CN107510695A - A kind of Pharmaceutical composition containing unformed Tadalafei solid dispersions and preparation method thereof - Google Patents
A kind of Pharmaceutical composition containing unformed Tadalafei solid dispersions and preparation method thereof Download PDFInfo
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- CN107510695A CN107510695A CN201610440524.1A CN201610440524A CN107510695A CN 107510695 A CN107510695 A CN 107510695A CN 201610440524 A CN201610440524 A CN 201610440524A CN 107510695 A CN107510695 A CN 107510695A
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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
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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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
The present invention relates to a kind of Pharmaceutical composition containing Tadalafei solid dispersions, it includes solid dispersions and at least one pharmaceutically acceptable auxiliary material that Tadalafei is formed with organic carrier, the weight of Tadalafei 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, Tadalafei is unformed shape, and the characteristic peak of the crystal without Tadalafei after the background peaks of organic carrier and pharmaceutic adjuvant is deducted in the X ray Powder Diffraction patterns of the composition.The invention further relates to a kind of preparation method of the Pharmaceutical composition of unformed Tadalafei.The Tadalafei Pharmaceutical composition stability and favorable dispersibility of the present invention, add the dissolution rate of Tadalafei, 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 contains unformed Tadalafei solid point
Pharmaceutical composition of granular media and preparation method thereof, and said composition treatment male erectile dysfunction
Purposes.
Background technology
Tadalafei (Tadalafil), entitled (6R, the 12aR) -6- of chemistry (1,3- benzene and two Evil cyclopentadienyl -5- bases) -2-
Methyl -2,3,6,7,12,12a- hexahydro pyrazines simultaneously [1', 2'-1,6]-pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone,
Trade name Tadalafil (Calais), is developed by Lilly Co., Eli., and in January, 2008 in U.S.
State lists, for treating male erectile dysfunction.
Polymorphism be present in tadalafil.Patent CN1045777 discloses a kind of tadalafil
White, needle-shaped crystals, i.e. Form I.Patent WO2006/049986 discloses the crystal formation of tadalafil
Form A, Form B and unformed.Patent WO2006/050458 discloses the crystal formation of tadalafil
IIth, III, IV, VI, VII and VIII.Although the solid form of existing a variety of tadalafils is disclosed,
But patent WO2001/008688 points out that tadalafil is a kind of insoluble drug, it is necessary to by obtained by
Crystal formation Form I further crushed, to increase the dissolution of the rate of dissolution of bulk drug, preparation
Degree and bioavilability.The patent is pointed out, it is necessary to by crystal formation drug powder or unformed drug powder system
It is equal to 40 microns of particulate into particle diameter distribution d90, i.e., more than 90% particle is less than 40 microns,
There can be preferable therapeutic effect.
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 insufficient and unformed active constituents of medicine of the Tadalafei in terms of bioavilability is in medicine
Good application prospect in terms of thing preparation, find new unformed Tadalafei 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 the medicinal of Tadalafei solid dispersions containing amorphous state
Composition and preparation method thereof, obtain the Tadalafei of the unformed shape of stability and favorable dispersibility
Pharmaceutical composition, the dissolution rate of Tadalafei 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 containing Tadalafei solid dispersions, its include Tadalafei with it is organic
The solid dispersions and at least one pharmaceutically acceptable auxiliary material that carrier is formed, the weight of Tadalafei
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, described Tadalafei is unformed shape, the X-ray powder of the composition
In last difraction spectrum, the characteristic peak without Tadalafei crystal after the background peaks of carrier and pharmaceutic adjuvant is deducted.
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 containing Tadalafei solid dispersions of the present invention, including such as
Lower step：
1) it is Tadalafei, at least one organic carrier and at least one is pharmaceutically acceptable auxiliary
The mixed thing of material, is heated to melting, wherein, the weight of Tadalafei 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, obtain him containing unformed shape
Up to the Pharmaceutical composition for drawing non-solid dispersion.
