CN103301066B - It is a kind of improve absorbent properties solid dispersions and its preparation - Google Patents
It is a kind of improve absorbent properties solid dispersions and its preparation Download PDFInfo
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- CN103301066B CN103301066B CN201210068420.4A CN201210068420A CN103301066B CN 103301066 B CN103301066 B CN 103301066B CN 201210068420 A CN201210068420 A CN 201210068420A CN 103301066 B CN103301066 B CN 103301066B
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The present invention relates to a kind of solid dispersions for improving absorbent properties and its preparations.Specifically, the present invention provides a kind of solid dispersions, the solid dispersions include the formula A compound of (A) as active constituent or derivatives thereof or its pharmaceutically acceptable salt, hydrate or solvate, and (B) hydrophilic macromolecular carrier.Wherein the weight ratio of (A) and (B) are 1: 1-1: 40.Solid dispersions provided by the invention can improve the dissolution in vitro of active constituent well, significantly improve absorption of the mammal to the active constituent, to efficiently reduce its dosage.
Description
Technical field
The invention belongs to field of medicaments, it is related to a kind of solid dispersions and its preparation, specifically a kind of improvement absorbent properties
Solid dispersions and its preparation.
Background technique
4- (4- (3- (4- chloro- 3- (trifluoromethyl) phenyl] uride) the fluoro- phenoxy group of -3-) -2- (N-1 ', 1 ', 1 '-three deuterium
For methyl) picolinamide, i.e. compound of formula I, the compound or its pharmaceutically acceptable salt are to phosphokinase (Kinase)
Such as raf kinases has excellent inhibition, can be used for treating tumour and its related disease.
The compound is colored powder, odorless, tasteless.It is easily dissolved in dimethyl sulfoxide or dimethylformamide, in tetrahydro
It is slightly molten in furans, methanol, the slightly soluble in acetone, dehydrated alcohol or glacial acetic acid, but it is almost insoluble in water.
Insoluble drug since compound of formula I water solubility is very poor, the solubility and solution rate in physiological fluid compared with
Low, dissolution rate is relatively low, eventually leads to that bioavilability is lower, seriously affects absorption of the mammal to compound of formula I, unfavorable
In the disease therapeuticing effect for giving full play to the compound.
Solid dispersions can be improved the bioavilability of insoluble drug, but existing solid dispersions, and highest is only
The area under the drug-time curve (AUC) of drug can be improved 2-6 times.For example, in CN101632630A, it is general for probucol
It spreads out and examines and PVP K30Solid dispersions, dog relative bioavailability also only improves only 5.8 times.
Therefore, the solid dispersions for developing a kind of compound of formula I that bioavilability significantly improves, to solution mammal
It is necessary to the problem of its active ingredient draws difference.
Summary of the invention
It is an object of the present invention to provide a kind of bioavilability significantly improve with formula A compound or derivatives thereof,
Or its pharmaceutically acceptable salt, hydrate or solvate are the solid dispersions of active constituent.
It is a further object of the present invention to provide the preparation methods of solid dispersions of the present invention.
Another object of the present invention is to provide the pharmaceutical composition of the solid dispersions.
First aspect present invention provides a kind of solid dispersions, including
(A) as formula A compound of active constituent or derivatives thereof or its pharmaceutically acceptable salt, hydrate or molten
Object is closed in agent, and
In formula, R CD3Or CH3；And
(B) hydrophilic macromolecular carrier；
Wherein, the weight ratio of (A) and (B) are 1: 1-1: 40.
In another preferred example, the hydrophilic macromolecular carrier is povidone or the macromolecule carrier containing povidone.
In another preferred example, the hydrophilic macromolecular carrier is PVP K30 or the macromolecule containing PVP K30
Carrier, wherein the content of PVP K30 is 10-100wt%, by the total weight of macromolecule carrier.
In another preferred example, the active constituent is Formulas I compound represented or its pharmaceutically acceptable salt, water
Close object or solvate:
In another preferred example, the macromolecule carrier containing PVP K30 also includes other water solubilitys selected from the group below
Carrier: polyethylene glycols, povidone class, cellulose family, it is surfactant-based, or combinations thereof；
Wherein, the polyethylene glycols are selected from the group: Macrogol 4000, Macrogol 6000, PEG 8000 or
A combination thereof；
The povidone class is selected from the group: 30 POVIDONE K 30 BP/USP 25,30 POVIDONE K 30 BP/USP 90, povidone S630, or combinations thereof；
The cellulose family is selected from the group: hydroxypropyl methylcellulose E5, hydroxypropyl methylcellulose E15, hydroxypropylcellulose L or its
Combination；
It is described surfactant-based to be selected from the group: poloxamer188, PLURONICS F87, or combinations thereof.
In another preferred example, the macromolecule carrier containing PVP K30 includes to be selected from 30 POVIDONE K 30 BP/USP 25, povidone
K90, povidone S630, or combinations thereof povidone class carrier.
In another preferred example, the weight ratio of the macromolecule carrier containing PVP K30 and other water-solubility carriers
It is 1: 4-4: 1；Preferably 1: 2-4: 1；It is more preferably 1: 1-4: 1.
In another preferred example, the weight ratio of described (A) and (B) are 1: 1-1: 20.
In another preferred example, the weight ratio of described (A) and (B) are 1: 2-1: 9.
In another preferred example, in the X-ray powder diffraction figure of the solid dispersions, do not have the solid and disperse
The X-ray diffraction characteristic peak of the active constituent of body.
