CN103301066A - Solid dispersion for improving absorbing property and preparation method thereof - Google Patents

Solid dispersion for improving absorbing property and preparation method thereof Download PDF

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CN103301066A
CN103301066A CN2012100684204A CN201210068420A CN103301066A CN 103301066 A CN103301066 A CN 103301066A CN 2012100684204 A CN2012100684204 A CN 2012100684204A CN 201210068420 A CN201210068420 A CN 201210068420A CN 103301066 A CN103301066 A CN 103301066A
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solid dispersion
formula
active component
chemical compound
carrier
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CN103301066B (en
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易必慧
尚晓芳
陆惠萍
盛泽林
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Suzhou Zehuang Biopharmaceutical Co., Ltd.
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Suzhou Zelgen Biopharmaceutical Co Ltd
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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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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Abstract

The invention relates to a solid dispersion for improving the absorbing property and a preparation method thereof. The solid dispersion comprises (A) a compound which serves as an active ingredient and is shown in a formula A in the specification or derivatives, pharmaceutically acceptable salts, hydrates or solvates of the compound and (B) a hydrophilic polymeric carrier, wherein the weight ratio of (A) to (B) is (1:1)-(1:40). The solid dispersion provided by the invention can well improve the dissolution rate in vitro of the active ingredient and obviously improve the active ingredient absorbability of mammals, thus effectively reducing the use dosage of the solid dispersion.

Description

A kind of solid dispersion and preparation thereof that improves absorbent properties
Technical field
The invention belongs to field of medicaments, relate to a kind of solid dispersion and preparation thereof, particularly a kind of solid dispersion and preparation thereof that improves absorbent properties.
Background technology
4-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl] uride)-3-fluoro-phenoxy group)-2-(N-1 ', 1 ', 1 '-three deuterium acute pyogenic infection of nails bases) picolinamide, it is formula I chemical compound, described chemical compound or its pharmaceutically acceptable salt to phosphokinase (Kinase) for example the raf kinases have excellent inhibition, can be used for treating tumor and relevant disease thereof.
Figure BDA0000143902330000011
This chemical compound is colored powder, odorless, tasteless.Very easily dissolving is slightly molten in oxolane, methanol in dimethyl sulfoxine or dimethyl formamide, slightly soluble in acetone, dehydrated alcohol or glacial acetic acid, but almost insoluble in water.
Because formula I compound water soluble extreme difference, it is insoluble drug, dissolubility and dissolution velocity in physiological fluid are lower, dissolution is also lower, finally cause bioavailability lower, have a strong impact on mammal to the absorption of formula I chemical compound, be unfavorable for giving full play to the disease therapeuticing effect of this chemical compound.
Solid dispersion can improve the bioavailability of insoluble drug, but existing solid dispersion, the highlyest the area under the drug-time curve (AUC) of medicine can only be improved 2-6 doubly.For example, among the CN101632630A, than probucol, probucol and PVP K 30Solid dispersion, its dog relative bioavailability has also only improved 5.8 times.
Therefore, develop the solid dispersion of the formula I chemical compound that a kind of bioavailability significantly improves, to solving mammal the problem of its active component absorption difference is necessary.
Summary of the invention
The solid dispersion take formula A chemical compound or derivatives thereof or its pharmaceutically acceptable salt, hydrate or solvate as active component that an object of the present invention is to provide that a kind of bioavailability significantly improves.
Another object of the present invention provides the preparation method of solid dispersion of the present invention.
A further object of the present invention provides the pharmaceutical composition of described solid dispersion.
First aspect present invention provides a kind of solid dispersion, comprises
(A) as formula A chemical compound or derivatives thereof or its pharmaceutically acceptable salt, hydrate or the solvate of active component, and
Figure BDA0000143902330000021
In the formula, R is CD 3Or CH 3And
(B) hydrophilic macromolecule carrier;
Wherein, (A) and (B) weight ratio is 1: 1-1: 40.
In another preference, described hydrophilic macromolecule carrier is polyvidone or the macromolecule carrier that contains polyvidone.
In another preference, described hydrophilic macromolecule carrier is PVP K30 or the macromolecule carrier that contains PVP K30, and wherein, the content of PVP K30 is 10-100wt%, by the gross weight of macromolecule carrier.
In another preference, described active component is the chemical compound shown in the formula I, or its pharmaceutically acceptable salt, hydrate or solvate:
In another preference, the described macromolecule carrier that contains PVP K30 also comprises and is selected from other water-solubility carriers of lower group: polyethylene glycols, polyvidone class, cellulose family, surfactant-based or its combination;
Wherein, described polyethylene glycols is selected from lower group: Macrogol 4000, polyethylene glycol 6000, PEG 8000 or its combination;
Described polyvidone class is selected from lower group: 30 POVIDONE K 30 BP/USP 25,30 POVIDONE K 30 BP/USP 90, polyvidone S630 or its combination;
Described cellulose family is selected from lower group: hypromellose E5, hypromellose E15, hyprolose L or its combination;
Describedly surfactant-basedly be selected from lower group: poloxamer188, PLURONICS F87 or its combination.
In another preference, the described macromolecule carrier that contains PVP K30 comprises the polyvidone class carrier that is selected from 30 POVIDONE K 30 BP/USP 25,30 POVIDONE K 30 BP/USP 90, polyvidone S630 or its combination.
In another preference, the part by weight of the described macromolecule carrier that contains PVP K30 and other water-solubility carriers is 1: 4-4: 1; Preferably be 1: 2-4: 1; More preferably be 1: 1-4: 1.
In another preference, described (A) and weight ratio (B) are 1: 1-1: 20.