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 of another Pharmaceutical composition containing Tadalafei solid dispersions
Method, comprise the following steps：
1) Tadalafei, at least one organic carrier and at least one pharmaceutically acceptable auxiliary material are existed
Mixed in solvent, mixing temperature is -50~150 DEG C, and formation contains Tadalafei, organic carrier and medicine
With the solution or suspension of auxiliary material, wherein, the weight ratio of Tadalafei and solvent is 0.001~100:1,
The weight of Tadalafei 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 containing unformed shape he reach
Draw the Pharmaceutical composition of non-solid dispersion.
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 containing unformed Tadalafei
The Pharmaceutical composition of pharmaceutically acceptable auxiliary material is used for the purposes for treating male erectile dysfunction.
The solid dispersions containing unformed Tadalafei and at least one of the present invention can pharmaceutically connect
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 characteristic peak of carrier and the background peaks of pharmaceutic adjuvant without Tadalafei crystalline state is deducted in spectrum, shows him
Da Lafei is unformed state.The crystalline state of Tadalafei is typically used 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 the Tadalafei of the present invention is unformed shape, 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 Tadalafei or its salt
Bioavilability.
The present invention adds with least one pharmaceutically into the solid dispersions containing unformed Tadalafei
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
Be widely used, be cheap, the pharmaceutic adjuvant that dissolubility is good, these pharmaceutic adjuvants with it is unformed he reach
Draw non-solid dispersion to mix, coordinate the technologies such as evaporation, spray drying, freeze-drying and hot-melt extruded
Can obtain the composition of unformed Tadalafei solid dispersions and pharmaceutic adjuvant, the increase present invention he
The stability of Da Lafei unformed shape.
The present invention select pharmaceutically widely used, cheap auxiliary material, obtain containing it is unformed he
Da Lafei solid dispersions 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) the composition tool of unformed Tadalafei solid dispersions and pharmaceutic adjuvant prepared by the present invention
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) composition of the Tadalafei solid dispersions of the unformed state of the present invention 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) the Tadalafei solid dispersions of unformed state and the group of pharmaceutic adjuvant that prepared by the present invention
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 unformed the Tadalafei solid dispersions and microcrystalline cellulose of the embodiment of the present invention 12
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 unformed the Tadalafei solid dispersions and colloidal silica of the embodiment of the present invention 32
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 of any Tadalafei may be used to prepare the solid dispersions of unformed Tadalafei.
Tadalafei (50 milligrams) and PVP K30 (100 milligrams) are dissolved in into tetrahydrofuran, and (900 is micro-
Rise) and methanol (600 microlitres) in, be heated to 60 DEG C stir dissolved clarifications, add microcrystalline cellulose (50
Milligram).Above-mentioned solution is cooled to rapidly -10 DEG C, separates out white solid, is filtered, vacuum drying, is obtained
To unformed Tadalafei solid dispersions and the composition of microcrystalline cellulose, the X-ray powder of said composition
Characteristic peak without Tadalafei crystal formation after the background peaks of deduction carrier and pharmaceutic adjuvant in last diffraction pattern.
Embodiment 2
Tadalafei (50 milligrams) and Macrogol 4000 (200 milligrams) are dissolved in acetic acid (800
Microlitre) and ethanol (600 microlitres) in, be uniformly mixed at 60 DEG C, add microcrystalline cellulose
Plain (50 milligrams).Above-mentioned solution is slowly concentrated to dryness in a rotary evaporator, obtains white solid,
The composition of i.e. unformed Tadalafei and microcrystalline cellulose, the X-ray powder diffraction figure of said composition
In, deduct the characteristic peak without Tadalafei crystal formation after the background peaks of carrier and pharmaceutic adjuvant.
Embodiment 3
(10 grams) of Tadalafei (5 grams) and PEG 8000 are added into methanol (600 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, collect outlet material, obtain white solid, further vacuum drying obtain it is unformed he
Up to the composition for drawing non-solid dispersion and Ac-Di-Sol, the X-ray powder of said composition
In last diffraction pattern, the characteristic peak without Tadalafei crystal formation after the background peaks of carrier and pharmaceutic adjuvant is deducted.