In another preferred example, there are following one or more features:
1. the area under the drug-time curve of the solid dispersions is that the active constituent of the solid dispersions is administered alone
6-20 times, preferably 7-15 times of area under the drug-time curve；
2. accumulation dissolution rate is big when the solid dispersions are 10 minutes in 37 DEG C, the sodium acetate buffer aqueous solution of pH4.5
In 70%, preferably 75-95%；
3. accumulation dissolution rate is when the solid dispersions are 120 minutes in 37 DEG C, the sodium acetate buffer aqueous solution of pH4.5
10-40 times, preferably 15-30 times of the active constituent accumulation dissolution rate of the solid dispersions.
In another preferred example, the area under the drug-time curve is measured in following animal: rat, mouse or
Dog.
Second aspect of the present invention provides a kind of preparation method of solid dispersions described in first aspect present invention, including side
Method:
(a) fusion method 1, comprising steps of
(a1) mixed active ingredient and hydrophilic macromolecular carrier, to obtain a mixture containing active constituent；
(a2) mixture containing active constituent that heating melting steps (a1) obtain, thus the mixture after being melted；
With
(a3) mixture after the melting that cooling step (a2) obtains, to obtain solid described in first aspect present invention
Dispersion；
Or
(b) fusion method 2, comprising steps of
(b1) heating melting hydrophilic macromolecular carrier, thus the carrier after being melted；
(b2) by after melting that step (b1) obtains carrier and active constituent mix after melt, thus after being melted
Mixture；With
(b3) mixture after the melting that cooling step (b2) obtains, to obtain solid described in first aspect present invention
Dispersion；
Or
(c) solvent method, comprising steps of
(c1) by active constituent and hydrophilic macromolecular carrier co-dissolve in solvent, to obtain a mixture；With
(c2) solvent in the mixture that step (c1) is obtained is removed, to obtain solid described in first aspect present invention
Dispersion；
Wherein, the active constituent be formula A compound or derivatives thereof or its pharmaceutically acceptable salt, hydrate or
Solvate,
In formula, R CD3Or CH3,
The hydrophilic macromolecular carrier is the hydrophilic macromolecular carrier containing PVP K30,
The solvent is selected from the group: methanol, ethyl alcohol, isopropanol, acetone, methylene chloride, tetrahydrofuran, or combinations thereof.
In another preferred example, the step (c2) comprising steps of
The solvent in the mixture that step (c1) is obtained is removed with Rotary Evaporators；Or
The solvent in the mixture that step (c1) obtains is dried and removed with spray dryer.
In another preferred example, the technological parameter of the drying are as follows: 110 DEG C~120 DEG C of inlet air temperature, power of fan 55%
~65%, wriggling pump power 50%~55%.
In another preferred example, the solid dispersions are further handled at least one other procedure of processing, described
Procedure of processing is to grind, sieve, roll, mill, screen, mix or combinations thereof.
Third aspect present invention provides a kind of pharmaceutical composition, and the composition includes:
(1) solid dispersions described in first aspect present invention；With
(2) pharmaceutically acceptable excipient.
In another preferred example, the excipient include: filler, diluent, sweetener, corrigent, antioxidant,
Toner, preservative, lubricant, adhesive, disintegrating agent or its mixing.
In another preferred example, the composition is capsule, tablet, pill, powder and granule.
In another preferred example, described pharmaceutical composition, for inhibiting the pharmaceutical composition of phosphokinase (such as raf kinases)
Object.
In another preferred example, the pharmaceutical composition is for treating and preventing cancer.
Fourth aspect present invention provides a kind of preparation method of third aspect present invention described pharmaceutical composition, this is sent out
Solid dispersions described in bright first aspect and the mixing of pharmaceutically acceptable excipient, so that the pharmaceutical composition be made
Object.
Fifth aspect present invention provides a kind of purposes of solid dispersions described in first aspect present invention, is used to prepare
Inhibit the drug of phosphokinase (such as raf kinases)；Or it is used to prepare the drug for the treatment of tumour.
Sixth aspect present invention provides a kind for the treatment of method, by solid dispersions described in (i) first aspect present invention
Or (ii) pharmaceutical composition as described in the third aspect of the present invention, it is applied to patient in need for the treatment of.
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention
It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist
This no longer tires out one by one states.
Detailed description of the invention
Fig. 1 shows the XRPD figure of solid dispersions 1.
Fig. 2 shows the XRPD figure of solid dispersions 2.
Fig. 3 shows the XRPD figure of solid dispersions 3.
Fig. 4 shows the XRPD figure of solid dispersions 4.
Fig. 5 shows the dissolution of compound of formula I, the physical mixture of compound of formula I and PVP K30 and solid dispersions 1
Curve.
Fig. 6 shows the dissolution of compound of formula I, the physical mixture of compound of formula I and PVP K30 and solid dispersions 2
Curve.
Fig. 7 shows the XRPD figure of solid dispersions 10.
Fig. 8 shows the dissolution curve of solid dispersions 10.
Fig. 9 shows the XRPD comparison diagram after 1,2,3 month accelerated stability test of solid dispersions 1,9 institute of result figure
Show: when being successively from top to bottom that compound of formula I, freshly prepd solid dispersions 1, solid dispersions 1 are placed one month, solid point
XRPD figure when granular media 1 is placed two months, when solid dispersions 1 are placed three months.
Figure 10 shows the XRPD comparison diagram after 1,2,3 month accelerated stability test of solid dispersions 2,10 institute of result figure
Show: when being successively from top to bottom that compound of formula I, freshly prepd solid dispersions 2, solid dispersions 2 are placed one month, solid point
XRPD figure when granular media 2 is placed two months, when solid dispersions 2 are placed three months.
Figure 11 shows the XRPD comparison diagram after 1,2,3 month accelerated stability test of solid dispersions 3,11 institute of result figure
Show: when being successively from top to bottom that compound of formula I, freshly prepd solid dispersions 3, solid dispersions 3 are placed one month, solid point
XRPD figure when granular media 3 is placed two months, when solid dispersions 3 are placed three months.
