X-ray powder diffraction figure
Characteristic peak.
Embodiment 46：Unformed Sai Lexipa and PVP K30 solid dispersions influence factor are tested
Material：The unformed Sai Lexipa of the gained of embodiment 1 and PVP K30 solid dispersions
Table 1：
Table 1 illustrates：Unformed Sai Lexipa is with PVP K30 solid dispersions in high temperature, high humidity bar
Under part, place 10 days, relevant material is without significantly changing, and no Sai Lexipa crystallizations are separated out.
Embodiment 47：Unformed Sai Lexipa and PVP K30 solid dispersions influence factor are tested
Material：The unformed Sai Lexipa of the gained of embodiment 1 and PVP K30 solid dispersions
Experiment condition：40 DEG C ± 2 DEG C of temperature, humidity 75% ± 5%
Table 2：
Table 2 illustrates：Unformed Sai Lexipa is with PVP K30 solid dispersions in accelerated test condition
Under, place 6 months, relevant material is without significantly changing, and no Sai Lexipa crystallizations are separated out.
The Sai Lexipa of the present invention and the unformed solid dispersions of pharmaceutic adjuvant, its dissolution rate substantially increase,
It is more beneficial for improving the bioavilability of medicine, allows medicament to preferably play clinical disease treatment effect,
(40 ± 2 DEG C, humidity 75% ± 5%) can keep good thing to the amorphous article under the conditions of accelerated test
Manage stability and chemical stability.
Claims (10)
1. a kind of unformed Sai Lexipa, it is characterised in that nothing in X-ray powder diffraction spectrum
Sai Lexipa characteristic peak.
2. a kind of unformed Sai Lexipa preparation method, comprises the following steps：
1) after Sai Lexipa solvents are dissolved, solution temperature is -50~150 DEG C, forms pleasure containing match
The solution of western handkerchief, wherein, the weight ratio of Sai Lexipa and solvent is 0.001~100:1；
It is characterized in that, solvent is selected from alcohols, phenols, ethers, halogenated hydrocarbons, ketone, aldehyde
At least one of class, nitrile, acid amides, sulfone, sulfoxide, carboxylic acid and water.
2) removing step 1) obtained by solution in solvent, or obtained solution is cooled rapidly,
Or poor solvent is rapidly joined, crystallization is carried out, the unformed of Sai Lexipa is obtained
Form.Characterized in that, the method for removing solvent is selected from：Evaporate, be evaporated in vacuo,
Spray drying, freeze-drying, hot-melt extruded, filtering, centrifugation or agitated thin film
At least one of.
3. a kind of Sai Lexipa and pharmaceutic adjuvant solid dispersions, it is characterised in that described solid
Body dispersion includes Sai Lexipa and pharmaceutic adjuvant, and both weight ratios are 1:0.1~100,
Wherein, described Sai Lexipa is unformed shape, the X-ray of the solid dispersions
In Powder Diffraction pattern, deduct after the background peaks of pharmaceutic adjuvant without Sai Lexipa crystal
Characteristic peak.
4. Sai Lexipa according to claim 3 and pharmaceutic adjuvant solid dispersions, it is special
Levy and be, at least one of described pharmaceutic adjuvant is selected from diluent, lubricant, glued
Mixture, disintegrant, surfactant, filmogen, coating material and capsule material
At least one of.
5. Sai Lexipa according to claim 3 and pharmaceutic adjuvant solid dispersions, it is special
Levy and be, at least one of described pharmaceutic adjuvant is selected from HPMC, hydroxyl
Propyl cellulose, PVP, polyethylene glycol, ethyl cellulose, microcrystalline cellulose,
Liposome, methacrylic acid copolymer, polyvinyl acetate, carboxymethylethylcellulose,
Carboxymethyl cellulose phthalic acid ester, hydroxypropyl methylcellulose phthalate,
HPMC acetate succinate, polyacrylic resin, carbopol,
Alginates, carragheen, caprolactone, natural gum, polyvinyl alcohol, pregelatinated form sediment
Powder, crosslinked starch, sodium carboxymethyl starch, dextrin, PEO, chitosan,
At least one of chitosan, ion exchange resin and collagen.