Embodiment 4
Tadalafei (1 gram) and HPMC E50 (0.2 gram) are added to methanol (200
Milliliter) in, it is heated to 40 DEG C and is uniformly mixed, adds PVPP (0.2 gram).Will
Above-mentioned solution freeze-drying, obtains white solid, i.e., unformed Tadalafei solid dispersions and crosslinking
The composition of PVP, in the X-ray powder diffraction figure of said composition, deduct carrier and pharmaceutic adjuvant
Background peaks after the characteristic peak without Tadalafei crystal formation.
Embodiment 5
By (5 grams) Tadalafei (1 gram), mannitol (5 grams) and PEG 8000 heating
To melting, room temperature is quickly cooled under stirring, obtains white solid.Above-mentioned solid is crushed, obtained
White powdery solids, i.e., the composition of unformed Tadalafei solid dispersions and mannitol, the group
In the X-ray powder diffraction figure of compound, without Tadalafei after the background peaks of deduction carrier and pharmaceutic adjuvant
The characteristic peak of crystal formation.
Embodiment 6
(10 grams) of Tadalafei (1 gram), mannitol (0.1 gram) and PEG20000 are added
Heat is well mixed to 240 DEG C, is quickly cooled to room temperature, obtains white solid.By above-mentioned solid powder
It is broken, obtain white powdery solids, i.e., the combination of unformed Tadalafei 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
The characteristic peak of Tadalafei crystal formation.
Embodiment 7
The mixture of Tadalafei (1 gram), acetic acid (20 grams) and liposome (4 grams) is heated
To 90 DEG C, stir lower well mixed.Microcrystalline cellulose (2 grams) is added, is stirred, vacuum
Evaporation of solvent, white solid is obtained, i.e., unformed Tadalafei solid dispersions and microcrystalline cellulose
The composition of element, in the X-ray powder diffraction figure of said composition, deduct the back of the body of carrier and pharmaceutic adjuvant
Characteristic peaks of the Jing Fenghou without Tadalafei crystal formation.
Embodiment 8
By Tadalafei (1 gram), tetrahydrofuran (60 grams) and methacrylic acid copolymer A types (4
Gram) mixture be heated to 50 DEG C, stir lower dissolved clarification, add PVPP (1 gram), very
Empty evaporation of solvent, it is cooled to room temperature and obtains white solid, i.e., unformed Tadalafei solid disperses
The composition of body and PVPP, in the X-ray powder diffraction figure of said composition, deduct carrier and
Characteristic peak without Tadalafei hydrobromate crystal formation after the background peaks of pharmaceutic adjuvant.
Embodiment 9
By the mixture of Tadalafei (1 gram), ethanol (300 grams) and ethyl cellulose (2 grams)
70 DEG C are heated to, is stirred, is well mixed, adds magnesium stearate (0.1 gram), vacuum evaporation removes
Remove solvent, be cooled to room temperature and obtain white solid, i.e., unformed Tadalafei solid dispersions and tristearin
The composition of sour magnesium, in the X-ray powder diffraction figure of said composition, deduct carrier and pharmaceutic adjuvant
Characteristic peak without Tadalafei crystal formation after background peaks.
Embodiment 10
By Tadalafei (1 gram), methanol (100 grams), dichloromethane (30 grams) and hydroxypropyl
Cellulose SSL (4 grams) mixture is heated to 30 DEG C, stirs dissolved clarification, adds microcrystalline cellulose
(0.5 gram), be evaporated in vacuo remove solvent, be cooled to room temperature and obtain white solid, i.e., it is unformed he
Up to the composition for drawing non-solid dispersion and microcrystalline cellulose, the X-ray powder diffraction figure of said composition
In, deduct the characteristic peak without Tadalafei hydrochloride Form after the background peaks of carrier and pharmaceutic adjuvant.