Figure 12 shows the XRPD comparison diagram after 1,2,3 month accelerated stability test of solid dispersions 4,12 institute of result figure
Show: when being successively from top to bottom that compound of formula I, freshly prepd solid dispersions 4, solid dispersions 4 are placed one month, solid point
XRPD figure when granular media 4 is placed two months, when solid dispersions 4 are placed three months.
Specific embodiment
The present inventor passes through long-term in-depth study, it has unexpectedly been found that, one kind includes the formula A of (A) as active constituent
Compound or derivatives thereof or its pharmaceutically acceptable salt, hydrate or solvate and (B) hydrophilic macromolecular carrier
The solid dispersions of (especially containing the macromolecule carrier of PVP K30), for active constituent, the solid dispersions
Area under the drug-time curve be about 6-20 times of active constituent；The solid dispersions significantly improve the external molten of its active constituent
Out-degree significantly improves absorption of the mammal to active constituent, to effectively reduce its dosage.In addition, the solid
Dispersion also has extraordinary stability, is extremely applicable to the pharmaceutical composition of preparation related disease.On this basis, it invents
People completes the present invention.
Solid dispersions
Solid dispersions (solid dispersion), which refer to for active constituent to be highly dispersed in (solid) carrier, to be formed
A kind of decentralized system existing in solid form.
Active constituent
As used herein, term " active constituent " refers to formula A compound or derivatives thereof or its is pharmaceutically acceptable
Salt, hydrate or solvate, in formula, R CD3Or CH3；
The term further includes and various crystalline forms, hydrate or the solvate of formula A compound or derivatives thereof.
Preferably, the formula A compound refers to compound of formula I or Formula II compound or its pharmaceutically acceptable salt.
As used herein, term " pharmaceutically acceptable salt " refers to that the compounds of this invention and acid or alkali are formed by suitable use
Make the salt of drug.Pharmaceutically acceptable salt includes inorganic salts and organic salt.A kind of preferred salt is the compounds of this invention and acid
The salt of formation.The acid for suitably forming salt includes but is not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid etc. are inorganic
Acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid,
Picric acid, methanesulfonic acid, benzene methanesulfonic acid, the organic acids such as benzene sulfonic acid；And the acidic amino acids such as aspartic acid, glutamic acid.
Preferably, the pharmaceutically acceptable salt is toluenesulfonate.
Carrier
Carrier used in solid dispersions, it is most common to have water-solubility carrier, slightly solubility carrier and enteric solubility carrier.
" carrier " of the present invention is hydrophilic macromolecular carrier, and preferably povidone or the macromolecule containing povidone carries
Body or PVP K30 or macromolecule carrier containing PVP K30, wherein the content of PVP K30 is 10-100wt%, is pressed
The total weight of macromolecule carrier.
It is highly preferred that the macromolecule carrier used in the present invention containing PVP K30 refers to that the weight content of PVP K30 is super
Cross the carrier of total weight of carrier 20%；Or the weight content of PVP K30 is more than the carrier of total weight of carrier 40%；Or povidone
The weight content of K30 is more than the carrier of total weight of carrier 60%.
It is, of course, also possible to contain other water-solubility carriers, for example including (but being not limited to): polyethylene glycols, povidone class,
Cellulose family, surfactant-based, mannitol, or combinations thereof.
The polyethylene glycols are selected from the group: Macrogol 4000 (PEG 4000), Macrogol 6000 (PEG6000),
PEG 8000 (PEG 8000) or combinations thereof；
The povidone class is selected from the group: 30 POVIDONE K 30 BP/USP 90 (PVP K90), 30 POVIDONE K 30 BP/USP 25 (PVP K25), povidone
S630, or combinations thereof；
The cellulose family is selected from the group: hydroxypropyl methylcellulose E5 (HPMC E5), hydroxypropyl methylcellulose E15 (HPMC
E15), hydroxypropylcellulose L (HPC-L), or combinations thereof；
It is described surfactant-based to be selected from the group: poloxamer188 (Poloxamer 407), PLURONICS F87
(Poloxamer 188), or combinations thereof.
Composition
Solid dispersions provided by the invention include
(A) as formula A compound of active constituent or derivatives thereof or its pharmaceutically acceptable salt, hydrate or molten
Object is closed in agent, wherein formula A compound is the same as the above.With
(B) hydrophilic macromolecular carrier；
Wherein, the weight ratio of (A) and (B) are 1: 1-1: 40.
Preferably, the weight ratio of described (A) and (B) are 1: 20-1: 1, preferably, the weight ratio of (A) and (B) are 1:
9-1∶2。
Preparation method
Solid dispersions of the present invention can be made by following method, however the condition of this method, such as carrier, molten
Following explanation is not limited to the time required to agent, the amount of each ingredient, preparation temperature, preparation etc..Solid dispersions of the present invention are also
Optionally various synthetic methods describing in the present specification or known in the art can be combined and be easily made, this
The combination of sample can readily be carried out by those skilled in the art in the invention.
Specifically, the preparation method can be fusion method, solvent method, solvent-fusion method or Dispersion on surface method.It is preferred that
Ground, the preparation method are fusion method or solvent method.
Fusion method
Common, the fusion method is to be uniformly mixed (A) active constituent, and (B) hydrophilic macromolecular carrier, uses water-bath
Or then oil bath heating is cooled to solid, the solid dispersions of the powdered active constituent is obtained after crushing to melting.
Alternatively, (A) active constituent after (B) hydrophilic macromolecular carrier heating melting, can will be added, then by melting
Mixture with vigorous stirring, is quickly cooled to solid, and the solid dispersions of the powdered active constituent are obtained after crushing.