In another preference, described (A) and weight ratio (B) are 1: 2-1: 9.
In another preference, in the X-ray powder diffraction pattern of described solid dispersion, do not have the X-ray diffraction characteristic peak of the active component of described solid dispersion.
In another preference, have following one or more feature:
1. the area under the drug-time curve of described solid dispersion be the active component of the described solid dispersion area under the drug-time curve when individually dosed 6-20 doubly, preferably 7-15 is doubly;
2. described solid dispersion in 37 ℃, the sodium acetate buffer aqueous solution of pH4.5 10 minutes the time accumulation dissolution preferably be 75-95% greater than 70%;
3. described solid dispersion in 37 ℃, the sodium acetate buffer aqueous solution of pH4.5 120 minutes the time accumulation dissolution be described solid dispersion active component accumulation dissolution 10-40 doubly, preferably be 15-30 times.
In another preference, described area under the drug-time curve records in following animal: rat, mice or dog.
Second aspect present invention provides the preparation method of the described solid dispersion of a kind of first aspect present invention, comprises method:
(a) fusion method 1, comprises step:
(a1) mixed active composition and hydrophilic macromolecule carrier, thus a mixture that contains active component obtained;
(a2) mixture that contains active component that obtains of heating and melting step (a1), thus mixture after the melting obtained; With
(a3) mixture after the melting that obtains of cooling step (a2), thus the described solid dispersion of first aspect present invention obtained;
Or
(b) fusion method 2, comprise step:
(b1) heating and melting hydrophilic macromolecule carrier, thus carrier after the melting obtained;
(b2) carrier after the melting that step (b1) is obtained and active component mix rear melting, thereby obtain the mixture after the melting; With
(b3) mixture after the melting that obtains of cooling step (b2), thus the described solid dispersion of first aspect present invention obtained;
Or
(c) solvent method comprises step:
(c1) active component and hydrophilic macromolecule carrier are dissolved in the solvent jointly, thereby obtain a mixture; With
(c2) remove solvent in the mixture that step (c1) obtains, thereby obtain the described solid dispersion of first aspect present invention;
Wherein, described active component is formula A chemical compound or derivatives thereof or its pharmaceutically acceptable salt, hydrate or solvate,
Figure BDA0000143902330000041
In the formula, R is CD 3Or CH 3,
Described hydrophilic macromolecule carrier is the hydrophilic macromolecule carrier that contains PVP K30,
Described solvent is selected from lower group: methanol, ethanol, isopropyl alcohol, acetone, dichloromethane, oxolane, or its combination.
In another preference, described step (c2) comprises step:
Remove solvent in the mixture that step (c1) obtains with Rotary Evaporators; Perhaps
Remove solvent in the mixture that step (c1) obtains with the spray dryer drying.
In another preference, the technological parameter of described drying is: 110 ℃～120 ℃ of inlet temperature, power of fan 55%～65%, peristaltic pump power 50%～55%.
In another preference, described solid dispersion is further processed with at least a other procedure of processing, and described procedure of processing is for to grind, to sieve, roll, mill, screen, mix or its combination.
Third aspect present invention provides a kind of pharmaceutical composition, and described compositions comprises:
(1) the described solid dispersion of first aspect present invention; With
(2) pharmaceutically acceptable excipient.
In another preference, described excipient comprises: filler, diluent, sweeting agent, correctives, antioxidant, coloring agent, antiseptic, lubricant, binding agent, disintegrating agent or its mixing.
In another preference, described compositions is capsule, tablet, pill, powder and granule.
In another preference, described pharmaceutical composition is for the pharmaceutical composition that suppresses phosphokinase (such as the raf kinases).
In another preference, described pharmaceutical composition is used for the treatment of and prophylaxis of cancer.
Fourth aspect present invention provides the preparation method of the described pharmaceutical composition of a kind of third aspect present invention, with the described solid dispersion of first aspect present invention and pharmaceutically acceptable mixed with excipients, thereby makes described pharmaceutical composition.
Fifth aspect present invention provides the purposes of the described solid dispersion of a kind of first aspect present invention, for the preparation of the medicine that suppresses phosphokinase (such as the raf kinases); Or for the preparation of the medicine for the treatment of tumor.
Sixth aspect present invention provides a kind of Therapeutic Method, with the described solid dispersion of (i) first aspect present invention or (ii) such as the described pharmaceutical composition of third aspect present invention, is applied to the patient who needs treatment.
In should be understood that within the scope of the present invention, above-mentioned each technical characterictic of the present invention and can making up mutually between specifically described each technical characterictic in below (eg embodiment), thus consist of new or preferred technical scheme.As space is limited, this tired stating no longer one by one.
Description of drawings
Fig. 1 has shown the XRPD figure of solid dispersion 1.
Fig. 2 has shown the XRPD figure of solid dispersion 2.
Fig. 3 has shown the XRPD figure of solid dispersion 3.
Fig. 4 has shown the XRPD figure of solid dispersion 4.
Fig. 5 has shown the physical mixture of formula I chemical compound, formula I chemical compound and PVP K30 and the stripping curve of solid dispersion 1.
Fig. 6 has shown the physical mixture of formula I chemical compound, formula I chemical compound and PVP K30 and the stripping curve of solid dispersion 2.
Fig. 7 has shown the XRPD figure of solid dispersion 10.
Fig. 8 has shown the stripping curve of solid dispersion 10.
Fig. 9 has shown solid dispersion 1 XRPD comparison diagram behind 1,2,3 month accelerated stability test, and the result is shown in Figure 9: be formula I chemical compound, freshly prepd solid dispersion 1, the XRPD figure when solid dispersion 1 is placed month, when solid dispersion 1 is placed two months, when solid dispersion 1 is placed three months from top to bottom successively.