Embodiment 11
By Tadalafei (1 gram), tetrahydrofuran (50 grams), dichloromethane (10 grams) and poly-vinegar
The mixture of sour ethene (4 grams) is heated to 30 DEG C, stirs dissolved clarification, adds microcrystalline cellulose (0.5
Gram) removing solvent is evaporated in vacuo, it is cooled to room temperature and obtains white solid, i.e., unformed Tadalafei is consolidated
The composition of body dispersion and microcrystalline cellulose, in the X-ray powder diffraction figure of said composition, deduct
Characteristic peak without Tadalafei isethionate crystal formation after the background peaks of carrier and pharmaceutic adjuvant.
Embodiment 12
(100 milligrams) of Tadalafei (50 milligrams) and polyacrylic resin Eudragit L100 are added
Enter to acetic acid (750 microlitres), stir dissolved clarification at 90 DEG C, add microcrystalline cellulose (100 milligrams).
Above-mentioned suspension is rapidly cooled to 20 DEG C, separates out white solid.Filtering, vacuum drying, are obtained white
Color solid, i.e., the composition of unformed Tadalafei 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
Characteristic peak without Tadalafei crystal formation after the background peaks of auxiliary material.The X-ray powder diffraction of microcrystalline cellulose
Figure is as shown in Figure 2.
Embodiment 13
By (5 milligrams) additions of Tadalafei (50 milligrams) and polyacrylic resin Eudragit S100
To acetic acid (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
White solid, i.e., the composition of unformed Tadalafei solid dispersions and sodium carboxymethyl starch, the group
In the X-ray powder diffraction figure of compound, without Tadalafei after the background peaks of deduction carrier and pharmaceutic adjuvant
The characteristic peak of crystal formation.
Embodiment 14
Tadalafei (50 milligrams) and carbopol Carbomer 940 (50 milligrams) are 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, obtained white
Color solid, i.e., the composition of unformed Tadalafei solid dispersions and microcrystalline cellulose, said composition
X-ray powder diffraction figure in, deduct after the background peaks of carrier and pharmaceutic adjuvant without Tadalafei crystal formation
Characteristic peak.
Embodiment 15
Tadalafei (50 milligrams) and pregelatinized starch Pharma-Gel (100 milligrams) are added to
Methanol (4 milliliters) and ethyl acetate (1 milliliter), are well mixed, add crosslinking carboxylic at room temperature
Sodium carboxymethylcellulose pyce (100 milligrams).Above-mentioned solution is slowly concentrated to dryness in a rotary evaporator,
Obtain white solid, i.e., the group of unformed Tadalafei solid dispersions and Ac-Di-Sol
Compound, in the X-ray powder diffraction figure of said composition, after the background peaks for deducting carrier and pharmaceutic adjuvant
Characteristic peak without Tadalafei crystal formation.
Embodiment 16
Tadalafei (50 milligrams) and high side chain crosslinked starch (50 milligrams) are added to n-butanol
(4 milliliters) and acetone (1 milliliter), stirs dissolved clarification, adds cross-linked carboxymethyl fiber at room temperature
Plain sodium (100 milligrams).Above-mentioned solution is slowly concentrated to dryness in a rotary evaporator, obtains white
Solid, i.e., the composition without unformed Tadalafei solid dispersions and Ac-Di-Sol,
In the X-ray powder diffraction figure of said composition, reached after deducting the background peaks of carrier and pharmaceutic adjuvant without him
Draw armorphous characteristic peak.
Embodiment 17
Tadalafei (50 milligrams) and sodium carboxymethylcellulose SCMC (500 milligrams) are 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 white solid, i.e., without
The composition of sizing Tadalafei solid dispersions and Ac-Di-Sol, said composition
In X-ray powder diffraction figure, without Tadalafei crystal formation after the background peaks of deduction carrier and pharmaceutic adjuvant
Characteristic peak.
Embodiment 18
Tadalafei (50 milligrams) and chitosan (500 milligrams) are added to dimethylformamide
(5 milliliters), stir dissolved clarification at room temperature, add microcrystalline cellulose (50 milligrams).Will be above-mentioned molten
Liquid is slowly concentrated to dryness in a rotary evaporator, obtains white solid, i.e., unformed Tadalafei solid
The composition of dispersion and microcrystalline cellulose, in the X-ray powder diffraction figure of said composition, deduct and carry
Characteristic peak without Tadalafei crystal formation after the background peaks of body and pharmaceutic adjuvant.