Solvent method
Common, the solvent method is by (A) active constituent, and (B) hydrophilic macromolecular carrier co-dissolve is in solvent
In, after mixture is uniform, the solvent in solution is removed, active constituent and hydrophilic macromolecular carrier can be made while being precipitated, crushed
The solid dispersions of the powdered active constituent can be obtained afterwards.
Solvent used in the solvent method include: methanol, ethyl alcohol, isopropanol, acetone, tetrahydrofuran, or combinations thereof.
Structural Identification
The Structural Identification method of solid dispersions includes differential scanning calorimetric analysis, X-ray powder diffraction etc..It is right respectively
The solid dispersions of active constituent, carrier and the method for the invention preparation have carried out X-ray powder diffraction (XRPD) detection,
Compare the XRPD spectrogram of three.
The characteristic peak of active constituent
After solid dispersions of the invention are made, the X-ray diffraction characteristic peak of active constituent substantially or entirely disappears
It loses.In other words, in the X-ray powder diffraction figure of solid dispersions of the present invention, the active constituent without the solid dispersions
X-ray diffraction characteristic peak.
Compound of formula I, 7.24 ± 0.1 °, 13.38 ± 0.1 °, 14.53 ± 0.1 °, 14.74 ± 0.1 °, 15.61 ±
0.1°、17.23±0.1°、18.57±0.1°、18.84±0.1°、19.81±0.1°、20.01±0.1°、23.42±0.1°、
24.24 ± 0.1 °, 25.85 ± 0.1 °, 26.39 ± 0.1 °, 27.43 ± 0.1 ° have strong diffraction maximum.
Formula II compound, 7.20 ± 0.1 °, 13.34 ± 0.1 °, 14.49 ± 0.1 °, 14.72 ± 0.1 °, 15.55 ±
0.1°、16.44±0.1°、17.17±0.1°、18.53±0.1°、18.81±0.1°、19.76±0.1°、19.97±0.1°、
23.41±0.1°、23.75±0.1°、24.22±0.1°、24.75±0.1°、25.90±0.1°、26.35±0.1°、27.42
± 0.1 °, 31.54 ± 0.1 ° has strong diffraction maximum.
The characteristic peak of carrier
Some carriers have strong diffraction maximum, for example, PEG4000 and PEG6000 has by force in 19.20 ± 0.1 °, 23.30 ± 0.1 °
Diffraction maximum.Poloxamer 407 has strong diffraction maximum in 19.16 ± 0.1 °, 23.33 ± 0.1 °.Some carriers do not have strong diffraction maximum,
For example, PVP K30, HPMC E5 and HPC-L do not detect strong diffraction maximum.
The characteristic peak of solid dispersions
The strong diffraction maximum of active constituent disappears in the XRPD spectrogram of solid dispersions prepared by the present invention, so that it is determined that this hair
The bright solid dispersions are successfully prepared, wherein the simple physical mixture of not instead of active constituent and carrier, with nothing
Sizing or molecular conformation exist.
Pharmaceutical composition
Term " the compounds of this invention " refers to formula A compound or derivatives thereof or its pharmaceutically acceptable salt.
Term " solid dispersions of the present invention " refers to that active constituent is formula A compound or derivatives thereof or it can pharmaceutically connect
The solid dispersion for the salt received.
Since the compounds of this invention has the excellent inhibitory activity to phosphokinase (Kinase) such as raf kinases, because
This solid dispersions of the present invention and it can be used for treating, in advance containing solid dispersions of the present invention pharmaceutical composition as main component
Anti- and alleviation is by the disease kinase mediated to phosphokinase (Kinase) such as raf.According to the prior art, the compounds of this invention
It can be used for treating following disease: cancer, cardiovascular disease, obesity, diabetes etc..
Pharmaceutical composition of the invention include safe and effective amount within the scope of solid dispersions of the present invention or its pharmacologically may be used
The salt of receiving and pharmacologically acceptable excipient.Wherein " safe and effective amount " refers to: the amount of solid dispersions of the present invention
It is enough to be obviously improved the state of an illness, and is unlikely to generate serious side effect.Consolidate in general, pharmaceutical composition contains the 1-2000mg present invention
Body dispersion/agent more preferably contains 10-200mg solid dispersions/agent of the present invention.Preferably, it is described it is " one " be one
Capsule or tablet.
" pharmaceutically acceptable excipient " refers to: one or more biocompatible solids or liquid filler or jello
Matter, they are suitable for people's use and it is necessary to have enough purity and sufficiently low toxicity." compatibility " referred to herein as combines
In object each component energy and solid dispersions of the invention and they between mutually admix, and significantly reduce solid dispersions
Drug effect.Pharmaceutically acceptable excipient partial example has cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl fibre
Tie up plain sodium, cellulose ethanoate etc.), gelatin, talcum, solid lubricant (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil
(such as soya-bean oil, sesame oil, peanut oil, olive oil), polyalcohol (such as propylene glycol, glycerol, mannitol, sorbierite), emulsifier
(such as tween), wetting agent (such as lauryl sodium sulfate), colorant, flavoring agent, stabilizer, antioxidant, preservative, without heat
Raw water etc..
The method of application of solid dispersions of the present invention or pharmaceutical composition is not particularly limited, representative method of application packet
Include (but being not limited to): in oral, tumor, rectum, parenteral (intravenous, intramuscular or subcutaneous) and local administration.
