CN105732642A - Eutectic crystal of CDK inhibitor and MEK inhibitor and preparation method of eutectic crystal - Google Patents
Eutectic crystal of CDK inhibitor and MEK inhibitor and preparation method of eutectic crystal Download PDFInfo
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- CN105732642A CN105732642A CN201610217050.4A CN201610217050A CN105732642A CN 105732642 A CN105732642 A CN 105732642A CN 201610217050 A CN201610217050 A CN 201610217050A CN 105732642 A CN105732642 A CN 105732642A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a eutectic crystal of a CDK inhibitor and an MEK inhibitor and a preparation method of the eutectic crystal, and particularly provides an eutectic crystal form named as a crystal form III.The crystal form III is good in stability and low in hygroscopicity, accords with the medicinal requirement and has the important value on medicine optimization and development in future.
Description
Technical field
The present invention relates to chemical medicine, particularly relate to eutectic of a kind of CDK inhibitor (LEE011) and mek inhibitor (MEK162) and preparation method thereof.
Background technology
Along with the continuous appearance of melanoma resistance problems, the drug combination of multiple target drugs has become the main development direction of targeted therapy research.NRAS gene mutation is the genovariation type that malignant melanoma of skin patient is common, accounts for 20%.NRAS gene mutation patient more after how bad, and the target therapeutic agent of lacking of property.Research finds, in the melanoma cell of NRAS sudden change, and MAPK signal path abnormal activation, and there is the imbalance of multiple cell cycle checkpoint.Therefore, suppress MAPK signal critical path molecule MEK simultaneously, and cell cycle key regulates kinase c DK4/6, it is possible to play collaborative Graft Versus Tumor, improve antitumor curative effect.
Novartis discloses the I phase clinical data of CDK inhibitor LEE011 (Ribociclib) and mek inhibitor MEK162 (Binimetinib) coupling treatment NRAS sudden change melanoma, the composition of medicine clinical effectiveness of clinical display LEE011 and MEK162 is good, and it is clinical that this combination at present is carrying out the II phase.
LEE011 is a kind of Cyclin dependent kinase 4/6 (CDK4/6) inhibitor, is used for treating Drug resistance breast carcinoma and melanoma medicine, and in preclinical study, performance is good, it is thus achieved that positive achievement in research, is currently in during the clinical III phase studies.The chemical name of LEE011 is 7-cyclopenta-2-(5-piperazine-1-base-pyridine-2-base amino)-7H-pyrrolo-[2,3-D] pyrimidine-6-carboxylic acid diformamide, shown in its structure such as formula (Ia):
MEK162 is a kind of oral mitogen activated protein kinase (MEK) inhibitor, it is in III clinical trial phase at present in the U.S., for NRAS gene mutation body melanoma, the treatment of BRAF gene mutation body melanoma and the rudimentary blood plasma ovarian cancer patients of recurrent.The chemical name of this medicine is: 5-[(4-bromo-2-fluorophenyl) amino] the fluoro-N-of-4-(2-hydroxyl-oxethyl)-1-methyl isophthalic acid H-benzimidazole-6-Methanamide, shown in its structural formula such as formula (Ib):
Patent WO2014097125A1 discloses the compositions of LEE011 and MEK162, but the physical mixed that said composition is two kinds of components, not forming eutectic between two kinds of components, this has the different of essence from the present invention.
Pharmaceutical co-crystals is the crystal in same crystal structure containing two kinds of molecules.Effect between two kinds of molecules is generally non-covalent bond (such as hydrogen bond, π-pi-conjugated, halogen key etc.).The formation of pharmaceutical co-crystals generally will not destroy the covalent bond of active constituents of medicine.Have been reported that and think, make medicine form eutectic and have an opportunity to improve crystal property and the physico-chemical property of medicine itself, such as bioavailability (Pharmaceut.Res.23 (8), 2006, pp.1888-1897.), such as stability and technique exploitability (Int.J.Pham.320,2006, pp.114-123.).Therefore to become of pharmaceutical solid preparation the newly selected for pharmaceutical co-crystals.
In prior art, pharmaceutical co-crystals is generally formed by active constituents of medicine and eutectic reagent, active constituents of medicine in eutectic generally adopts structural rigidity relatively strong and symmetry is higher and relative molecular mass is relatively low and contains the good donor of proton or the compound molecule of receptor, and eutectic reagent mostly is pharmaceutic adjuvant, vitamin, aminoacid and food additive etc..At present, there is not yet and two kinds of active constituents of medicine are made eutectic and studies the relevant report of its therapeutic effect, particularly have no the relevant report that two kinds of active constituents of medicine of LEE011 and MEK162 are formed eutectic.
