CN107510847A - A kind of Pharmaceutical composition that XiLin solid dispersions are won containing unformed pa and preparation method thereof - Google Patents
A kind of Pharmaceutical composition that XiLin solid dispersions are won containing unformed pa and preparation method thereof Download PDFInfo
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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Abstract
The present invention relates to a kind of Pharmaceutical composition that XiLin solid dispersions are won containing pa, it includes pa and wins solid dispersions and at least one pharmaceutically acceptable auxiliary material that XiLin is formed with organic carrier, the weight that pa wins XiLin is 20% the 80% of the gross weight of solid dispersions, the weight of auxiliary material is the 0.1%~80% of the weight of solid dispersions, wherein, it be unformed shape that pa, which wins XiLin, wins the characteristic peak of the crystal in XiLin in the X ray Powder Diffraction patterns of the composition after the background peaks of deduction organic carrier and pharmaceutic adjuvant without pa.The preparation method of the Pharmaceutical composition in XiLin is won the invention further relates to a kind of unformed pa.The pa of the present invention wins XiLin Pharmaceutical composition stability and favorable dispersibility, add the dissolution rate that pa wins XiLin, 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 composition of the present invention is simple to operate, and cost is cheap, 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 one kind wins XiLin solid point containing unformed pa
Pharmaceutical composition of granular media and preparation method thereof, and the purposes of said composition treating cancer.
Background technology
Pa wins XiLin (Palbociclib), the entitled 6- acetyl group -8- cyclopenta -5- methyl -2- [5- of chemistry
(1- piperazinyls) pyridine -2- bases amino] -8H- pyridos [2,3-d] pyrimidin-7-ones, trade name Ibrance,
It is a kind of new drug of oral treatment metastatic breast cancer of Pfizer's exploitation, it is cell that pa, which wins XiLin,
Cyclin dependent kinase 4,6 suppression medicine, are mainly prevented by suppressing CDK4/6 activity
Cell is by the G1 phases to S phases and then suppresses synthesizing for DNA.Clinical experimental study discovery, Pa Boxi
Woods combine Letrozole to postclimacteric local infiltration patient with breast cancer or the estrogen diagnosed recently by
Body (ER) is positive, and patient negative HER-2 is highly effective.Pa wins XiLin in 2 months 2015
Obtain within 3rd food and drug administration (FDA) approval listing.Food Bureau of Drugs Supervision of the U.S. (FDA)
It is a kind of breakthrough medicine to claim the medicine, using the teaching of the invention it is possible to provide the drug effect more lasting than medicine currently on the market.
Although pa is won the effect of XiLin and has been widely recognized as, but still some defects be present.Patent
WO2014128588 discloses two kinds of crystal formations that pa wins XiLin free alkali：Form A and Form B,
But and have no unformed report.That the medicine is used for preparation is free alkali crystal formation Form A, although
Form A are thermodynamically stable crystal formations, and stable type is good, but the solubility from the crystal formation in water
Extremely low, under near-neutral sulfite deinking, solubility is only 19 mg/litres.Therefore, the medicine is slightly solubility medicine
Thing, its extremely low water solubility have had a strong impact on the bioavilability of medicine.In addition, drug effect between patient
Differ greatly, the patient for having 13% grinds that drug absorption is extremely low, and medicine can be improved slightly after the meal by taking to original
Absorption, the edible low-fat diet equivalent to 3 grams of peanut oil can improve absorption 12%, and edible suitable
Absorption 21% can be improved in the high lipid food of 67 grams of peanut oil, but high lipid food is to the health of patient
There is sizable harm.
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, reduce dosage, reduce toxic side effect, it will usually open
The new solid forms of dispensing thing, therefore, develop that the drug solubility is more preferable, bioavilability 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, make the medicine being possessed of good qualities.
Because pa wins insufficient and unformed active constituents of medicine of the XiLin in terms of bioavilability in medicine
Good application prospect in terms of thing preparation, find new unformed pa and win XiLin and preparation method thereof just
Seem very necessary.
The content of the invention
It is an object of the invention to provide a kind of pa containing amorphous state to win the medicinal of XiLin solid dispersions
Composition and preparation method thereof, the pa for obtaining the unformed shape of stability and favorable dispersibility win XiLin
Pharmaceutical composition, the dissolution rate that pa wins XiLin being added, the preparation method is not limited by drying process,
Also do not limited by solvent species and quantity of solvent, easy to operate, cost is cheap, 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 Pharmaceutical composition that XiLin solid dispersions are won containing pa, its include pa win XiLin with it is organic
The solid dispersions and at least one pharmaceutically acceptable auxiliary material, pa that carrier is formed win the weight in XiLin
The 20%-80% of the gross weight for solid dispersions is measured, the weight of auxiliary material is the weight of solid dispersions
0.1%~80%, wherein, it is unformed shape that described pa, which wins XiLin, the X-ray powder of the composition
In last difraction spectrum, the characteristic peak of XiLin crystal is won after the background peaks of deduction carrier and pharmaceutic adjuvant without pa.
Further, described organic carrier is selected from polymer and copolymer.
Preferably, described organic carrier is selected from HPMC, hydroxypropyl cellulose, poly- dimension
Ketone, polyethylene glycol, ethyl cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate,
Carboxymethylethylcellulose, carboxymethyl cellulose phthalic acid ester, HPMC neighbour benzene two
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.
Make in Chinese pharmacology of the present invention when acceptable auxiliary material and pharmaceutic adjuvant production medicine and prescription being dispensed
Excipient and additives, including excipient, propellant, solubilizer, cosolvent, emulsifying agent,
It is colouring agent, binder, disintegrant, filler, lubricant, wetting agent, osmotic pressure regulator, steady
Determine agent, glidant, flavouring, preservative, suspending agent, coating material, aromatic, anti-binder,
Integrated agent, penetration enhancer, pH value regulator, buffer, plasticizer, surfactant, hair
Infusion, defoamer, thickener, inclusion agents, NMF, absorbent, diluent, flocculant with it is anti-
Flocculant, antioxidant, adsorbent, filter aid, release retarding agent etc..