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.In these solid formulations
In type, solid dispersions of the present invention are mixed at least one conventional inert excipients (or carrier), such as sodium citrate or di(2-ethylhexyl)phosphate
Calcium, or mixed with following compositions: (a) filler or expanding material, for example, starch, lactose, sucrose, glucose, microcrystalline cellulose, sweet
Reveal pure and mild silicic acid；(b) adhesive, for example, hypromellose, alginates, gelatin, polyvinylpyrrolidone, sucrose and
Arabic gum；(c) moisturizer, for example, glycerol；(d) disintegrating agent, for example, agar, calcium carbonate, potato starch or tapioca,
Alginic acid, certain composition silicates, croscarmellose sodium and sodium carbonate；(e) retarding solvent, such as paraffin；(f) it absorbs and accelerates
Agent, for example, quaternary ammonium compound；(g) wetting agent, such as cetanol, lauryl sodium sulfate and glycerin monostearate；(h) it inhales
Attached dose, for example, kaolin；(i) lubricant, for example, talcum, calcium stearate, magnesium stearate, solid polyethylene glycol, dodecane
Or mixtures thereof base sodium sulphate,.In capsule, tablet and pill, dosage form also may include buffer.
Coating and shell material preparation can be used in solid dosage forms such as tablet, sugar-pill, capsule, pill and granule, such as casing and
Other materials well known in the art.They may include opacifying agent, also, the release of solid dispersions can be in this composition
The mode of delay discharges in certain a part in the digestive tract.The example of adoptable embedding component is polymeric material and wax class object
Matter.When necessary, solid dispersions can also be with one of above-mentioned excipient or a variety of formation microencapsulation forms.
Liquid formulation for oral administration includes pharmaceutically acceptable lotion, solution, suspension, syrup or tincture.
Other than solid dispersions, liquid dosage form may include the inert diluent routinely used in this field, such as water or other solvents, increase
Solvent and emulsifier, example know, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-BDO, dimethyl formyl
The mixture of amine and oil, especially cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these substances
Deng.
Other than these inert diluents, composition also may include auxiliary agent, such as wetting agent, emulsifier and suspending agent, sweet taste
Agent, tender taste agent and fragrance.
Other than solid dispersions, suspension may include suspending agent, for example, ethoxylation isooctadecane alcohol, polyoxyethylene
Sorbierite and Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or the mixture of these substances etc..
Composition for parenteral injection may include physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid,
Suspension or lotion, and the aseptic powdery for re-dissolving into sterile Injectable solution or dispersion liquid.It is suitable aqueous and
Nonaqueous carrier, diluent, solvent or excipient include water, ethyl alcohol, polyalcohol and its suitable mixture.
The dosage form of solid dispersions of the present invention for local administration includes ointment, powder, patch, stock solution and sucking
Agent.Solid dispersions aseptically with physiologically acceptable carrier and any preservative, buffer, or when necessary may
The propellant needed is mixed together.
Solid dispersions of the present invention can be administered alone, or be administered in combination with other pharmaceutically acceptable compounds.
When using pharmaceutical composition, be the solid dispersions of the present invention of safe and effective amount are applicable to treatment mammal (such as
People), wherein application when dosage be the effective dosage pharmaceutically thought, for the people of 60kg weight, day dosage
Usually 1~2000mg, preferably 20~500mg.Certainly, specific dosage be also contemplated that administration route, patient health situation etc. because
Element, within the scope of these are all skilled practitioners technical ability.
Present invention has the main advantage that
(1) one kind is provided with formula A compound or derivatives thereof or its pharmaceutically acceptable salt, hydrate or solvent
The solid dispersions that object is active constituent are closed, the solid dispersions significantly improve the dissolution in vitro of active constituent, very
Be conducive to absorption of the mammal to the active constituent.And itself relative to its active compound component, the solid
Dispersion has significantly excellent internal pharmacokinetic parameter (especially area under the drug-time curve), and highly stable.
(2) a kind of preparation method of solid dispersions is provided.
Below with reference to specific implementation, the present invention is further explained.It should be understood that these embodiments be merely to illustrate the present invention and
It is not used in and limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to normal condition,
Or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are calculated by weight.
" API " refers to active constituent as used herein.
Embodiment
The dissolution test method of solid dispersions
According to the Pharmacopoeia of the People's Republic of China two annex XC the second methods of dissolution method (paddle method) of version in 2010 into
Row detection.Condition is as follows: dissolution medium: 0.1% lauryl sodium sulfate pH, 4.5 Acetic acid-sodium acetate buffer 900mL/ dissolution
Cup；Temperature: 37 ± 0.5 DEG C；Revolving speed: 100 revs/min.
Specifically, sample is divided into three groups, every group of sample is respectively configured 3 parts.Wherein, the 1st group of sample is active constituent；The
2 groups of samples are that active constituent and carrier are only passed through simple physical method (as stirred) mixed sample.Third group sample
Product are the solid dispersions that middle preparation method obtains according to various embodiments.Table specific as follows.
Using the dissolution medium, the dissolution rate of above 3 groups of samples is conventionally detected respectively, every group 3 parts of detection
Sample takes its average value.Compare 3 groups of test result.
1 solid dispersions 1 of embodiment
Compound of formula I and PVP K30, weight ratio 1: 9, solvent (dehydrated alcohol) method
The PVP K30 of the compound of formula I and 9 parts by weight that weigh 1 parts by weight is set in same flask, and flask sets 80 DEG C of oil baths
In, dehydrated alcohol is added into flask, close plug stirs under the conditions of condensate return, until compound and the equal dissolved clarification of PVPK30,
It is stirred for 30 minutes.The liquid of dissolved clarification is quickly evaporated with rotary evaporator at 80 DEG C, solid is obtained.Solid is true at 50 DEG C
It is 24 hours dry in empty drying box, it is finely ground to get solid dispersions 1.
Test results are shown in figure 1 by its XRPD, and in solid dispersions 1, the diffraction maximum (characteristic peak) of compound of formula I all disappears
It loses, exists with unformed or molecular conformation.
2 solid dispersions 2 of embodiment
Compound of formula I and PVP K30, weight ratio 1: 4, solvent (dehydrated alcohol) method
The preparation method is the same as that of Example 1, and difference is that the weight ratio of compound of formula I and PVP K30 are 1: 4.