Embodiment 19
Tadalafei (50 milligrams) and sodium carboxymethyl starch Explotab (500 milligrams) are added to
Dimethyl acetamide (5 milliliters), is uniformly mixed at room temperature, adds lactose (100 milligrams).
Above-mentioned solution is slowly concentrated to dryness in a rotary evaporator, obtains white solid, i.e., it is unformed he reach
Draw the composition of non-solid dispersion and lactose, in the X-ray powder diffraction figure of said composition, deduct
Characteristic peak without Tadalafei crystal formation after the background peaks of carrier and pharmaceutic adjuvant.
Embodiment 20
Tadalafei (50 milligrams) and alginates E401 (500 milligrams) are added to methanol (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 white solid, i.e., unformed Tadalafei solid dispersions with
The composition of lactose, in the X-ray powder diffraction figure of said composition, deduct carrier and pharmaceutic adjuvant
Characteristic peak without Tadalafei crystal formation after background peaks.
Embodiment 21
By Tadalafei (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, obtain white solid, i.e., the composition of unformed Tadalafei solid dispersions and lactose, the group
In the X-ray powder diffraction figure of compound, without Tadalafei after the background peaks of deduction carrier and pharmaceutic adjuvant
The characteristic peak of crystal formation.
Embodiment 22
Tadalafei (50 milligrams) and carragheen E407 (500 milligrams) are 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 white
Color solid, i.e., the composition of unformed Tadalafei solid dispersions and microcrystalline cellulose, said composition
X-ray powder diffraction figure in, deduct after the background peaks of carrier and pharmaceutic adjuvant without Tadalafei crystal formation
Characteristic peak.
Embodiment 23
Tadalafei (50 milligrams) and chitosan (5 grams) are suspended in methanol (50 milliliters), 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 white solid, i.e., it is unformed
The composition of Tadalafei solid dispersions and lactose, in the X-ray powder diffraction figure of said composition,
Characteristic peak without Tadalafei crystal formation after the background peaks of deduction carrier and pharmaceutic adjuvant.
Embodiment 24
Tadalafei (30 milligrams) and polyacrylic resin Eudragit E100 (30 milligrams) is molten
In DMF (600 microlitres), 50 DEG C of stirring dissolved clarifications are heated to, add lactose
(30 milligrams).Above-mentioned solution is cooled to 10 DEG C, separates out white solid, is filtered, dries, obtains
To unformed Tadalafei solid dispersions and the composition of lactose, the X-ray powder of said composition spreads out
Penetrate in figure, deduct the characteristic peak without Tadalafei crystal formation after the background peaks of carrier and pharmaceutic adjuvant.
Embodiment 25
Tadalafei (30 milligrams) and collagen Peptan (300 milligrams) are dissolved in acetic acid (900
Microlitre) and acetonitrile (600 microlitres) in, be heated to 50 DEG C stirring dissolved clarifications, add microcrystalline cellulose
(30 milligrams).Above-mentioned solution is cooled to 10 DEG C, separates out white solid, is filtered, dries, obtains
To unformed Tadalafei and collagen Peptan composition, the X-ray powder of said composition
In diffraction pattern, the characteristic peak without Tadalafei crystal formation after the background peaks of carrier and pharmaceutic adjuvant is deducted.
Embodiment 26
Tadalafei (30 milligrams) and gummy Galactosol (300 milligrams) are dissolved in tetrahydrofuran
In (900 microlitres) and methanol (600 microlitres), 50 DEG C of stirring dissolved clarifications are heated to, add crystallite
Cellulose (30 milligrams).Above-mentioned solution is cooled to 10 DEG C, separates out white solid, is filtered, is done
It is dry, the composition of unformed Tadalafei solid dispersions and microcrystalline cellulose is obtained, said composition
In X-ray powder diffraction figure, without Tadalafei crystal formation after the background peaks of deduction carrier and pharmaceutic adjuvant
Characteristic peak.