Figure 10 has shown solid dispersion 2 XRPD comparison diagram behind 1,2,3 month accelerated stability test, and the result is shown in Figure 10: be formula I chemical compound, freshly prepd solid dispersion 2, the XRPD figure when solid dispersion 2 is placed month, when solid dispersion 2 is placed two months, when solid dispersion 2 is placed three months from top to bottom successively.
Figure 11 has shown solid dispersion 3 XRPD comparison diagram behind 1,2,3 month accelerated stability test, and the result is shown in Figure 11: be formula I chemical compound, freshly prepd solid dispersion 3, the XRPD figure when solid dispersion 3 is placed month, when solid dispersion 3 is placed two months, when solid dispersion 3 is placed three months from top to bottom successively.
Figure 12 has shown solid dispersion 4 XRPD comparison diagram behind 1,2,3 month accelerated stability test, and the result is shown in Figure 12: be formula I chemical compound, freshly prepd solid dispersion 4, the XRPD figure when solid dispersion 4 is placed month, when solid dispersion 4 is placed two months, when solid dispersion 4 is placed three months from top to bottom successively.
The specific embodiment
The inventor is by long-term and deep research, be surprised to find that, a kind of comprising (A) is as the formula A chemical compound or derivatives thereof of active component or its pharmaceutically acceptable salt, hydrate or solvate and (B) solid dispersion of hydrophilic macromolecule carrier (macromolecule carrier that especially contains PVP K30), for active component, the area under the drug-time curve of described solid dispersion is about 6-20 times of active component; Described solid dispersion obviously improves the dissolution in vitro of its active component, significantly improves mammal to the absorption of active component, thereby effectively reduces its using dosage.In addition, described solid dispersion also has extraordinary stability, extremely is applicable to prepare the pharmaceutical composition of relevant disease.On this basis, the inventor has finished the present invention.
Solid dispersion
Solid dispersion (solid dispersion) refers to a kind of disperse system that exists with solid form that the active component high degree of dispersion is formed in (solid) carrier.
Active component
As used herein, term " active component " refers to formula A chemical compound or derivatives thereof or its pharmaceutically acceptable salt, hydrate or solvate, and in the formula, R is CD 3Or CH 3
Figure BDA0000143902330000061
This term also comprises and various crystalline forms, hydrate or the solvate of formula A chemical compound or derivatives thereof.
Preferably, described formula A chemical compound refers to formula I chemical compound or formula II chemical compound or its pharmaceutically acceptable salt.
Figure BDA0000143902330000071
As used herein, term " pharmaceutically acceptable salt " refers to the formed salt that is suitable as medicine of the compounds of this invention and acid or alkali.Pharmaceutically acceptable salt comprises inorganic salt and organic salt.The preferred salt of one class is the compounds of this invention and the sour salt that forms.The acid that is fit to formation salt includes, but are not limited to: the mineral acids such as hydrochloric acid, hydrobromic acid, Fluohydric acid., sulphuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propanoic 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 acid such as benzenesulfonic acid; And the acidic amino acid such as aspartic acid, glutamic acid.
Preferably, described pharmaceutically acceptable salt is toluenesulfonate.
Carrier
The carrier that solid dispersion is used, the most frequently used have water-solubility carrier, slightly solubility carrier and an enteric solubility carrier.
" carrier " of the present invention is the hydrophilic macromolecule carrier, be preferably polyvidone or contain the macromolecule carrier of polyvidone, perhaps PVP K30 or contain the macromolecule carrier of PVP K30, wherein, the content of PVP K30 is 10-100wt%, by the gross weight of macromolecule carrier.
More preferably, the macromolecule carrier that contains PVP K30 that the present invention is used refers to that the weight content of PVP K30 surpasses the carrier of total weight of carrier 20%; Or the weight content of PVP K30 surpasses the carrier of total weight of carrier 40%; Or the weight content of PVP K30 surpasses the carrier of total weight of carrier 60%.
Certainly, can also contain other water-solubility carriers, for example include, but is not limited to: polyethylene glycols, polyvidone class, cellulose family, surfactant-based, mannitol or its combination.
Described polyethylene glycols is selected from lower group: Macrogol 4000 (PEG 4000), polyethylene glycol 6000 (PEG6000), PEG 8000 (PEG 8000) or its combination;
Described polyvidone class is selected from lower group: 30 POVIDONE K 30 BP/USP 90 (PVP K90), 30 POVIDONE K 30 BP/USP 25 (PVP K25), polyvidone S630 or its combination;
Described cellulose family is selected from lower group: hypromellose E5 (HPMC E5), hypromellose E15 (HPMC E15), hyprolose L (HPC-L) or its combination;
Describedly surfactant-basedly be selected from lower group: poloxamer188 (Poloxamer 407), PLURONICS F87 (Poloxamer 188) or its combination.
Form
Solid dispersion provided by the invention comprises
(A) as formula A chemical compound or derivatives thereof or its pharmaceutically acceptable salt, hydrate or the solvate of active component, wherein, formula A chemical compound is with described in above.With
(B) hydrophilic macromolecule carrier;
Wherein, (A) and (B) weight ratio is 1: 1-1: 40.
Preferably, described (A) and weight ratio (B) they are 1: 20-1: 1, and preferably, described (A) and weight ratio (B) they are 1: 9-1: 2.