The preparation method of the Pharmaceutical composition that XiLin solid dispersions are won containing pa of the present invention, including such as
Lower step：
1) pa is won into XiLin, at least one organic carrier and at least one pharmaceutically acceptable auxiliary
The mixed thing of material, is heated to melting, wherein, the weight that pa wins XiLin is solid dispersions
The 20%-80% of gross weight, the weight of auxiliary material is the weight of solid dispersions
0.1%~80%；
2) cooled down after being well mixed, obtained mixture is crushed, obtains the pa containing unformed shape
The Pharmaceutical composition of rich XiLin solid dispersions.
Further, the organic carrier described in step 1) is selected from polymer and copolymer.
Preferably, it is fine to be selected from HPMC, hydroxypropyl for the pharmaceutic adjuvant described in step 1)
Dimension element, PVP, it is polyethylene glycol, ethyl cellulose, liposome, methacrylic acid copolymer, poly-
Vinyl acetate, carboxymethylethylcellulose, carboxymethyl cellulose phthalic acid ester, hydroxypropyl are fine
Tie up plain phthalic acid ester, HPMC acetate succinate, polyacrylic resin, poly-
Carboxylic ethene, alginates, carragheen, caprolactone, natural gum, polyvinyl alcohol, pregelatinized starch,
Crosslinked starch, sodium carboxymethyl starch, dextrin, PEO, chitosan, chitosan and collagen
At least one of albumen.
The present invention provides the preparation side that another kind wins the Pharmaceutical composition of XiLin solid dispersions containing pa
Method, comprise the following steps：
1) pa is won into XiLin, at least one organic carrier and at least one pharmaceutically acceptable auxiliary material to exist
Mixed in solvent, mixing temperature is -50~150 DEG C, is formed and wins XiLin, organic carrier and medicine containing pa
With the solution or suspension of auxiliary material, wherein, it is 0.001~100 that pa, which wins XiLin and the weight ratio of solvent,:1,
The weight that pa wins XiLin is the 20%-80% of the gross weight of solid dispersions, and the weight of auxiliary material is solid
The 0.1%~80% of the weight of dispersion；
2) removing step 1) solvent in obtained solution or suspension, obtain the Pa Bo containing unformed shape
The Pharmaceutical composition of XiLin solid dispersions.
Further, the organic carrier described in step 1) is selected from polymer and copolymer.
Preferably, it is fine to be selected from HPMC, hydroxypropyl for the pharmaceutic adjuvant described in step 1)
Dimension element, PVP, it is polyethylene glycol, ethyl cellulose, liposome, methacrylic acid copolymer, poly-
Vinyl acetate, carboxymethylethylcellulose, carboxymethyl cellulose phthalic acid ester, hydroxypropyl are fine
Tie up plain phthalic acid ester, HPMC acetate succinate, polyacrylic resin, poly-
Carboxylic ethene, alginates, carragheen, caprolactone, natural gum, polyvinyl alcohol, pregelatinized starch,
Crosslinked starch, sodium carboxymethyl starch, dextrin, PEO, chitosan, chitosan, ion
At least one of exchanger resin and collagen.
Also, the 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,
The method that step 2) removes solvent includes：Evaporate, be evaporated in vacuo, being spray-dried, being freeze-dried,
Hot-melt extruded, filtering, centrifugation or agitated thin film.
Present invention also offers a kind of solid dispersions and at least one that XiLin is won containing unformed pa
The Pharmaceutical composition of pharmaceutically acceptable auxiliary material is used for the purposes for treating following disease：The disease bag
Include：Breast cancer, oophoroma, cervix cancer, prostate cancer, carcinoma of testis, cancer of the esophagus, stomach cancer, skin
Skin cancer, lung cancer, osteocarcinoma, colon cancer, cancer of pancreas, thyroid cancer, cancer of bile ducts, the vestibule of mouth diease and pharynx
Cancer (oral cavity), lip cancer, tongue cancer, mouth cancer, pharynx cancer, carcinoma of small intestine, colon-rectum, colorectal cancer,
The carcinoma of the rectum, brain and central nervous system cancer, glioblast cancer, nerve metrocyte carcinoma, angling spine skin
Cancer, epidermoid carcinoma, large cell carcinoma, gland cancer, ovarian follicle cancer, undifferentiated carcinoma, papillary carcinoma, essence member are thin
Born of the same parents' cancer, melanoma, sarcoma, carcinoma of urinary bladder, liver cancer, kidney, bone marrow disorder disease, lymph deficiency disorder,
Hodgkin's disease, Skin Cell cancer and leukaemia.
The solid dispersions that XiLin is won containing unformed pa of the present invention can pharmaceutically connect with least one
The Pharmaceutical composition for the auxiliary material received, radiated using Cu-K α, to spend the X-ray powder diffraction that 2 θ are represented
The background peaks of deduction carrier and pharmaceutic adjuvant win the characteristic peak of XiLin crystalline state without pa in spectrum, show pa
Rich XiLin is unformed state.The crystalline state in XiLin is typically won using pa in the prior art, has no its nothing
The report for state of shaping.Normally due to the orderly and periodic arrangement of amorphous material molecule, is reduced intermolecular
The energy of interaction, energy is relatively low, and it is unformed shape that the pa of the present invention, which wins XiLin, and molecule is in height
Disordered state is spent, the surface free energy of material is bigger, and the molecule in solid matter is compared with crystalline solid material
Molecule have higher energy, it is easier to it is scattered, increase its dissolution rate, improve pa and win XiLin or its salt
Bioavilability.