Test results are shown in figure 2 by its XRPD, and in solid dispersions 2, the diffraction maximum (characteristic peak) of compound of formula I all disappears
It loses, exists with unformed or molecular conformation.
3 solid dispersions 3 of embodiment
Compound of formula I and PVP K30, weight ratio 1: 3, solvent (dehydrated alcohol) method
The preparation method is the same as that of Example 1, and difference is that the weight ratio of compound of formula I and PVP K30 are 1: 3.
Test results are shown in figure 3 by its XRPD, and in solid dispersions 3, the diffraction maximum (characteristic peak) of compound of formula I all disappears
It loses, exists with unformed or molecular conformation.
4 solid dispersions 4 of embodiment
Compound of formula I and PVP K30, weight ratio 1: 2, solvent (dehydrated alcohol) method
The preparation method is the same as that of Example 1, and difference is that the weight ratio of compound of formula I and PVP K30 are 1: 2.
Test results are shown in figure 4 by its XRPD, and in solid dispersions 4, the diffraction maximum (characteristic peak) of compound of formula I all disappears
It loses, exists with unformed or molecular conformation.
Embodiment 5-9 solid dispersions 5-9
The preparation method is the same as that of Example 1, and actual conditions are shown in Table 1.
Table 1
| Embodiment | Active constituent/carrier (weight ratio) | Solvent |
| 5 | Compound of formula I/PVP K90 (1: 4) | Dehydrated alcohol |
| 6 | Compound of formula I/PVP K25 (1: 4) | Dehydrated alcohol |
| 7 | Compound of formula I/PVP S630 (1: 4) | Dehydrated alcohol |
| 8 | Compound of formula I/HPMC E5 (1: 5) | Dehydrated alcohol |
| 9 | Compound of formula I/HPC-L (1: 5) | Acetone |
The dissolution rate test of 10 solid dispersions 1 of embodiment
With reference to 2010 editions two annex XC dissolution rate test methods of Chinese Pharmacopoeia, 0.1% lauryl sodium sulfate pH is measured
4.5 Acetic acid-sodium acetate buffer 900mL, are placed in 1000mL stripping rotor, and temperature is kept for 37 ± 0.5 DEG C.
Be separately added into compound of formula I, compound of formula I and PVP K30 physical mixture (compound of formula I and PVPK30's
Weight is respectively 50mg and 450mg), solid dispersions 1 (500mg), paddle speed be 100rpm, respectively at 2min, 5min, 10min,
15min, 20min, 30min, 45min, 60min, 120min sample 5mL and take clear filtrate dilute with 0.45 μm of filtering with microporous membrane
Drug concentration is measured after releasing, and calculates the dissolution rate of three.
As a result as shown in figure 5, dissolution rate < 2% of the compound of formula I in 10min, the object of compound of formula I and PVP K30
The dissolution rate < 5% of mixture is managed, the dissolution rate of solid dispersions 1 is 78%, using PVP K30 as the solid dispersions pole of matrix
The earth improves the dissolution rate of compound of formula I.
The dissolution rate test of 11 solid dispersions 2 of embodiment
Dissolution test method is the same as embodiment 10.
Test results are shown in figure 6, when 30min, the dissolution rate < 2% of compound of formula I, compound of formula I and PVPK30's
The dissolution rate < 5% of physical mixture, the dissolution rate of solid dispersions 2 (carrier is PVP K30) are 78%.
When 120min, the dissolution of dissolution≤5% of compound of formula I, the physical mixture of compound of formula I and carrier is slightly better than
Compound of formula I, but≤10%, the dissolution about 80% for the solid dispersions that compound of formula I is formed with carrier.
The result shows that: the dissolution rate of solid dispersions will be significantly better than the physics of compound of formula I and compound of formula I and carrier
Mixture.In addition, PVP K30 is that the solid dispersions of carrier greatly improve the dissolution rate of compound of formula I, it is significantly better than
Using other common carriers (such as PEG 6000, hydroxypropyl methylcellulose E5), (dissolved out at 30 minutes also superior to PVP K90 and K25
Spend 65-70%).
The internal medicine generation research of 12 solid dispersions 2 of embodiment
It chooses solid dispersions 2 and carries out internal medicine generation test with corresponding API (i.e. compound of formula I).
86 week old Wistar rats of male, weight 170g or so are divided into 2 groups, every group 4.Animal feeding is in IVC animal
In room, 12 hours light and shade alternatings.Using hardwood wood shavings as padding.Animal gives feed and sterilized tap water, free diet.
Fasting 16h before administration, 2h restores to food after administration.After overnight fasting, 4mg/kg solid dispersions 1 or corresponding are given in stomach-filling
API 1%CMC suspension, administration capacity be 10ml/kg.0.5,1.0,2.0,4.0,6.0,8.0,24,48 and after administration
72h is set in heparinised tubes through rat eye rear vein beard extracting vein blood 0.2ml, and 3500rpm is centrifuged 10min, isolated blood
Slurry samples, -20 DEG C of preservations.
The plasma sample content of the LC-MS/MS analysis method quantitative detection API by verifying.Pharmacokinetic parameter
It will be calculated based on the blood concentration of every rat in different time points.Parameter is referring to table 2.
The results are shown in Table 2: compound of formula I and PVP K30 are by medicine generation in 2 body of solid dispersions made from 1: 4 weight ratio
AUC0-∞About 9.03 times of compound of formula I.
Table 2
13 solid dispersions 10 of embodiment
Formula II compound and PVP K30, weight ratio 1: 4, solvent (dehydrated alcohol) method
The preparation method is the same as that of Example 1, and difference is Formula II compound instead of compound of formula I, Formula II compound and PVP
The weight ratio of K30 is 1: 4.
Test results are shown in figure 7 by its XRPD, and in solid dispersions 10, the diffraction maximum (characteristic peak) of Formula II compound is all
It disappears, exists with unformed or molecular conformation.