Embodiment 27
By Tadalafei (30 milligrams) and hydroxypropyl methylcellulose phthalate HPMCP (30
Milligram) ethanol (750 microlitres) and acetic acid (750 microlitres) are added to, it is mixed to be heated to 80 DEG C of stirrings
Close uniform, addition sodium carboxymethylcellulose (30 milligrams).Above-mentioned solution is delayed in a rotary evaporator
Slow concentration removes solvent, obtains white solid, i.e., unformed Tadalafei and sodium carboxymethylcellulose
Composition, in the X-ray powder diffraction figure of said composition, deduct the background peaks of carrier and pharmaceutic adjuvant
Characteristic peak afterwards without Tadalafei crystal formation.
Embodiment 28
Tadalafei (30 milligrams) and caprolactone (300 milligrams) are added to ethanol (750
Microlitre) and dimethylformamide (750 microlitres), it is heated to 80 DEG C and is uniformly mixed, adds
Lactose (200 milligrams).By above-mentioned solution, slowly concentration removes solvent in a rotary evaporator, obtains
White solid, i.e., the composition of unformed Tadalafei solid dispersions and lactose, said composition
In X-ray powder diffraction figure, without Tadalafei crystal formation after the background peaks of deduction carrier and pharmaceutic adjuvant
Characteristic peak.
Embodiment 29
Tadalafei (30 milligrams) and dextrin Maltrin M100 (300 milligrams) are added to ethanol
(750 microlitres) and acetic acid (750 microlitres), is heated to 80 DEG C and is uniformly mixed, add breast
Sugared (200 milligrams).By above-mentioned solution, slowly concentration removes solvent in a rotary evaporator, obtains white
Color solid, i.e., the composition of unformed Tadalafei solid dispersions and lactose, the X- of said composition
In ray powder diffraction pattern, the spy without Tadalafei crystal formation after the background peaks of carrier and pharmaceutic adjuvant is deducted
Levy peak.
Embodiment 30
Tadalafei (30 milligrams) and sodium carboxymethylcellulose SCMS (3 milligrams) are added to four
Hydrogen furans (30 milliliters), is heated to 100 DEG C and is uniformly mixed, add microcrystalline cellulose (30
Milligram).By above-mentioned solution, slowly concentration removes solvent in a rotary evaporator, obtains white solid,
The composition of i.e. unformed Tadalafei solid dispersions and microcrystalline cellulose, the X-ray of said composition
In powder diagram, without Tadalafei hydrochloride Form after the background peaks of deduction carrier and pharmaceutic adjuvant
Characteristic peak.
Embodiment 31
Tadalafei (30 milligrams) and sodium carboxymethylcellulose SCMC (30 milligrams) are added to
Methanol (300 microlitres) and acetic acid (600 microlitres), it is uniformly mixed at 70 DEG C, adds micro-
Crystalline cellulose (60 milligrams).By above-mentioned solution, slowly concentration removes solvent in a rotary evaporator, obtains
To white solid, i.e., the composition of unformed Tadalafei solid dispersions and microcrystalline cellulose, the group
In the X-ray powder diffraction figure of compound, without Tadalafei after the background peaks of deduction carrier and pharmaceutic adjuvant
The characteristic peak of crystal formation.
Embodiment 32
By (30 milligrams) additions of Tadalafei (5 milligrams) and PEO Polyox WSR301
To methanol (300 microlitres) and tetrahydrofuran (600 microlitres), it is uniformly mixed at 60 DEG C,
Add colloidal silica Aerosil 200 (20 milligrams).By above-mentioned solution in a rotary evaporator
Slowly concentration removes solvent, obtains white solid, i.e., unformed Tadalafei solid dispersions and glue
State silica Aerosil 200 composition, X-ray powder diffraction figure such as Fig. 3 of said composition
It is shown, without Tadalafei after the background peaks of deduction carrier and pharmaceutic adjuvant in X-ray powder diffraction figure
The characteristic peak of crystal formation.