The present invention is added with least one pharmaceutically into the solid dispersions that XiLin is won containing unformed pa
Acceptable auxiliary material, and dispersed, by the polymer network structure of pharmaceutic adjuvant by drug molecule
Barrier, suppress the generation of crystallization, it is preferably kept scattered and unformed state.The present invention uses
It is widely used, is cheap, the pharmaceutic adjuvant that dissolubility is good, these pharmaceutic adjuvants is won with unformed pa
XiLin solid dispersions mixing, coordinates the technologies such as evaporation, spray drying, freeze-drying and hot-melt extruded
The composition that unformed pa wins XiLin solid dispersions and pharmaceutic adjuvant can be obtained, increases pa of the present invention
The stability of the unformed shape in rich XiLin.
The present invention selects pharmaceutically widely used, cheap auxiliary material, obtains containing unformed pa
The solid dispersions in rich XiLin and the composition of pharmaceutic adjuvant, it is easy to develop pharmaceutical formulation, it is of the invention
Preparation method is not limited by drying process, is not also limited by solvent species and quantity of solvent, operation letter
Just, cost is cheap, it is easy to accomplish, industrialized production can be achieved.
Compared with prior art, the beneficial effects of the invention are as follows：
1) unformed pa prepared by the present invention wins XiLin solid dispersions and the composition of pharmaceutic adjuvant has
There are high dispersion and stability, after solid pharmaceutical preparation is made, point of drug particle can be made by disintegration
The degree of dissipating is more preferable, and scattered and dissolution rate faster, is advantageous to the absorption of medicine.Therefore, unformed shape
The dissolution rate of state medicine substantially increases, and is more beneficial for absorption of the body to medicine, improves the biology of medicine
Availability, allow medicament to preferably play clinical disease treatment effect.
2) pa of the unformed state of the present invention wins the composition of XiLin solid dispersions and pharmaceutic adjuvant
Preparation method is not limited by drying process, is not also limited by solvent species and quantity of solvent, operation letter
Just, cost is cheap, it is easy to accomplish, industrialized production can be achieved.
3) pa of unformed state prepared by the present invention wins the group of XiLin solid dispersions and pharmaceutic adjuvant
Compound (40 ± 2 DEG C, humidity 75% ± 5%) under the conditions of accelerated test, good physics can be kept steady
Qualitative and chemical stability.Therefore, the present invention will have broad application prospects.
Brief description of the drawings
Fig. 1 is that the unformed pa of the embodiment of the present invention 12 wins XiLin solid dispersions and microcrystalline cellulose
Composition X-ray powder diffraction figure.
Fig. 2 is the X-ray powder diffraction figure of the microcrystalline cellulose used in the embodiment of the present invention
Fig. 3 is that the unformed pa of the embodiment of the present invention 32 wins XiLin solid dispersions and colloidal silica
The X-ray powder diffraction figure of silicon Aerosil 200 composition.
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 gathers on Ultima IV x-ray diffractometers.
The method parameter of X-ray powder diffraction of the present 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
The physical form that any pa wins XiLin may be used to prepare the solid dispersions that unformed pa wins XiLin.
By pa win XiLin (50 milligrams) and PVP K30 (100 milligrams) be dissolved in n-butanol (600 microlitres),
In methyl phenyl ethers anisole (900 microlitres) and methanol (600 microlitres), 60 DEG C of stirring dissolved clarifications are heated to, are added micro-
Crystalline cellulose (50 milligrams).Above-mentioned solution is cooled to rapidly -10 DEG C, separates out yellow solid, is filtered,
Vacuum drying, obtain the composition that unformed pa wins XiLin solid dispersions and microcrystalline cellulose, the combination
In the X-ray powder diffraction figure of thing XiLin crystal formation is won after the background peaks of deduction carrier and pharmaceutic adjuvant without pa
Characteristic peak.
Embodiment 2
Pa is won into XiLin (50 milligrams) and Macrogol 4000 (200 milligrams) is dissolved in ethanol (600
Microlitre) and water (600 microlitres) in, be uniformly mixed at -40 DEG C, add microcrystalline cellulose
(50 milligrams).Above-mentioned solution is slowly concentrated to dryness in a rotary evaporator, obtains yellow solid,
I.e. unformed pa wins the composition of XiLin and microcrystalline cellulose, the X-ray powder diffraction figure of said composition
In, deduct the characteristic peak for winning XiLin crystal formation after the background peaks of carrier and pharmaceutic adjuvant without pa.
Embodiment 3
Pa is won into XiLin (5 grams) and (10 grams) of PEG 8000 adds methanol (300 milliliters)
In, 60 DEG C of stirring dissolved clarifications are heated to, add Ac-Di-Sol (0.1 gram).Will be upper
Solution JISL mini spray dryers LSD-48 dryings are stated, maintain 60 DEG C of inlet temperature, outlet
Temperature 50 C, outlet material is collected, obtains yellow solid, further vacuum drying obtains unformed pa
The composition of rich XiLin solid dispersions and Ac-Di-Sol, the X-ray powder of said composition
In last diffraction pattern, the characteristic peak of XiLin crystal formation is won after the background peaks of deduction carrier and pharmaceutic adjuvant without pa.
Embodiment 4
Pa is won into XiLin (1 gram) and HPMC E50 (0.2 gram) is added to water (10 millis
Rise) in, it is heated to 40 DEG C and is uniformly mixed, adds PVPP (0.2 gram).Will be upper
Solution freeze-drying is stated, obtains yellow solid, i.e., it is poly- with crosslinking that unformed pa wins XiLin solid dispersions
The composition of ketone is tieed up, in the X-ray powder diffraction figure of said composition, deducts carrier and pharmaceutic adjuvant
The characteristic peak of XiLin crystal formation is won after background peaks without pa.
Embodiment 5
Pa is won into (5 grams) XiLin (1 gram), mannitol (5 grams) and PEG 8000 heating
To melting, room temperature is quickly cooled under stirring, obtains yellow solid.Above-mentioned solid is crushed, obtained
White powdery solids, i.e., unformed pa win the composition of XiLin solid dispersions and mannitol, the group
In the X-ray powder diffraction figure of compound, XiLin is won without pa after the background peaks of deduction carrier and pharmaceutic adjuvant
The characteristic peak of crystal formation.