The dissolution rate test of 14 solid dispersions 10 of embodiment
Dissolution test method is the same as embodiment 10.
Specifically, sample is configured into 2 parts (respectively sample 1 and sample 2).It tests according to the method described above respective
Dissolution rate, and calculate average value (as average).
Test results are shown in figure 8, when 30min, when the dissolution rate of solid dispersions 10 is about 72.5%, 120min, Gu
The dissolution of body dispersion 10 is about 94%.As it can be seen that the dissolution for the solid dispersions 10 that Formula II compound and carrier PVP K30 are formed
Degree is fine.
The internal medicine generation research of 15 solid dispersions 10 of embodiment
It chooses solid dispersions 10 and carries out internal medicine generation test with corresponding API (i.e. Formula II compound).
Test method is the same as embodiment 12.
The results are shown in Table 3: in 10 body of solid dispersions of Formula II compound and PVP K30 by the preparation of 1: 4 weight ratio
The AUC in medicine generationlastAbout 13.5 times of Formula II compound.
Table 3
16 solid dispersions of embodiment, 1 accelerated stability test
It chooses solid dispersions 1 and carries out accelerated stability test (40 DEG C, 75%RH), 1,2,3 month when takes out progress
X-ray powder diffraction.
XRPD result as shown in figure 9, show solid dispersions 1 after 1,2,3 month accelerated stability test, it is highly stable
(the X- diffractive features peak of no API, and curve is essentially identical) generates (i.e. original unformed or molecular state without crystal form
Do not change), it is still with solid dispersions existing for amorphous or molecular state.
Shown in result figure 9: being successively that compound of formula I, freshly prepd solid dispersions 1, solid dispersions 1 are put from top to bottom
XRPD figure when setting one month, when solid dispersions 1 are placed two months, when solid dispersions 1 are placed three months.
17 solid dispersions of embodiment, 2 accelerated stability test
It chooses solid dispersions 2 and carries out accelerated stability test (40 DEG C, 75%RH), 1,2,3 month when takes out progress
X-ray powder diffraction.
The results are shown in Figure 10 by XRPD, show solid dispersions 2 after 1,2,3 month accelerated stability test, very surely
Fixed (the X- diffractive features peak of no API, and curve is essentially identical) generates (i.e. original unformed or molecularity without crystal form
State does not change), it is still with solid dispersions existing for amorphous or molecular state.
Shown in result figure 10: being successively compound of formula I, freshly prepd solid dispersions 2, solid dispersions 2 from top to bottom
XRPD figure when placing one month, when solid dispersions 2 are placed two months, when solid dispersions 2 are placed three months.
18 solid dispersions of embodiment, 3 accelerated stability test
It chooses solid dispersions 3 and carries out accelerated stability test (40 DEG C, 75%RH), 1,2,3 month when takes out progress
X-ray powder diffraction.
XRPD result is as shown in figure 11, show solid dispersions 3 after 1,2,3 month accelerated stability test, very surely
Fixed (the X- diffractive features peak of no API, and curve is essentially identical) generates (i.e. original unformed or molecularity without crystal form
State does not change), it is still with solid dispersions existing for amorphous or molecular state.
Shown in result figure 11: being successively compound of formula I, freshly prepd solid dispersions 3, solid dispersions 3 from top to bottom
XRPD figure when placing one month, when solid dispersions 3 are placed two months, when solid dispersions 3 are placed three months.
19 solid dispersions of embodiment, 4 accelerated stability test
It chooses solid dispersions 4 and carries out accelerated stability test (40 DEG C, 75%RH), 1,2,3 month when takes out progress
X-ray powder diffraction.
XRPD result is as shown in figure 12, show solid dispersions 4 after 1,2,3 month accelerated stability test, very surely
Fixed (the X- diffractive features peak of no API, and curve is essentially identical) generates (i.e. original unformed or molecularity without crystal form
State does not change), it is still with solid dispersions existing for amorphous or molecular state.
Shown in result figure 12: being successively compound of formula I, freshly prepd solid dispersions 4, solid dispersions 4 from top to bottom
XRPD figure when placing one month, when solid dispersions 4 are placed two months, when solid dispersions 4 are placed three months.
Embodiment 20-24 solid dispersions 11-15
Active constituent: compound of formula I
Carrier: the mixed carrier of PVP K30 and other carriers
The preparation method is the same as that of Example 1, and difference is mixed carrier using condition as shown in table 4.
Table 4
Its XRPD test result shows in solid dispersions that the diffraction maximum (characteristic peak) of compound of formula I all disappears, with
Unformed form exists.
The internal medicine generation test (operation is the same) of solid dispersions 11-15 shows: the internal medicine generation of solid dispersions
AUClastAbout 7-15 times of API.
As it can be seen that the solid dispersions of the carrier prepared by the present invention comprising active constituent and the K30 containing PVP are highly stable；And
For active constituent, solid dispersions of the invention have the dissolution rate significantly improved, solid especially of the present invention point
The area under the drug-time curve of granular media is 6-20 times of area under the drug-time curve when its active constituent is administered alone, preferably 7-15
Times, it is more preferably 9-14 times.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
Claims (15)
1. a kind of solid dispersions, which is characterized in that be made of following components (A) and component (B):
(A) as the Formulas I of active constituent or Formula II compound or its pharmaceutically acceptable salt；
And
(B) hydrophilic macromolecular carrier；The hydrophilic macromolecular carrier is PVP K30；
Wherein, the weight ratio of (A) and (B) are 1:3-1:4.
2. solid dispersions as described in claim 1, which is characterized in that the weight ratio of (A) and (B) are 1:4.
3. solid dispersions as described in claim 1, which is characterized in that the compound is Formula II compound, and (A) and
(B) weight ratio is 1:4.