Preparation method
Solid dispersion of the present invention can make by following method, yet the condition of the method is not limited to following explanation such as the amount of carrier, solvent, each composition, preparation temperature, preparation required time etc.Solid dispersion of the present invention can also be chosen various synthetic methods that will describe in this manual or known in the art wantonly and combine and make easily, and such combination can be easy to carry out by those skilled in the art in the invention.
Particularly, described preparation method can be fusion method, solvent method, solvent-fusion method or surperficial dispersion method.Preferably, described preparation method is fusion method or solvent method.
Fusion method
Common, described fusion method is with (A) active component, and (B) hydrophilic macromolecule carrier mix homogeneously, is heated to melting with water-bath or oil bath, then is cooled to solid, obtains the solid dispersion of pulverous described active component after the pulverizing.
Perhaps, can be with behind (B) hydrophilic macromolecule carrier heating and melting, add again (A) active component, then with the mixture of melting under vigorous stirring, be cooled to rapidly solid, obtain the solid dispersion of pulverous described active component after the pulverizing.
Solvent method
Common, described solvent method is with (A) active component, (B) the hydrophilic macromolecule carrier is dissolved in the solvent jointly, after mixture is even, remove the solvent in the solution, active component and hydrophilic macromolecule carrier are separated out simultaneously, can obtain the solid dispersion of pulverous described active component after the pulverizing.
The employed solvent of described solvent method comprises: methanol, ethanol, isopropyl alcohol, acetone, oxolane or its combination.
Structural Identification
The Structural Identification method of solid dispersion comprises differential scanning calorimetric analysis, X-ray powder diffraction etc.To the solid dispersion of active component, carrier and the method for the invention preparation, carried out X-ray powder diffraction (XRPD) and detected, relatively three's XRPD spectrogram respectively.
The characteristic peak of active component
After making solid dispersion of the present invention, the X-ray diffraction characteristic peak of active component basically or complete obiteration.In other words, in the X-ray powder diffraction pattern of solid dispersion of the present invention, do not have the X-ray diffraction characteristic peak of the active component of described solid dispersion.
Formula I chemical compound, it has strong diffraction maximum at 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 °.
Formula II chemical compound, it has strong diffraction maximum at 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 °.
The characteristic peak of carrier
Some carrier has strong diffraction maximum, and for example, PEG4000 and PEG6000 have strong diffraction maximum at 19.20 ± 0.1 °, 23.30 ± 0.1 °.Poloxamer 407 has strong diffraction maximum at 19.16 ± 0.1 °, 23.33 ± 0.1 °.Some carrier does not have strong diffraction maximum, and for example, PVP K30, HPMC E5 and HPC-L all do not detect strong diffraction maximum.
The characteristic peak of solid dispersion
The strong diffraction maximum of active component disappears in the XRPD spectrogram of the solid dispersion of the present invention's preparation, thereby determine that solid dispersion of the present invention is successfully prepared, wherein not the simple physical mixture of active component and carrier, but exist with unformed or molecular conformation.
Pharmaceutical composition
Term " the compounds of this invention " refers to formula A chemical compound or derivatives thereof or its pharmaceutically acceptable salt.
Term " solid dispersion of the present invention " refers to that active component is the solid dispersion of formula A chemical compound or derivatives thereof or its pharmaceutically acceptable salt.
Excellent for example kinase whose inhibitions of raf is active to phosphokinase (Kinase) because the compounds of this invention has, so solid dispersion of the present invention and to contain solid dispersion of the present invention be that the pharmaceutical composition of main component can be used for treatment, prevention and alleviation by to phosphokinase (Kinase) the kinase mediated disease of raf for example.According to prior art, the compounds of this invention can be used for treating following disease: cancer, cardiovascular disease, obesity, diabetes etc.
Pharmaceutical composition of the present invention comprises on solid dispersion of the present invention in the safe and effective weight range or its pharmacology acceptable excipient on the acceptable salt and pharmacology.Wherein " safe and effective amount " refers to: the amount of solid dispersion of the present invention is enough to obviously improve the state of an illness, and is unlikely to produce serious side effect.Usually, pharmaceutical composition contains 1-2000mg solid dispersion/agent of the present invention, more preferably, contains 10-200mg solid dispersion/agent of the present invention.Preferably, described " potion " is a capsule or tablet.
" pharmaceutically acceptable excipient " refers to: one or more compatibility solids or liquid filler or gelatinous mass, they are suitable for the people uses, and enough purity and enough low toxicity must be arranged." compatibility " referred to herein as each component energy and solid dispersion of the present invention and mutually blending between them in the compositions, and the drug effect of not obvious reduction solid dispersion.Pharmaceutically acceptable excipient part example has cellulose and derivant (such as sodium carboxymethyl cellulose, ethyl cellulose sodium, cellulose ethanoate etc.) thereof, gelatin, Talcum, kollag (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as Oleum Glycines, Oleum sesami, Oleum Arachidis hypogaeae semen, Fructus Canarii albi wet goods), polyhydric alcohol (such as propylene glycol, glycerol, mannitol, sorbitol etc.), emulsifying agent (such as tween
Figure BDA0000143902330000101
), wetting agent (such as sodium lauryl sulphate), coloring agent, flavoring agent, stabilizing agent, antioxidant, antiseptic, apirogen water etc.
The method of application of solid dispersion of the present invention or pharmaceutical composition is not particularly limited, and representational method of application comprises (but being not limited to): in oral, the tumor, rectum, parenteral (intravenous, intramuscular or subcutaneous) and topical.