Embodiment 6
Pa is won into (10 grams) of XiLin (1 gram), mannitol (0.1 gram) and PEG20000 to add
Heat is well mixed to 240 DEG C, is quickly cooled to room temperature, obtains yellow solid.By above-mentioned solid powder
It is broken, white powdery solids are obtained, i.e., unformed pa wins the combination of XiLin solid dispersions and mannitol
Thing, in the X-ray powder diffraction figure of said composition, deduct nothing after the background peaks of carrier and pharmaceutic adjuvant
Pa wins the characteristic peak of XiLin crystal formation.
Embodiment 7
Pa is won into XiLin (1 gram), methyl phenyl ethers anisole (10 grams), n-butanol (20 grams) and liposome (4
Gram) mixture be heated to 90 DEG C, stir lower well mixed.Microcrystalline cellulose (2 grams) is added,
Stir, be evaporated in vacuo and remove solvent, obtain yellow solid, i.e., unformed pa wins XiLin solid point
The composition of granular media and microcrystalline cellulose, in the X-ray powder diffraction figure of said composition, deduct carrier
With the characteristic peak for winning XiLin crystal formation after the background peaks of pharmaceutic adjuvant without pa.
Embodiment 8
Pa is won into XiLin (1 gram), methanol (20 grams) and methacrylic acid copolymer A types (4 grams)
Mixture be heated to 50 DEG C, stir lower dissolved clarification, add PVPP (1 gram), vacuum is steamed
Hair remove solvent, be cooled to room temperature and obtain yellow solid, i.e., unformed pa win XiLin solid dispersions with
The composition of PVPP, in the X-ray powder diffraction figure of said composition, deduct carrier and medicinal
The characteristic peak of XiLin hydrobromate crystal formation is won after the background peaks of auxiliary material without pa.
Embodiment 9
Pa is won into XiLin (1 gram), n-butanol (20 grams), methyl phenyl ethers anisole (10 grams) and ethyl cellulose
The mixture of plain (2 grams) is heated to 30 DEG C, stirs, and is well mixed, adds magnesium stearate (0.1
Gram), it is evaporated in vacuo and removes solvent, is cooled to room temperature and obtains yellow solid, i.e., unformed pa wins XiLin
The composition of solid dispersions and magnesium stearate, in the X-ray powder diffraction figure of said composition, deduct
The characteristic peak of XiLin crystal formation is won after the background peaks of carrier and pharmaceutic adjuvant without pa.
Embodiment 10
It is fine that pa is won into XiLin (1 gram), methanol (10 grams), dichloromethane (10 grams) and hydroxypropyl
The mixture for tieing up plain SSL (4 grams) is heated to 30 DEG C, stirs dissolved clarification, adds microcrystalline cellulose (0.5
Gram), it is evaporated in vacuo and removes solvent, is cooled to room temperature and obtains yellow solid, i.e., unformed pa wins XiLin
The composition of solid dispersions and microcrystalline cellulose, in the X-ray powder diffraction figure of said composition, button
Except the characteristic peak for winning XiLin hydrochloride Form after the background peaks of carrier and pharmaceutic adjuvant without pa.
Embodiment 11
Pa is won into XiLin (1 gram), methanol (20 grams), dichloromethane (10 grams) and poly-vinegar acid second
The mixture of alkene (4 grams) is heated to 30 DEG C, stirs dissolved clarification, adds microcrystalline cellulose (0.5 gram)
It is evaporated in vacuo and removes solvent, be cooled to room temperature and obtain yellow solid, i.e., unformed pa wins XiLin solid point
The composition of granular media and microcrystalline cellulose, in the X-ray powder diffraction figure of said composition, deduct carrier
With the characteristic peak for winning XiLin isethionate crystal formation after the background peaks of pharmaceutic adjuvant without pa.
Embodiment 12
Pa is won into XiLin (50 milligrams) and (100 milligrams) of polyacrylic resin Eudragit L100 add
Enter to methanol (750 microlitres), stir dissolved clarification at 60 DEG C, add microcrystalline cellulose (100 milligrams).
Above-mentioned suspension is rapidly cooled to 60 DEG C, separates out yellow solid.Filtering, vacuum drying, obtain Huang
Color solid, i.e., unformed pa win the composition of XiLin solid dispersions and microcrystalline cellulose, said composition
X-ray powder diffraction figure as shown in figure 1, deducting carrier and medicinal in X-ray powder diffraction figure
The characteristic peak of XiLin crystal formation is won after the background peaks of auxiliary material without pa.The X-ray powder diffraction of microcrystalline cellulose
Figure is as shown in Figure 2.
Embodiment 13
Pa is won into (5 milligrams) additions in XiLin (50 milligrams) and polyacrylic resin Eudragit S100
To methanol (4 milliliters) and ethyl acetate (1 milliliter), dissolved clarification is stirred at -30 DEG C.Adding carboxylic first
Base sodium starch (100 milligrams).Above-mentioned solution is slowly concentrated to dryness in a rotary evaporator, obtained
Yellow solid, i.e., unformed pa win the composition of XiLin solid dispersions and sodium carboxymethyl starch, the group
In the X-ray powder diffraction figure of compound, XiLin is won without pa after the background peaks of deduction carrier and pharmaceutic adjuvant
The characteristic peak of crystal formation.
Embodiment 14
Pa is won into XiLin (50 milligrams) and carbopol Carbomer 940 (50 milligrams) is added to
Methanol (4 milliliters) and tetrahydrofuran (1 milliliter), it is uniformly mixed at 30 DEG C, adds micro-
Crystalline cellulose (50 milligrams).Above-mentioned solution is slowly concentrated to dryness in a rotary evaporator, obtains Huang
Color solid, i.e., unformed pa win the composition of XiLin solid dispersions and microcrystalline cellulose, said composition
X-ray powder diffraction figure in, deduct and win XiLin crystal formation without pa after the background peaks of carrier and pharmaceutic adjuvant
Characteristic peak.