4. solid dispersions as described in claim 1, which is characterized in that the compound is compound of formula I, and (A) and (B)
Weight ratio be 1:4.
5. solid dispersions as described in claim 1, which is characterized in that the X-ray powder diffraction figure of the solid dispersions
In, the X-ray diffraction characteristic peak of the active constituent without the solid dispersions.
6. a kind of preparation method of solid dispersions described in claim 1, which is characterized in that including method:
(a) fusion method 1, comprising steps of
(a1) mixed active ingredient and hydrophilic macromolecular carrier, to obtain a mixture containing active constituent；
(a2) mixture containing active constituent that heating melting steps (a1) obtain, thus the mixture after being melted；With
(a3) mixture after the melting that cooling step (a2) obtains, to obtain solid dispersions described in claim 1；
Or
(b) fusion method 2, comprising steps of
(b1) heating melting hydrophilic macromolecular carrier, thus the carrier after being melted；
(b2) by after melting that step (b1) obtains carrier and active constituent mix after melt, thus the mixing after being melted
Object；With
(b3) mixture after the melting that cooling step (b2) obtains, to obtain solid dispersions described in claim 1；
Or
(c) solvent method, comprising steps of
(c1) by active constituent and hydrophilic macromolecular carrier co-dissolve in solvent, to obtain a mixture；With
(c2) solvent in the mixture that step (c1) is obtained is removed, to obtain solid dispersions described in claim 1；
Wherein, the active constituent is Formulas I or Formula II compound or its pharmaceutically acceptable salt,
The hydrophilic macromolecular carrier is PVP K30,
The solvent is selected from the group: methanol, ethyl alcohol, isopropanol, acetone, methylene chloride, tetrahydrofuran, or combinations thereof.
7. preparation method as claimed in claim 6, which is characterized in that the step (c2) is comprising steps of use Rotary Evaporators
Remove the solvent in the mixture that step (c1) is obtained；Or the mixture that step (c1) obtains is dried and removed with spray dryer
In solvent；Wherein, the technological parameter of the drying are as follows: 110 DEG C~120 DEG C of inlet air temperature, power of fan 55%~65% is compacted
Dynamic pump power 50%~55%.
8. preparation method as claimed in claim 6, which is characterized in that in addition the solid dispersions further use at least one
Procedure of processing processing, the procedure of processing is to grind, sieve, roll, mill, screen, mix or combinations thereof.
9. a kind of pharmaceutical composition, which is characterized in that the composition includes:
(1) the described in any item solid dispersions of claim 1-5；With
(2) pharmaceutically acceptable excipient.
10. pharmaceutical composition as claimed in claim 9, which is characterized in that the excipient includes: filler, diluent, sweet tea
Taste agent, corrigent, antioxidant, colorant, preservative, lubricant, adhesive, disintegrating agent or its mixing.
11. pharmaceutical composition as claimed in claim 9, which is characterized in that the composition is capsule, tablet, pill, dissipates
Agent and granule.
12. pharmaceutical composition as claimed in claim 9, which is characterized in that described pharmaceutical composition, for inhibiting phosphokinase
Pharmaceutical composition.
13. pharmaceutical composition as claimed in claim 9, which is characterized in that the pharmaceutical composition is for treating and preventing
Cancer.
14. a kind of preparation method of pharmaceutical composition as claimed in claim 9, which is characterized in that by any one of claim 1-5
The solid dispersions and the mixing of pharmaceutically acceptable excipient, so that the pharmaceutical composition be made.
15. a kind of purposes of solid dispersions as described in claim 1, which is characterized in that be used to prepare inhibition phosphokinase
Drug；Or it is used to prepare the drug for the treatment of tumour.
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| CN104557687A (en) * | 2013-10-25 | 2015-04-29 | 苏州泽璟生物制药有限公司 | Fluorine-containing deuterated omega-diphenylurea hydrate and crystal form substance thereof |
| WO2015085888A1 (en) * | 2013-12-09 | 2015-06-18 | Jiangsu Medolution Limited | 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)-n-d3-methylpicolinamide monohydrate |
| CN104434809B (en) * | 2014-12-10 | 2018-10-16 | 北京科莱博医药开发有限责任公司 | A kind of olaparib solid dispersion preparation and preparation method thereof |
| CN107661296A (en) * | 2016-07-27 | 2018-02-06 | 江苏先声药业有限公司 | A kind of Rui Gefeini solid dispersions and preparation method thereof |
| CN109276543B (en) * | 2017-07-19 | 2021-01-08 | 深圳微芯生物科技股份有限公司 | Sitaglipta solid dispersion and preparation method and application thereof |
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| CN102459180B (en) * | 2009-06-09 | 2014-05-14 | 江苏迈度药物研发有限公司 | Urea derivatives as kinase inhibitors |
| CN102199121B (en) * | 2010-05-27 | 2013-10-30 | 四川大学 | 4-(4-(3-trifluoro methyl) benzamido phenoxyl)-2-(methyl carbamyl) pyridine salt, its preparation method and application |
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| CN101048140A (en) * | 2004-08-27 | 2007-10-03 | 拜耳制药公司 | Novel pharmaceutical compositions for the treatment of cancer |
| CN101287463A (en) * | 2004-08-27 | 2008-10-15 | 拜耳制药公司 | New pharmaceutical compositions comprising 4-(4-(3-(4-chloro-3-trifluoromethyl-phenyl)-ureido)-3-fluoro-phenoxy)-pyridine-2-carboxylic acid for the treatment of hyper-proliferative disorders |
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| WO2023155307A1 (en) | 2022-02-21 | 2023-08-24 | 北京睿创康泰医药研究院有限公司 | Sorafenib or donafenib oral preparation with low dose and high drug exposure, and application thereof |
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