The solid dosage forms that is used for oral administration comprises capsule, tablet, pill, powder and granule.In these solid dosage formss, solid dispersion of the present invention mixes with at least a conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mix with following compositions: (a) filler or bulking agent, for example, starch, lactose, sucrose, glucose, microcrystalline Cellulose, mannitol and silicic acid; (b) binding agent, for example, hydroxypropyl methylcellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and arabic gum; (c) wetting agent, for example, glycerol; (d) disintegrating agent, for example, agar, calcium carbonate, potato starch or tapioca, alginic acid, some composition silicate, cross-linking sodium carboxymethyl cellulose and sodium carbonate; (e) retarding solvent, for example paraffin; (f) absorb accelerator, for example, quaternary ammonium compound; (g) wetting agent, for example spermol, sodium lauryl sulphate and glyceryl monostearate; (h) adsorbent, for example, Kaolin; (i) lubricant, for example, Talcum, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulphate, or its mixture.In capsule, tablet and the pill, dosage form also can comprise buffer agent.
Solid dosage forms such as tablet, sugar pill, capsule, pill and granule can adopt coating and the preparation of shell material, such as casing and other material well known in the art.They can comprise opacifying agent, and, discharge in the mode that the release of solid dispersion can postpone in this compositions certain part in digestive tract.The example of adoptable embedding component is polymeric material and Wax.In case of necessity, solid dispersion also can with above-mentioned excipient in one or more form microencapsulation form.
The liquid dosage form that is used for oral administration comprises pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture.Except solid dispersion, liquid dosage form can comprise the conventional inert diluent that adopts in this area, such as water or other solvent, solubilizing agent and emulsifying agent, example is known, the mixture of ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3 butylene glycol, dimethyl formamide and oil, particularly Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, maize embryo oil, olive oil, Oleum Ricini and Oleum sesami or these materials etc.
Except these inert diluents, compositions also can comprise auxiliary agent, such as wetting agent, emulsifying agent and suspending agent, sweeting agent, the agent of tender flavor and spice.
Except solid dispersion, suspension can comprise suspending agent, for example, and the mixture of ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol and Isosorbide Dinitrate, microcrystalline Cellulose, aluminium methoxide and agar or these materials etc.
The compositions that is used for parenteral injection can comprise physiologically acceptable aseptic moisture or anhydrous solution, dispersion liquid, suspension or emulsion, and is used for again being dissolved into aseptic Injectable solution or the sterilized powder of dispersion liquid.Suitable moisture and nonaqueous carrier, diluent, solvent or excipient comprise water, ethanol, polyhydric alcohol and suitable mixture thereof.
The dosage form that is used for the solid dispersion of the present invention of topical comprises ointment, powder, patch, propellant and inhalant.Solid dispersion under aseptic condition with physiologically acceptable carrier and any antiseptic, buffer agent, or the propellant that may need in case of necessity is mixed together.
Solid dispersion of the present invention can be individually dosed, perhaps with other pharmaceutically acceptable chemical compound administering drug combinations.When making pharmaceutical composition, it is the mammal (such as the people) that the solid dispersion of the present invention of safe and effective amount need to be applicable to treatment, the effective dosage of dosage for pharmaceutically thinking when wherein using, for the people of 60kg body weight, day dosage is generally 1～2000mg, preferred 20～500mg.Certainly, concrete dosage also should be considered the factors such as route of administration, patient health situation, and these all are within the skilled practitioners skill.
Major advantage of the present invention is:
(1) provides a kind of solid dispersion take formula A chemical compound or derivatives thereof or its pharmaceutically acceptable salt, hydrate or solvate as active component, described solid dispersion has significantly improved the dissolution in vitro of active component, is very beneficial for mammal to the absorption of this active component.And with respect to its active compound component itself, described solid dispersion has the body giving drugs into nose of remarkable excellence for kinetic parameter (especially area under the drug-time curve), and highly stable.
(2) provide a kind of preparation method of described solid dispersion.
Below in conjunction with implementation, further set forth the present invention.Should be understood that these embodiment only to be used for explanation the present invention and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise percentage ratio and umber calculate by weight.
" API " as used herein refers to active component.
Embodiment
The dissolution method of testing of solid dispersion
Detect according to Pharmacopoeia of the People's Republic of China version in 2010 two appendix XC dissolution method the second method (oar method).Condition is as follows: dissolution medium: 0.1% sodium lauryl sulphate pH, 4.5 acetic acid-sodium-acetate buffer 900mL/ stripping rotor; Temperature: 37 ± 0.5 ℃; Rotating speed: 100 rev/mins.
Particularly, sample is divided into three groups, every group of sample configures respectively 3 parts.Wherein, the 1st group of sample is active component; The 2nd group of sample is just active component and carrier to be passed through the mixed sample of simple physical method (as stirring).The 3rd group of sample is the solid dispersion that obtains according to preparation method among each embodiment.Table specific as follows.
Figure BDA0000143902330000121
Use described dissolution medium, detect respectively the dissolution of above 3 groups of samples according to conventional method, every group is detected 3 duplicate samples, gets its meansigma methods.Compare 3 groups test result.
Embodiment 1 solid dispersion 1
Formula I chemical compound and PVP K30, part by weight are 1: 9, solvent (dehydrated alcohol) method
Take by weighing the formula I chemical compound of 1 weight portion and the PVP K30 of 9 weight portions and put in the same flask, flask is put in 80 ℃ of oil baths, adds dehydrated alcohol to flask, and close plug stirs under the condensate return condition, until chemical compound and PVPK30 are all molten clear, and restir 30 minutes.Molten clear liquid with rotary evaporator quick evaporate to dryness 80 ℃ the time, is obtained solid.50 ℃ of vacuum drying oven inner dryings 24 hours, porphyrize namely got solid dispersion 1 with solid.