Summary of the invention
The present inventor passes through lot of experiments, is surprised to find that LEE011 and MEK162 both active constituents of medicine can form eutectic, and this eutectic has the clear superiority being suitable to the aspects such as production and application.
An object of the present invention is to provide CDK inhibitor (LEE011) and the eutectic of mek inhibitor (MEK162), eutectic good stability provided by the present invention, low in hygroscopicity, meets medicinal requirements.
The preparation method that the two of the object of the invention are to provide described eutectic, although being also likely to be obtained eutectic of the present invention possibly through other modes, but the preparation method of eutectic of the present invention is simple, with low cost, the clinic of the composition of medicine of following LEE011 and MEK162 is optimized and exploitation has important value.
For achieving the above object, the present invention adopts the following technical scheme that
A kind of eutectic of CDK inhibitor (LEE011) and mek inhibitor (MEK162), shown in the structural formula of described eutectic such as formula (I):
Wherein, x is the number between 0～3.What this x represented is in every mole of eutectic molecule, participates in constituting the molal quantity of the water of crystal lattices.X is probably 0, and when for 0, eutectic is anhydrous crystalline, and x is likely larger than 0, and now corresponding eutectic is hydrate, and the value of x can be integer or non-integer.
Preferably, x is 0,1,2 or 3.
According to the present invention, when mentioning " eutectic ", not only include LEE011 and the MEK162 situation combined by non-covalent bonds such as conventional eutectic bond power such as hydrogen bonds, also include LEE011 and the MEK162 situation combined by the form of covalent bond and the aforementioned double situation deposited of two kinds of situations.As long as combined by both drug molecules form eutectic, no matter which kind of form is its adhesion be, all belongs to the protection category of the present invention.
A specific aspect according to the present invention, the present invention provides a kind of eutectic, the X-ray powder diffraction figure that called after crystal form II I, this crystal form II I record with CuK alpha ray has characteristic peak in 2theta value for 18.8 ° ± 0.2 °, 20.5 ° ± 0.2 °, 23.1 ° ± 0.2 ° place.
According to a preferred aspect, the X-ray powder diffraction figure of crystal form II I provided by the invention is also the place in 22.6 ° ± 0.2 °, 4.3 ° ± 0.2 °, 12.7 ° ± 0.2 ° or many places have characteristic peak in 2theta value.According to a specific aspect, the X-ray powder diffraction figure of crystal form II I provided by the invention is also that 22.6 ° ± 0.2 °, 4.3 ° ± 0.2 °, 12.7 ° ± 0.2 ° place is respectively provided with characteristic peak in 2theta value.
According to another preferred aspect, the X-ray powder diffraction figure of crystal form II I provided by the invention is also the place in 26.2 ° ± 0.2 °, 24.7 ° ± 0.2 °, 21.6 ° ± 0.2 ° or many places have characteristic peak in 2theta value.According to a specific aspect, the X-ray powder diffraction figure of crystal form II I provided by the invention is also that 26.2 ° ± 0.2 °, 24.7 ° ± 0.2 °, 21.6 ° ± 0.2 ° place is respectively provided with characteristic peak in 2theta value.
According to third preferred aspect, the X-ray powder diffraction figure of crystal form II I provided by the invention is also the place in 22.6 ° ± 0.2 °, 4.3 ° ± 0.2 °, 12.7 ° ± 0.2 °, 26.2 ° ± 0.2 °, 24.7 ° ± 0.2 °, 21.6 ° ± 0.2 ° or many places have characteristic peak in 2theta value.
According to a most preferably aspect, the X-ray powder diffraction figure of crystal form II I provided by the invention is also that 22.6 ° ± 0.2 °, 4.3 ° ± 0.2 °, 12.7 ° ± 0.2 °, 26.2 ° ± 0.2 °, 24.7 ° ± 0.2 °, 21.6 ° ± 0.2 ° place is respectively provided with characteristic peak in 2theta value.In a detailed description of the invention according to the program, the X-ray powder diffraction figure of crystal form II I is substantially consistent with Fig. 1.Which show totally 41 characteristic peaks, position and the peak intensity of these characteristic peaks are as shown in table 2.According to, in another detailed description of the invention of the program, showing totally 38 characteristic peaks in the X-ray powder diffraction figure of crystal form II I, position and the peak intensity of these characteristic peaks are as shown in table 3.According in an also detailed description of the invention of the program, showing totally 29 characteristic peaks in the X-ray powder diffraction figure of crystal form II I, position and the peak intensity of these characteristic peaks are as shown in table 4.
It is further preferred that crystal form II I provided by the invention starts first endothermic peak occur near heating to 70～78 DEG C, starting second endothermic peak occur near heating to 114～126 DEG C, its differential scanning calorimetric thermogram is substantially as shown in Figure 2.