Embodiment 33
Tadalafei (30 milligrams) and polyvinyl alcohol EG-40 (60 milligrams) are added to methanol (300
Microlitre) in, dissolved clarification is stirred at 60 DEG C, lactose (30 milligrams) is added and is rotating above-mentioned solution
Slowly concentration removes solvent in evaporator, obtains white solid, i.e., unformed Tadalafei solid point
The composition of granular media and lactose, in the X-ray powder diffraction figure of said composition, deduct carrier and medicine
With the characteristic peak without Tadalafei crystal formation after the background peaks of auxiliary material.
Embodiment 34
By Tadalafei (50 milligrams) and HPMC acetate succinate Agoat MG
(2 grams) are added to ethanol (10 milliliters) and tetrahydrofuran (2 milliliters), are stirred at 80 DEG C
Uniformly, microcrystalline cellulose (50 milligrams) is added.Above-mentioned solution is slowly dense in a rotary evaporator
It is reduced to dry, obtains white solid, i.e., the group of unformed Tadalafei solid dispersions and microcrystalline cellulose
Compound, in the X-ray powder diffraction figure of said composition, after the background peaks for deducting carrier and pharmaceutic adjuvant
Characteristic peak without Tadalafei crystal formation.
Embodiment 35
Tadalafei (50 milligrams) and carboxymethylethylcellulose (2 grams) are added to ethanol (10
Milliliter) and acetic acid (1 milliliter), it is uniformly mixed at 80 DEG C, adds cross-linked carboxymethyl fiber
Plain sodium (50 milligrams).Above-mentioned solution is slowly concentrated to dryness in a rotary evaporator, it is solid to obtain white
Body, i.e., the composition of unformed Tadalafei solid dispersions and Ac-Di-Sol, the group
In the X-ray powder diffraction figure of compound, without Tadalafei after the background peaks of deduction carrier and pharmaceutic adjuvant
The characteristic peak of crystal formation.
Embodiment 36：The influence of the composition of unformed Tadalafei solid dispersions and microcrystalline cellulose
Factorial experiments
Material：The combination of the unformed Tadalafei solid dispersions of the gained of embodiment 12 and microcrystalline cellulose
Thing
Table 1：
Table 1 illustrates：Composition containing unformed Tadalafei solid dispersions and microcrystalline cellulose is in height
Under temperature, super-humid conditions, place 10 days, relevant material without significantly changing, analyse by no Tadalafei crystallization
Go out.
Embodiment 37：The acceleration of the composition of unformed Tadalafei solid dispersions and microcrystalline cellulose
Stability experiment
Material：The combination of the unformed Tadalafei solid dispersions of the gained of embodiment 12 and microcrystalline cellulose
Thing
Experiment condition：40 DEG C ± 2 DEG C of temperature, humidity 75% ± 5%
Table 2：
Table 2 illustrates：Composition containing unformed Tadalafei solid dispersions and microcrystalline cellulose is adding
Under fast experimental condition, place 6 months, without significantly changing, no Tadalafei crystallization separates out relevant material.
The composition containing unformed Tadalafei solid dispersions and pharmaceutic adjuvant 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 containing Tadalafei solid dispersions, it is characterised in that the composition The solid dispersions and at least one formed comprising Tadalafei with organic carrier can pharmaceutically connect The auxiliary material received, the weight of Tadalafei 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, described Tadalafei is without fixed Kenel, in the X-ray powder diffraction spectrum of the composition, deduct organic carrier and medicinal auxiliary Characteristic peak without Tadalafei crystal after the background peaks of material.
- 2. the Pharmaceutical composition according to claim 1 containing Tadalafei solid dispersions, its feature It is, described organic carrier is selected from polymer and copolymer.
- 3. the Pharmaceutical composition containing unformed Tadalafei solid dispersions 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.
- 4. a kind of Pharmaceutical composition containing unformed Tadalafei solid dispersions described in claim 1 Preparation method, comprise the following steps：1) Tadalafei, at least one organic carrier and at least one pharmaceutically acceptable auxiliary material are mixed Thing, it is heated to melting, wherein, the weight of Tadalafei 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 Ta Dala containing unformed shape The Pharmaceutical composition of non-solid dispersion.