Its XRPD test result as shown in Figure 1, in the solid dispersion 1, the diffraction maximum of formula I chemical compound (characteristic peak) all disappears, and exists with unformed or molecular conformation.
Embodiment 2 solid dispersion 2
Formula I chemical compound and PVP K30, part by weight are 1: 4, solvent (dehydrated alcohol) method
Preparation method is with embodiment 1, and difference is that the part by weight of formula I chemical compound and PVP K30 is 1: 4.
Its XRPD test result as shown in Figure 2, in the solid dispersion 2, the diffraction maximum of formula I chemical compound (characteristic peak) all disappears, and exists with unformed or molecular conformation.
Embodiment 3 solid dispersion 3
Formula I chemical compound and PVP K30, part by weight are 1: 3, solvent (dehydrated alcohol) method
Preparation method is with embodiment 1, and difference is that the part by weight of formula I chemical compound and PVP K30 is 1: 3.
Its XRPD test result as shown in Figure 3, in the solid dispersion 3, the diffraction maximum of formula I chemical compound (characteristic peak) all disappears, and exists with unformed or molecular conformation.
Embodiment 4 solid dispersion 4
Formula I chemical compound and PVP K30, part by weight are 1: 2, solvent (dehydrated alcohol) method
Preparation method is with embodiment 1, and difference is that the part by weight of formula I chemical compound and PVP K30 is 1: 2.
Its XRPD test result as shown in Figure 4, in the solid dispersion 4, the diffraction maximum of formula I chemical compound (characteristic peak) all disappears, and exists with unformed or molecular conformation.
Embodiment 5-9 solid dispersion 5-9
Preparation method is with embodiment 1, and actual conditions sees Table 1.
Table 1
Embodiment Active component/carrier (weight ratio) Solvent
5 Formula I chemical compound/PVP K90 (1: 4) Dehydrated alcohol
6 Formula I chemical compound/PVP K25 (1: 4) Dehydrated alcohol
7 Formula I chemical compound/PVP S630 (1: 4) Dehydrated alcohol
8 Formula I chemical compound/HPMC E5 (1: 5) Dehydrated alcohol
9 Formula I chemical compound/HPC-L (1: 5) Acetone
The dissolution test of embodiment 10 solid dispersion 1
With reference to 2010 editions two appendix XC dissolutions of Chinese Pharmacopoeia method of testing, measure 0.1% sodium lauryl sulphate pH, 4.5 acetic acid-sodium-acetate buffer 900mL, place the 1000mL stripping rotor, temperature keeps 37 ± 0.5 ℃.
The physical mixture (weight of formula I chemical compound and PVPK30 is respectively 50mg and 450mg), the solid dispersion 1 (500mg) that add respectively formula I chemical compound, formula I chemical compound and PVP K30, oar speed is 100rpm, respectively at 2min, 5min, 10min, 15min, 20min, 30min, 45min, 60min, the 120min 5mL that takes a sample, with 0.45 μ m filtering with microporous membrane, measure drug level after getting the clear filtrate dilution, calculate three's dissolution.
The result as shown in Figure 5, the dissolution of formula I chemical compound when 10min＜2%, the dissolution of the physical mixture of formula I chemical compound and PVP K30＜5%, the dissolution of solid dispersion 1 are 78%, and the solid dispersion take PVP K30 as substrate has greatly improved the dissolution of formula I chemical compound.
The dissolution test of embodiment 11 solid dispersion 2
The dissolution method of testing is with embodiment 10.
Test result as shown in Figure 6, during 30min, the dissolution of formula I chemical compound＜2%, the dissolution of the physical mixture of formula I chemical compound and PVPK30＜5%, the dissolution of solid dispersion 2 (carrier is PVP K30) is 78%.
During 120min, the stripping of formula I chemical compound≤5%, the stripping of the physical mixture of formula I chemical compound and carrier slightly is better than formula I chemical compound, but≤10%, the stripping of the solid dispersion that formula I chemical compound and carrier form approximately 80%.
The result shows: the dissolution of solid dispersion will be significantly better than the physical mixture of formula I chemical compound and formula I chemical compound and carrier.In addition, PVP K30 is the dissolution that the solid dispersion of carrier has all improved formula I chemical compound greatly, significantly be better than adopting other carriers (such as PEG 6000, hypromellose E5) commonly used, also be better than PVP K90 and K25 (30 minutes time dissolution 65-70%).
The body giving drugs into nose of embodiment 12 solid dispersion 2 is for research
Choose solid dispersion 2 and carry out the body giving drugs into nose for test with corresponding API (being formula I chemical compound).
8 male 6 the week age Wistar rat, about body weight 170g, be divided into 2 groups, 4 every group.Animal feeding is in the IVC Animal House, and 12 hours light and shades alternately.With the hardwood wood shavings as bedding and padding.Animal gives feedstuff and the tap water through sterilizing, free diet.Fasting 16h before administration, 2h recovers feeding after the administration.Behind the overnight fasting, gavage gives the 1%CMC suspension of the API of 4mg/kg solid dispersion 1 or correspondence, and the administration capacity is 10ml/kg.After administration 0.5,1.0,2.0,4.0,6.0,8.0,24,48 and 72h through rat eye rear vein beard extracting vein blood 0.2ml, put in the heparinization test tube, the centrifugal 10min of 3500rpm separates to obtain plasma sample ,-20 ℃ of preservations.
The content of plasma sample through the LC-MS/MS analytical method detection by quantitative API of checking.Pharmacokinetic parameter will calculate based on the blood drug level of every rat in different time points.Parameter is referring to table 2.