Embodiment 15
Pa is won into XiLin (50 milligrams) and pregelatinized starch Pharma-Gel (100 milligrams) is added to
Methanol (4 milliliters) and water (1 milliliter), are well mixed at room temperature, add cross-linked carboxymethyl fibre
Tie up plain sodium (100 milligrams).Above-mentioned solution is slowly concentrated to dryness in a rotary evaporator, obtains Huang
Color solid, i.e., unformed pa win the composition of XiLin solid dispersions and Ac-Di-Sol,
In the X-ray powder diffraction figure of said composition, won after deducting the background peaks of carrier and pharmaceutic adjuvant without pa
The characteristic peak of XiLin crystal formation.
Embodiment 16
Pa is won into XiLin (50 milligrams) and high side chain crosslinked starch (50 milligrams) is added to methanol (4
Milliliter) and water (1 milliliter), dissolved clarification is stirred at room temperature, adds Ac-Di-Sol (100
Milligram).Above-mentioned solution is slowly concentrated to dryness in a rotary evaporator, obtains yellow solid, i.e., without
Unformed pa wins the composition of XiLin solid dispersions and Ac-Di-Sol, said composition
In X-ray powder diffraction figure, XiLin crystal formation is won without pa after the background peaks of deduction carrier and pharmaceutic adjuvant
Characteristic peak.
Embodiment 17
Pa is won into XiLin (50 milligrams) and sodium carboxymethylcellulose SCMC (500 milligrams) is added to
Dimethyl sulfoxide (DMSO) (5 milliliters), stirs dissolved clarification, adds Ac-Di-Sol (100 at room temperature
Milligram).Above-mentioned solution is slowly concentrated to dryness in a rotary evaporator, obtains yellow solid, i.e., without
Pa of shaping wins the composition of XiLin solid dispersions and Ac-Di-Sol, said composition
In X-ray powder diffraction figure, XiLin crystal formation is won without pa after the background peaks of deduction carrier and pharmaceutic adjuvant
Characteristic peak.
Embodiment 18
Pa is won into XiLin (50 milligrams) and chitosan (500 milligrams) is added to ethanol (5 milliliters),
Dissolved clarification is stirred at room temperature, adds microcrystalline cellulose (50 milligrams).By above-mentioned solution in rotary evaporation
Slowly it is concentrated to dryness in device, obtains yellow solid, i.e., unformed pa wins XiLin solid dispersions and crystallite
The composition of cellulose, in the X-ray powder diffraction figure of said composition, deduct carrier and pharmaceutic adjuvant
Background peaks after the characteristic peak of XiLin crystal formation is won without pa.
Embodiment 19
Pa is won into XiLin (50 milligrams) and sodium carboxymethyl starch Explotab (500 milligrams) is added to
Ethanol (5 milliliters), is uniformly mixed at room temperature, adds lactose (100 milligrams).Will be upper
State solution to be slowly concentrated to dryness in a rotary evaporator, obtain yellow solid, i.e., unformed pa wins XiLin
The composition of solid dispersions and lactose, in the X-ray powder diffraction figure of said composition, deduct carrier
With the characteristic peak for winning XiLin crystal formation after the background peaks of pharmaceutic adjuvant without pa.
Embodiment 20
Pa is won into XiLin (50 milligrams) and alginates E401 (500 milligrams) is added to ethanol (5 millis
Rise), it is uniformly mixed at room temperature, is adding lactose (10 milligrams).Above-mentioned solution is being rotated
Slowly be concentrated to dryness in evaporator, obtain yellow solid, i.e., unformed pa win XiLin solid dispersions with
The composition of lactose, in the X-ray powder diffraction figure of said composition, deduct carrier and pharmaceutic adjuvant
The characteristic peak of XiLin crystal formation is won after background peaks without pa.
Embodiment 21
Pa is won into XiLin (50 milligrams) and carboxymethyl cellulose phthalic acid ester Agucoat CPD (0.5
Gram) methanol (30 milliliters) is suspended in, it is heated to 50 DEG C and is uniformly mixed, adds lactose (50
Milligram).By above-mentioned solution, slowly concentration removes most of solvent in a rotary evaporator, filters, does
It is dry, yellow solid is obtained, i.e., unformed pa wins the composition of XiLin solid dispersions and lactose, the group
In the X-ray powder diffraction figure of compound, XiLin is won without pa after the background peaks of deduction carrier and pharmaceutic adjuvant
The characteristic peak of crystal formation.
Embodiment 22
Pa is won into XiLin (50 milligrams) and carragheen E407 (500 milligrams) is suspended in methanol (30
Milliliter), it is heated to 50 DEG C and is uniformly mixed, adds microcrystalline cellulose (50 milligrams).Will
Slowly concentration removes most of solvent to above-mentioned solution in a rotary evaporator, filters, dries, obtain Huang
Color solid, i.e., unformed pa win the composition of XiLin solid dispersions and microcrystalline cellulose, said composition
X-ray powder diffraction figure in, deduct and win XiLin crystal formation without pa after the background peaks of carrier and pharmaceutic adjuvant
Characteristic peak.
Embodiment 23
Pa is won into XiLin (50 milligrams) and chitosan (5 grams) is suspended in methanol (50 milliliters), is added
Heat is uniformly mixed to 50 DEG C, adds lactose (100 milligrams).Above-mentioned solution is steamed in rotation
Send out slowly to concentrate in device and remove most of solvent, filter, dry, obtain yellow solid, i.e., it is unformed
Pa wins the composition of XiLin solid dispersions and lactose, in the X-ray powder diffraction figure of said composition,
The characteristic peak of XiLin crystal formation is won after the background peaks of deduction carrier and pharmaceutic adjuvant without pa.