6. a kind of preparation method of the solid dispersions of Sai Lexipa and pharmaceutic adjuvant, including it is as follows
Step：
1) Sai Lexipa and pharmaceutic adjuvant are mixed in a solvent, mixing temperature is
- 50~150 DEG C, solution or suspension containing Sai Lexipa and pharmaceutic adjuvant are formed, its
In, the weight ratio of Sai Lexipa and solvent is 0.001~100:1, Sai Lexipa and medicine
It is 1 with the weight ratio of auxiliary material:0.1~100；
2) removing step 1) solvent in obtained solution or suspension, obtain unformed shape
Sai Lexipa and pharmaceutic adjuvant solid dispersions.
7. the system of the solid dispersions of Sai Lexipa according to claim 6 and pharmaceutic adjuvant
Preparation Method, it is characterised in that the pharmaceutic adjuvant is selected from diluent, lubricant, glued
Mixture, disintegrant, surfactant, filmogen, coating material and capsule material
At least one of.
8. the system of the solid dispersions of Sai Lexipa according to claim 6 and pharmaceutic adjuvant
Preparation Method, it is characterised in that described pharmaceutic adjuvant be selected from HPMC,
Hydroxypropyl cellulose, PVP, polyethylene glycol, ethyl cellulose, liposome, first
Base acrylic copolymer, polyvinyl acetate, carboxymethylethylcellulose, carboxymethyl are fine
The plain phthalic acid ester of dimension, hydroxypropyl methylcellulose phthalate, hydroxypropyl
Cellulose acetate succinate, polyacrylic resin, carbopol, alginates,
Carragheen, caprolactone, natural gum, polyvinyl alcohol, pregelatinized starch, crosslinking
Starch, sodium carboxymethyl starch, dextrin, PEO, chitosan, chitosan
With collagen, cyclodextrin, lactose, galactolipin, PEARLITOL 25C, sorbierite, wood
At least one of sugar alcohol, urea.
9. a kind of Pharmaceutical composition, it is characterised in that the Pharmaceutical composition contains unformed match
Le Xipa solid dispersions and at least one pharmaceutically acceptable auxiliary material.
10. Pharmaceutical composition as claimed in claim 9, the use for preparing pulmonary hypertension medicine
On the way.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112107559A (en) * | 2019-06-20 | 2020-12-22 | 普济生物科技（台州）有限公司 | Oral transmucosal pharmaceutical dosage form |
| CN112472675A (en) * | 2020-12-17 | 2021-03-12 | 江苏豪森药业集团有限公司 | Sparapage tablet and preparation method thereof |
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| CN1516690A (en) * | 2001-04-26 | 2004-07-28 | �ձ���ҩ��ʽ���� | Heterocyclic derivatives and medicines |
| CN102716493A (en) * | 2011-03-31 | 2012-10-10 | 天津药物研究院 | Copolymer containing amorphous agomelatine, and preparation method, pharmaceutical composition and application thereof |
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- 2016-04-12 CN CN201610225862.3A patent/CN107286104A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1516690A (en) * | 2001-04-26 | 2004-07-28 | �ձ���ҩ��ʽ���� | Heterocyclic derivatives and medicines |
| CN102716493A (en) * | 2011-03-31 | 2012-10-10 | 天津药物研究院 | Copolymer containing amorphous agomelatine, and preparation method, pharmaceutical composition and application thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112107559A (en) * | 2019-06-20 | 2020-12-22 | 普济生物科技（台州）有限公司 | Oral transmucosal pharmaceutical dosage form |
| CN112107559B (en) * | 2019-06-20 | 2023-09-08 | 普济生物科技（台州）有限公司 | Oral transmucosal pharmaceutical dosage form |
| CN112472675A (en) * | 2020-12-17 | 2021-03-12 | 江苏豪森药业集团有限公司 | Sparapage tablet and preparation method thereof |
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