The result is as shown in table 2: the AUC in 2 body giving drugs into nose generations of solid dispersion that formula I chemical compound and PVP K30 make by 1: 4 weight ratio 0-∞Be about 9.03 times of formula I chemical compound.
Table 2
Figure BDA0000143902330000151
Embodiment 13 solid dispersion 10
Formula II chemical compound and PVP K30, part by weight are 1: 4, solvent (dehydrated alcohol) method
Preparation method is with embodiment 1, and difference is that formula II chemical compound has replaced formula I chemical compound, and the part by weight of formula II chemical compound and PVP K30 is 1: 4.
Its XRPD test result as shown in Figure 7, in the solid dispersion 10, the diffraction maximum of formula II chemical compound (characteristic peak) all disappears, and exists with unformed or molecular conformation.
The dissolution test of embodiment 14 solid dispersion 10
The dissolution method of testing is with embodiment 10.
Particularly, with 2 parts (being respectively sample 1 and sample 2) of sample configuration.According to the method described above test dissolution separately, and calculating mean value (being average).
Test result as shown in Figure 8, during 30min, when the dissolution of solid dispersion 10 was about 72.5%, 120min, the stripping of solid dispersion 10 was about 94%.As seen, the dissolution of the solid dispersion 10 of formula II chemical compound and carrier PVP K30 formation is fine.
The body giving drugs into nose of embodiment 15 solid dispersion 10 is for research
Choose solid dispersion 10 and carry out the body giving drugs into nose for test with corresponding API (being formula II chemical compound).
Method of testing is with embodiment 12.
The result is as shown in table 3: formula II chemical compound and PVP K30 are by the AUC in 10 body giving drugs into nose generations of solid dispersion of 1: 4 part by weight preparation LastBe about 13.5 times of formula II chemical compound.
Table 3
Figure BDA0000143902330000161
Embodiment 16 solid dispersion 1 accelerated stability test
Choose solid dispersion 1 carry out accelerated stability test (40 ℃ 75%RH), are all taken out in the time of 1,2,3 month and carry out the X-ray powder diffraction.
XRPD result as shown in Figure 9, show that solid dispersion 1 is behind 1,2,3 month accelerated stability test, highly stable (without the X-diffractive features peak of API, and curve is basic identical), all do not have crystal formation to generate (being that original unformed or molecularity does not change), remain with solid dispersion amorphous or that molecularity exists.
The result is shown in Figure 9: be formula I chemical compound, freshly prepd solid dispersion 1, the XRPD figure when solid dispersion 1 is placed month, when solid dispersion 1 is placed two months, when solid dispersion 1 is placed three months from top to bottom successively.
Embodiment 17 solid dispersion 2 accelerated stability tests
Choose solid dispersion 2 carry out accelerated stability test (40 ℃ 75%RH), are all taken out in the time of 1,2,3 month and carry out the X-ray powder diffraction.
XRPD result as shown in figure 10, show that solid dispersion 2 is behind 1,2,3 month accelerated stability test, highly stable (without the X-diffractive features peak of API, and curve is basic identical), all do not have crystal formation to generate (being that original unformed or molecularity does not change), remain with solid dispersion amorphous or that molecularity exists.
The result is shown in Figure 10: be formula I chemical compound, freshly prepd solid dispersion 2, the XRPD figure when solid dispersion 2 is placed month, when solid dispersion 2 is placed two months, when solid dispersion 2 is placed three months from top to bottom successively.
Embodiment 18 solid dispersion 3 accelerated stability tests
Choose solid dispersion 3 carry out accelerated stability test (40 ℃ 75%RH), are all taken out in the time of 1,2,3 month and carry out the X-ray powder diffraction.
XRPD result as shown in figure 11, show that solid dispersion 3 is behind 1,2,3 month accelerated stability test, highly stable (without the X-diffractive features peak of API, and curve is basic identical), all do not have crystal formation to generate (being that original unformed or molecularity does not change), remain with solid dispersion amorphous or that molecularity exists.
The result is shown in Figure 11: be formula I chemical compound, freshly prepd solid dispersion 3, the XRPD figure when solid dispersion 3 is placed month, when solid dispersion 3 is placed two months, when solid dispersion 3 is placed three months from top to bottom successively.
Embodiment 19 solid dispersion 4 accelerated stability tests
Choose solid dispersion 4 carry out accelerated stability test (40 ℃ 75%RH), are all taken out in the time of 1,2,3 month and carry out the X-ray powder diffraction.
XRPD result as shown in figure 12, show that solid dispersion 4 is behind 1,2,3 month accelerated stability test, highly stable (without the X-diffractive features peak of API, and curve is basic identical), all do not have crystal formation to generate (being that original unformed or molecularity does not change), remain with solid dispersion amorphous or that molecularity exists.
The result is shown in Figure 12: be formula I chemical compound, freshly prepd solid dispersion 4, the XRPD figure when solid dispersion 4 is placed month, when solid dispersion 4 is placed two months, when solid dispersion 4 is placed three months from top to bottom successively.
Embodiment 20-24 solid dispersion 11-15
Active component: formula I chemical compound
Carrier: the mixed carrier of PVP K30 and other carriers
Preparation method is with embodiment 1, and difference is that mixed carrier adopts condition as shown in table 4.
Table 4
Figure BDA0000143902330000181
Its XRPD test result shows, in the solid dispersion, the diffraction maximum of formula I chemical compound (characteristic peak) all disappears, and exists with unformed form.
The body giving drugs into nose of solid dispersion 11-15 shows for test (operation the same): the AUC in body giving drugs into nose generation of solid dispersion LastBe about the 7-15 of API doubly.