Embodiment 24
Pa is won into XiLin (30 milligrams) and polyacrylic resin Eudragit E100 (30 milligrams) are molten
In n-butanol (600 microlitres), methyl phenyl ethers anisole (900 microlitres) and N,N-dimethylformamide (600
Microlitre) in, 50 DEG C of stirring dissolved clarifications are heated to, add lactose (30 milligrams).By above-mentioned solution
10 DEG C are cooled to, separates out yellow solid, is filtered, is dried, the rich XiLin solid of unformed pa is obtained and disperses
The composition of body and lactose, in the X-ray powder diffraction figure of said composition, deduct carrier and medicinal auxiliary
The characteristic peak of XiLin crystal formation is won after the background peaks of material without pa.
Embodiment 25
Pa is won into XiLin (30 milligrams) and collagen Peptan (300 milligrams) is dissolved in n-butanol (600
Microlitre), in methyl phenyl ethers anisole (900 microlitres) and acetonitrile (600 microlitres), it is molten to be heated to 50 DEG C of stirrings
Clearly, microcrystalline cellulose (30 milligrams) is added.Above-mentioned solution is cooled to 10 DEG C, separates out yellow
Solid, filter, dry, obtain unformed pa and win XiLin and collagen Peptan composition, should
In the X-ray powder diffraction figure of composition, without Pa Boxi after the background peaks of deduction carrier and pharmaceutic adjuvant
The characteristic peak of woods crystal formation.
Embodiment 26
Pa is won into XiLin (30 milligrams) and gummy Galactosol (300 milligrams) is dissolved in n-butanol (600
Microlitre), in methyl phenyl ethers anisole (900 microlitres) and methanol (600 microlitres), it is molten to be heated to 50 DEG C of stirrings
Clearly, microcrystalline cellulose (30 milligrams) is added.Above-mentioned solution is cooled to 10 DEG C, separates out yellow
Solid, filter, dry, obtain the combination that unformed pa wins XiLin solid dispersions and microcrystalline cellulose
Thing, in the X-ray powder diffraction figure of said composition, deduct nothing after the background peaks of carrier and pharmaceutic adjuvant
Pa wins the characteristic peak of XiLin crystal formation.
Embodiment 27
Pa is won into XiLin (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 and is stirred
Uniformly, sodium carboxymethylcellulose (30 milligrams) is added.Above-mentioned solution is slow in a rotary evaporator
Concentration removes solvent, obtains yellow solid, i.e., unformed pa wins the group of XiLin and sodium carboxymethylcellulose
Compound, in the X-ray powder diffraction figure of said composition, after the background peaks for deducting carrier and pharmaceutic adjuvant
The characteristic peak of XiLin crystal formation is won without pa.
Embodiment 28
Pa is won into XiLin (30 milligrams) and caprolactone (300 milligrams) is added to ethanol (750
Microlitre) and water (750 microlitres), it is heated to 80 DEG C and is uniformly mixed, adds lactose (200
Milligram).By above-mentioned solution, slowly concentration removes solvent in a rotary evaporator, obtains yellow solid,
I.e. unformed pa wins the composition of XiLin solid dispersions and lactose, and the X-ray powder of said composition spreads out
Penetrate in figure, win the characteristic peak of XiLin crystal formation after the background peaks of deduction carrier and pharmaceutic adjuvant without pa.
Embodiment 29
Pa is won into XiLin (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, add lactose
(200 milligrams).By above-mentioned solution, slowly concentration removes solvent in a rotary evaporator, obtains yellow
Solid, i.e., unformed pa win the composition of XiLin solid dispersions and lactose, the X-ray of said composition
In powder diagram, the characteristic peak of XiLin crystal formation is won after the background peaks of deduction carrier and pharmaceutic adjuvant without pa.
Embodiment 30
Pa is won into XiLin (30 milligrams) and sodium carboxymethylcellulose SCMS (3 milligrams) is added to water
(30 milliliters), it is heated to 100 DEG C and is uniformly mixed, adds microcrystalline cellulose (30 milligrams).
By above-mentioned solution, slowly concentration removes solvent in a rotary evaporator, obtains yellow solid, i.e., unformed
Pa wins the composition of XiLin solid dispersions and microcrystalline cellulose, the X-ray powder diffraction of said composition
In figure, the characteristic peak of XiLin hydrochloride Form is won after the background peaks of deduction carrier and pharmaceutic adjuvant without pa.
Embodiment 31
Pa is won into XiLin (30 milligrams) and sodium carboxymethylcellulose SCMC (30 milligrams) is added to
Methanol (300 microlitres) and water (60 microlitres), it is uniformly mixed at 60 DEG C, adds crystallite fibre
Dimension is plain (60 milligrams).By above-mentioned solution, slowly concentration removes solvent in a rotary evaporator, obtains Huang
Color solid, i.e., unformed pa win the composition of XiLin solid dispersions and microcrystalline cellulose, said composition
X-ray powder diffraction figure in, deduct and win XiLin crystal formation without pa after the background peaks of carrier and pharmaceutic adjuvant
Characteristic peak.
Embodiment 32
Pa is won into (30 milligrams) additions in XiLin (5 milligrams) and PEO Polyox WSR301
To methanol (300 microlitres) and water (60 microlitres), it is uniformly mixed at 60 DEG C, adds colloidal state
Silica Aerosil 200 (20 milligrams).Above-mentioned solution is slowly concentrated in a rotary evaporator
Solvent is removed, obtains yellow solid, i.e., unformed pa wins XiLin solid dispersions and colloidal silica
Silicon Aerosil 200 composition, the X-ray powder diffraction figure of said composition as shown in figure 3,
In X-ray powder diffraction figure XiLin crystal formation is won after the background peaks of deduction carrier and pharmaceutic adjuvant without pa
Characteristic peak.
Embodiment 33
Pa is won into XiLin (30 milligrams) and polyvinyl alcohol EG-40 (60 milligrams) is added to methanol (300
Microlitre) and water (60 microlitres), dissolved clarification is stirred at 60 DEG C, and adding (30 milligrams) of lactose will
Slowly concentration removes solvent to above-mentioned solution in a rotary evaporator, obtains yellow solid, i.e., unformed
Pa wins the composition of XiLin solid dispersions and lactose, in the X-ray powder diffraction figure of said composition,
The characteristic peak of XiLin crystal formation is won after the background peaks of deduction carrier and pharmaceutic adjuvant without pa.