- 5. the group of the pharmaceutic adjuvant according to claim 4 containing unformed Tadalafei solid dispersions The preparation method of compound, it is characterised in that described organic carrier is selected from polymer and copolymer.
- 6. the pharmaceutic adjuvant containing unformed Tadalafei solid dispersions 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.
- 7. a kind of Pharmaceutical composition containing unformed Tadalafei solid dispersions described in claim 1 Preparation method, comprise the following steps：1) Tadalafei, at least one organic carrier and at least one pharmaceutically acceptable auxiliary material are existed Mixed in solvent, mixing temperature be -50~150 DEG C, formed containing Tadalafei, organic carrier and The solution or suspension of pharmaceutic adjuvant, wherein, the weight ratio of Tadalafei and solvent is 0.001~100:1, the weight of Tadalafei 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 Ta Dala of unformed shape Non- Pharmaceutical composition.
- 8. the Pharmaceutical composition according to claim 7 containing unformed Tadalafei solid dispersions 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 containing unformed Tadalafei solid dispersions 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 containing unformed Tadalafei solid dispersions 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 containing unformed Tadalafei solid dispersions, it is used for Prepare the purposes for the treatment of male erectile dysfunction medicine.
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| CN201610440524.1A CN107510695A (en) | 2016-06-17 | 2016-06-17 | A kind of Pharmaceutical composition containing unformed Tadalafei solid dispersions and preparation method thereof |
| PCT/CN2016/098094 WO2017041679A1 (en) | 2015-09-07 | 2016-09-05 | Solid dispersion of tadalafil and pharmaceutical excipients, and preparation method for solid dispersion |
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| CN201610440524.1A CN107510695A (en) | 2016-06-17 | 2016-06-17 | A kind of Pharmaceutical composition containing unformed Tadalafei solid dispersions and preparation method thereof |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108033960A (en) * | 2018-01-23 | 2018-05-15 | 中国药科大学 | A kind of common amorphous substance of Tadalafei |
| CN108047225A (en) * | 2018-01-11 | 2018-05-18 | 中国药科大学 | A kind of Tadalafei is total to amorphous substance |
| CN114028349A (en) * | 2021-10-12 | 2022-02-11 | 南京恒正药物研究院有限公司 | Tadalafil orally disintegrating tablet |
| CN115872997A (en) * | 2022-12-09 | 2023-03-31 | 国科温州研究院(温州生物材料与工程研究所) | Tadalafil-polyglutamic acid amorphous composition and preparation method and application thereof |
| CN117257804A (en) * | 2023-10-17 | 2023-12-22 | 深圳市新阳唯康科技有限公司 | Darafenib pharmaceutical composition as well as preparation method and application thereof |
| WO2024192981A1 (en) * | 2023-03-20 | 2024-09-26 | 深圳市翰慧医药科技有限公司 | Tadalafil gastric-soluble rapid-release solid dispersion, tablet, and use thereof |
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- 2016-06-17 CN CN201610440524.1A patent/CN107510695A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108047225A (en) * | 2018-01-11 | 2018-05-18 | 中国药科大学 | A kind of Tadalafei is total to amorphous substance |
| CN108033960A (en) * | 2018-01-23 | 2018-05-15 | 中国药科大学 | A kind of common amorphous substance of Tadalafei |
| CN114028349A (en) * | 2021-10-12 | 2022-02-11 | 南京恒正药物研究院有限公司 | Tadalafil orally disintegrating tablet |
| CN115872997A (en) * | 2022-12-09 | 2023-03-31 | 国科温州研究院(温州生物材料与工程研究所) | Tadalafil-polyglutamic acid amorphous composition and preparation method and application thereof |
| WO2024192981A1 (en) * | 2023-03-20 | 2024-09-26 | 深圳市翰慧医药科技有限公司 | Tadalafil gastric-soluble rapid-release solid dispersion, tablet, and use thereof |
| CN117257804A (en) * | 2023-10-17 | 2023-12-22 | 深圳市新阳唯康科技有限公司 | Darafenib pharmaceutical composition as well as preparation method and application thereof |
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