As seen, the present invention preparation comprise active component and contain the solid dispersion of carrier of PVP K30 highly stable; And than active component, solid dispersion of the present invention has the dissolution that significantly improves, the area under the drug-time curve of solid dispersion especially of the present invention be the area under the drug-time curve of its active component when individually dosed 6-20 doubly, preferably 7-15 more preferably be 9-14 times doubly.
All quote in this application as a reference at all documents that the present invention mentions, just as each piece document is quoted separately as a reference.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.

Claims (12)

1. a solid dispersion is characterized in that, comprises
(A) as formula A chemical compound or derivatives thereof or its pharmaceutically acceptable salt, hydrate or the solvate of active component, and
Figure FDA0000143902320000011
In the formula, R is CD 3Or CH 3And
(B) hydrophilic macromolecule carrier;
Wherein, (A) and (B) weight ratio is 1: 1-1: 40.
2. solid dispersion as claimed in claim 1 is characterized in that, described hydrophilic macromolecule carrier is polyvidone or the macromolecule carrier that contains polyvidone.
3. solid dispersion as claimed in claim 1 is characterized in that, described hydrophilic macromolecule carrier is PVP K30 or the macromolecule carrier that contains PVP K30, and wherein, the content of PVP K30 is 10-100wt%, by the gross weight of macromolecule carrier.
4. solid dispersion as claimed in claim 1 is characterized in that, described active component is the chemical compound shown in the formula I, or its pharmaceutically acceptable salt, hydrate or solvate:
Figure FDA0000143902320000012
5. solid dispersion as claimed in claim 3 is characterized in that, the described macromolecule carrier that contains PVP K30 also comprises and is selected from other water-solubility carriers of lower group: polyethylene glycols, polyvidone class, cellulose family, surfactant-based or its combination;
Wherein, described polyethylene glycols is selected from lower group: Macrogol 4000, polyethylene glycol 6000, PEG 8000 or its combination;
Described polyvidone class is selected from lower group: 30 POVIDONE K 30 BP/USP 25,30 POVIDONE K 30 BP/USP 90, polyvidone S630 or its combination;
Described cellulose family is selected from lower group: hypromellose E5, hypromellose E15, hyprolose L or its combination;
Describedly surfactant-basedly be selected from lower group: poloxamer188, PLURONICS F87 or its combination.
6. solid dispersion as claimed in claim 1 is characterized in that, described (A) and weight ratio (B) are 1: 1-1: 20.
7. solid dispersion as claimed in claim 1 is characterized in that, in the X-ray powder diffraction pattern of described solid dispersion, does not have the X-ray diffraction characteristic peak of the active component of described solid dispersion.
8. solid dispersion as claimed in claim 1 is characterized in that, has following one or more feature:
1. the area under the drug-time curve of described solid dispersion be the active component of the described solid dispersion area under the drug-time curve when individually dosed 6-20 doubly, preferably 7-15 is doubly;
2. described solid dispersion in 37 ℃, the sodium acetate buffer aqueous solution of pH4.5 10 minutes the time accumulation dissolution preferably be 75-95% greater than 70%;
3. described solid dispersion in 37 ℃, the sodium acetate buffer aqueous solution of pH4.5 120 minutes the time accumulation dissolution be described solid dispersion active component accumulation dissolution 10-40 doubly, preferably be 15-30 times.
9. the preparation method of the described solid dispersion of claim 1 is characterized in that, comprises method:
(a) fusion method 1, comprises step:
(a1) mixed active composition and hydrophilic macromolecule carrier, thus a mixture that contains active component obtained;
(a2) mixture that contains active component that obtains of heating and melting step (a1), thus mixture after the melting obtained; With
(a3) mixture after the melting that obtains of cooling step (a2), thus solid dispersion claimed in claim 1 obtained;
Or
(b) fusion method 2, comprise step:
(b1) heating and melting hydrophilic macromolecule carrier, thus carrier after the melting obtained;
(b2) carrier after the melting that step (b1) is obtained and active component mix rear melting, thereby obtain the mixture after the melting; With
(b3) mixture after the melting that obtains of cooling step (b2), thus solid dispersion claimed in claim 1 obtained;
Or
(c) solvent method comprises step:
(c1) active component and hydrophilic macromolecule carrier are dissolved in the solvent jointly, thereby obtain a mixture; With
(c2) remove solvent in the mixture that step (c1) obtains, thereby obtain solid dispersion claimed in claim 1;
Wherein, described active component is formula A chemical compound or derivatives thereof or its pharmaceutically acceptable salt, hydrate or solvate,
Figure FDA0000143902320000031
In the formula, R is CD 3Or CH 3,
Described hydrophilic macromolecule carrier is the hydrophilic macromolecule carrier that contains PVP K30,
Described solvent is selected from lower group: methanol, ethanol, isopropyl alcohol, acetone, dichloromethane, oxolane, or its combination.
10. a pharmaceutical composition is characterized in that, described compositions comprises:
(1) each described solid dispersion of claim 1-8; With
(2) pharmaceutically acceptable excipient.
In another preference, described excipient comprises: filler, diluent, sweeting agent, correctives, antioxidant, coloring agent, antiseptic, lubricant, binding agent, disintegrating agent or its mixing.
11. the preparation method of pharmaceutical composition as claimed in claim 10 is characterized in that, with each described solid dispersion of claim 1-8 and pharmaceutically acceptable mixed with excipients, thereby makes described pharmaceutical composition.
12. the purposes of a solid dispersion as claimed in claim 1 is characterized in that, for the preparation of the medicine that suppresses phosphokinase (such as the raf kinases); Or for the preparation of the medicine for the treatment of tumor.
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