Embodiment 34
Pa is won into XiLin (50 milligrams) and HPMC acetate succinate Agoat MG
(2 grams) are added to ethanol (10 milliliters) and water (2 milliliters), are uniformly mixed at 80 DEG C,
Add microcrystalline cellulose (50 milligrams).Above-mentioned solution is slowly concentrated to dryness in a rotary evaporator,
Yellow solid is obtained, i.e., unformed pa wins the composition of XiLin solid dispersions and microcrystalline cellulose, should
In the X-ray powder diffraction figure of composition, without Pa Boxi after the background peaks of deduction carrier and pharmaceutic adjuvant
The characteristic peak of woods crystal formation.
Embodiment 35
Pa is won into XiLin (50 milligrams) and carboxymethylethylcellulose (2 grams) is added to ethanol (10
Milliliter) and water (1 milliliter), it is uniformly mixed at 80 DEG C, adds cross-linked carboxymethyl cellulose
Sodium (50 milligrams).Above-mentioned solution is slowly concentrated to dryness in a rotary evaporator, obtains yellow solid,
I.e. unformed pa wins the composition of XiLin solid dispersions and Ac-Di-Sol, said composition
X-ray powder diffraction figure in, deduct and win XiLin crystal formation without pa after the background peaks of carrier and pharmaceutic adjuvant
Characteristic peak.
Embodiment 36：Unformed pa wins the influence of the composition of XiLin solid dispersions and microcrystalline cellulose
Factorial experiments
Material：The unformed pa of the gained of embodiment 12 wins the combination of XiLin solid dispersions and microcrystalline cellulose
Thing
Table 1：
Table 1 illustrates：Unformed pa win the composition of XiLin solid dispersions and microcrystalline cellulose high temperature,
Under super-humid conditions, place 10 days, relevant material without significantly changing, win XiLin crystallization and separate out by no pa.
Embodiment 37：Unformed pa wins the acceleration of the composition of XiLin solid dispersions and microcrystalline cellulose
Stability experiment
Material：The unformed pa of the gained of embodiment 12 wins the combination of XiLin solid dispersions and microcrystalline cellulose
Thing
Experiment condition：40 DEG C ± 2 DEG C of temperature, humidity 75% ± 5%
Table 2：
Table 2 illustrates：Unformed pa wins XiLin solid dispersions and the composition of microcrystalline cellulose is accelerating
Under experimental condition, place 6 months, relevant material without significantly changing, win XiLin crystallization and separate out by no pa.
The composition that XiLin solid dispersions and pharmaceutic adjuvant are won containing unformed pa of the present invention, its dissolution
The obvious increase of degree, it is more beneficial for improving the bioavilability of medicine, it is clinical allows medicament to preferably performance
Disease treatment acts on, the amorphous article (40 ± 2 DEG C, humidity 75% ± 5%) under the conditions of accelerated test,
Good physical stability and chemical stability can be kept.
Claims (11)
- A kind of 1. Pharmaceutical composition that XiLin solid dispersions are won containing pa, it is characterised in that the composition Solid dispersions that XiLin formed with organic carrier are won comprising pa and at least one can pharmaceutically be connect The auxiliary material received, the weight that pa wins XiLin are the 20%-80% of the gross weight of solid dispersions, auxiliary material Weight is the 0.1%~80% of the weight of solid dispersions, wherein, it is without fixed that described pa, which wins XiLin, Kenel, in the X-ray powder diffraction spectrum of the composition, deduct organic carrier and medicinal auxiliary The characteristic peak of XiLin crystal is won after the background peaks of material without pa.
- 2. the Pharmaceutical composition according to claim 1 that XiLin solid dispersions are won containing pa, its feature It is, described organic carrier is selected from polymer and copolymer.
- 3. the Pharmaceutical composition that XiLin solid dispersions are won containing unformed pa according to claim 1-2, Characterized in that, the organic carrier is selected from HPMC, hydroxypropyl cellulose, poly- dimension Ketone, polyethylene glycol, ethyl cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate, Carboxymethylethylcellulose, carboxymethyl cellulose phthalic acid ester, HPMC neighbour's benzene Dicarboxylic acid esters, HPMC acetate succinate, polyacrylic resin, carbopol, Alginates, carragheen, caprolactone, natural gum, polyvinyl alcohol, pregelatinized starch, crosslinking Starch, sodium carboxymethyl starch, dextrin, PEO, chitosan, chitosan, ion are handed over Change at least one of resin and collagen.
- A kind of 4. Pharmaceutical composition that XiLin solid dispersions are won containing unformed pa described in claim 1 Preparation method, comprise the following steps：1) pa is won into XiLin, at least one organic carrier and at least one pharmaceutically acceptable auxiliary material to mix Thing, it is heated to melting, wherein, the weight that pa wins XiLin is the gross weight of solid dispersions 20%-80%, the weight of auxiliary material is the 0.1%~80% of the weight of solid dispersions；2) cooled down after being well mixed, obtained mixture is crushed, obtains the Pa Boxi containing unformed shape The Pharmaceutical composition of woods solid dispersions.
- 5. the group of the pharmaceutic adjuvant according to claim 4 that XiLin solid dispersions are won containing unformed pa The preparation method of compound, it is characterised in that described organic carrier is selected from polymer and copolymer.
- 6. the pharmaceutic adjuvant that XiLin solid dispersions are won containing unformed pa according to claim 4-5 The preparation method of composition, it is characterised in that described organic carrier be selected from HPMC, Hydroxypropyl cellulose, PVP, polyethylene glycol, ethyl cellulose, liposome, methacrylic acid Copolymer, polyvinyl acetate, carboxymethylethylcellulose, carboxymethyl cellulose phthalic acid ester, Hydroxypropyl methylcellulose phthalate, HPMC acetate succinate, poly- third Olefin(e) acid resin, carbopol, alginates, carragheen, caprolactone, natural gum, polyethylene Alcohol, pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, PEO, shell gather At least one of sugar, chitosan and collagen.
- A kind of 7. Pharmaceutical composition that XiLin solid dispersions are won containing unformed pa described in claim 1 Preparation method, comprise the following steps：1) pa is won into XiLin, at least one organic carrier and at least one pharmaceutically acceptable auxiliary material to exist Mixed in solvent, mixing temperature be -50~150 DEG C, formed containing pa win XiLin, organic carrier and The solution or suspension of pharmaceutic adjuvant, wherein, pa wins XiLin and the weight ratio of solvent is 0.001~100:1, the weight that pa wins XiLin is the 20%-80% of the gross weight of solid dispersions, The weight of auxiliary material is the 0.1%~80% of the weight of solid dispersions；2) removing step 1) solvent in obtained solution or suspension, obtain the Pa Boxi of unformed shape The Pharmaceutical composition of woods.
- 8. the Pharmaceutical composition according to claim 7 that XiLin solid dispersions are won containing unformed pa Preparation method, it is characterised in that the pharmaceutic adjuvant is selected from polymer selected from described organic carrier And copolymer.
- 9. the Pharmaceutical composition that XiLin solid dispersions are won containing unformed pa according to claim 7-8 Preparation method, it is characterised in that described organic carrier be selected from HPMC, hydroxypropyl Base cellulose, PVP, polyethylene glycol, ethyl cellulose, liposome, methacrylic acid copolymer Thing, polyvinyl acetate, carboxymethylethylcellulose, carboxymethyl cellulose phthalic acid ester, hydroxyl Third methyl cellulose phthalate ester, HPMC acetate succinate, polypropylene Acid resin, carbopol, alginates, carragheen, caprolactone, natural gum, polyvinyl alcohol, Pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, PEO, chitosan, At least one of chitosan, ion exchange resin and collagen.
- 10. the Pharmaceutical composition according to claim 7 that XiLin solid dispersions are won containing unformed pa Preparation method, it is characterised in that the step 1) solvent is selected from containing less than 12 carbon atoms Alcohols, phenols, ethers, halogenated hydrocarbons, ketone, aldehydes, nitrile, acid amides, sulfone, sulfoxide, carboxylic At least one of acid and water；The method that step 2) removes solvent includes：Evaporate, be evaporated in vacuo, Spray drying, freeze-drying, hot-melt extruded, filtering, centrifugation or agitated thin film.
- 11. such as the claim 1-4 Pharmaceutical composition that XiLin solid dispersions are won containing unformed pa, it is used for The purposes for the treatment of cancer medicine is prepared, the cancer includes：Breast cancer, oophoroma, cervix cancer, Prostate cancer, carcinoma of testis, cancer of the esophagus, stomach cancer, cutaneum carcinoma, lung cancer, osteocarcinoma, colon cancer, pancreas Gland cancer, thyroid cancer, cancer of bile ducts, the vestibule of mouth diease and pharynx cancer (oral cavity), lip cancer, tongue cancer, mouth Cancer, pharynx cancer, carcinoma of small intestine, colon-rectum, colorectal cancer, the carcinoma of the rectum, brain and central nervous system System cancer, glioblast cancer, nerve metrocyte carcinoma, angling spine skin cancer, epidermoid carcinoma, maxicell Cancer, gland cancer, ovarian follicle cancer, undifferentiated carcinoma, papillary carcinoma, the first cell cancer of essence, melanoma, meat Knurl, carcinoma of urinary bladder, liver cancer, kidney, bone marrow disorder disease, lymph deficiency disorder, hodgkin's disease, skin Skin cell cancer and leukaemia.
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| PCT/CN2016/097412 WO2017036390A1 (en) | 2015-09-01 | 2016-08-30 | Composition of palbociclib or pharmaceutically acceptable salt thereof and pharmaceutical excipient, and preparation method therefor |
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Cited By (4)
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| CN108017629A (en) * | 2016-11-04 | 2018-05-11 | 上海奥博生物医药技术有限公司 | A kind of Pa Boxini amorphous states |
| CN112569361A (en) * | 2020-12-30 | 2021-03-30 | 扬子江药业集团上海海尼药业有限公司 | Periploca forrestii dry suspension composition and preparation method thereof |
| WO2022068877A1 (en) * | 2020-09-29 | 2022-04-07 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical compositions of amorphous solid dispersions and methods of preperation thereof |
| US11464779B2 (en) | 2016-03-29 | 2022-10-11 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical formulation of palbociclib and a preparation method thereof |
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| CN105616419A (en) * | 2014-11-07 | 2016-06-01 | 江苏豪森药业集团有限公司 | Pharmaceutical composition containing cyclin inhibitor solid dispersion, and preparation method thereof |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11464779B2 (en) | 2016-03-29 | 2022-10-11 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical formulation of palbociclib and a preparation method thereof |
| CN108017629A (en) * | 2016-11-04 | 2018-05-11 | 上海奥博生物医药技术有限公司 | A kind of Pa Boxini amorphous states |
| WO2022068877A1 (en) * | 2020-09-29 | 2022-04-07 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical compositions of amorphous solid dispersions and methods of preperation thereof |
| US11471418B2 (en) | 2020-09-29 | 2022-10-18 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical compositions of amorphous solid dispersions and methods of preparation thereof |
| CN112569361A (en) * | 2020-12-30 | 2021-03-30 | 扬子江药业集团上海海尼药业有限公司 | Periploca forrestii dry suspension composition and preparation method thereof |
| CN112569361B (en) * | 2020-12-30 | 2023-01-10 | 扬子江药业集团上海海尼药业有限公司 | Piperazine Bai Xili dry suspension composition and preparation method thereof |
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