It is further preferred that when crystal form II I provided by the invention is near heating is to 114 DEG C, have the loss in weight gradient of about 4.4～4.8%, its thermogravimetric analysis figure is as shown in Figure 3.
According to the present invention, in crystal form II I the content (or x value) of water be preferably 0.5～3 mole between any number, more preferably any number between 2～3 moles, more preferably 2 moles or 3 moles, wherein with 2 moles for most preferably.
The preparation method that another purpose of the present invention is to provide a kind of described eutectic, it includes mixing LEE011 and MEK162 in one or more the dicyandiamide solution in alcohol organic solvent, organic solvent of ketone, ether organic solvent, nitrile organic solvent, water, then passes through volatilization, stirring or cooling and obtains described eutectic.
Preferably, at 0～50 DEG C, described LEE011 and described MEK162 is mixed in described dicyandiamide solution.
Further, described alcohol organic solvent includes but not limited to methanol, ethanol, isopropanol etc.；Described organic solvent of ketone includes but not limited to acetone, methyl ethyl ketone, methyl iso-butyl ketone (MIBK) etc.；Described ether organic solvent includes but not limited to cyclic ethers class, alkyl ether etc., wherein alkyl ether such as such as oxolane, Isosorbide-5-Nitrae dioxane, methyl tertiary butyl ether(MTBE) etc.；Described nitrile organic solvent includes but not limited to acetonitrile etc..
Preferably, described dicyandiamide solution is one or more in acetonitrile, ethanol, methanol, water.
According to the present invention, when described dicyandiamide solution is methanol, the eutectic obtained is crystal form II I.
A specific aspect according to the present invention, the preparation method that the present invention provides a kind of described eutectic, the preparation method of crystal form II I includes method one or method two:
Method one: being mixed with the mixed solvent system of water, organic solvent of ketone, ether organic solvent or nitrile organic solvent in alcohol organic solvent or alcohol organic solvent by LEE011 and MEK162 eutectic crystal formation I, the method then passing through volatilization obtains crystal form II I；Crystal formation I can pass through to prepare example 1 and prepare.
Method two: mixed in alcohol organic solvent by LEE011 and MEK162, the method then passing through volatilization obtains crystal form II I.
Preferably, in method one, the volume ratio that feeds intake of the mixed solvent system of feed intake quality and described alcohol organic solvent or alcohol organic solvent and water, organic solvent of ketone, ether organic solvent or the nitrile organic solvent of described crystal formation I is 8～25mg/mL.
Preferably, in method one, being mixed by described crystal formation I in alcohol organic solvent, the method then passing through volatilization obtains crystal form II I.
It is further preferable that described alcohol organic solvent includes methanol.
Preferably, in method two, the mass ratio that feeds intake of described LEE011 and described MEK162 is 1:0.9～1.1.
Preferably, in method two, the volume ratio that feeds intake of feed intake quality and the described alcohol organic solvent of described MEK162 is 6～7mg/mL.
3rd purpose of the present invention is to provide a kind of Pharmaceutical composition, and including active component and pharmaceutically acceptable excipient, described active component includes described eutectic.
A specific aspect according to the present invention, the present invention provides a kind of Pharmaceutical composition, and including active component and pharmaceutically acceptable excipient, described active component is crystal form II I.
4th purpose of the present invention is to provide a kind of described eutectic purposes in preparation treatment cancer drug preparation.
A specific aspect according to the present invention, the present invention provides a kind of crystal form II I purposes in preparation treatment cancer drug preparation.
5th purpose of the present invention is to provide a kind of described eutectic purposes in treatment cancer.
6th purpose of the present invention is to provide a kind of method treating cancer, and it includes applying eutectic as above or Pharmaceutical composition to patient.
Further, described cancer includes but not limited to melanoma, cancer of pancreas, ovarian cancer, breast carcinoma, lymphoma, pulmonary carcinoma.
Accompanying drawing explanation
Fig. 1 is the XRPD figure of the crystal form II I that embodiment 1 prepares；
Fig. 2 is the DSC figure of the crystal form II I that embodiment 1 prepares；
Fig. 3 is the TGA figure of the crystal form II I that embodiment 1 prepares；
Fig. 4 is the DVS figure of crystal form II I；
Fig. 5 is that crystal form II I is 25 DEG C/60%RH condition stability inferior comparison diagram (upper figure is the XRPD figure before placing, and figure below is the XRPD figure after placing 30 days)；
Fig. 6 is that crystal form II I is 40 DEG C/75%RH condition stability inferior comparison diagram (upper figure is the XRPD figure before placing, and figure below is the XRPD figure after placing 30 days)；
Fig. 7 is the nuclear-magnetism figure of crystal form II I.
Detailed description of the invention
Hereinafter the present invention will be expanded on further by specific embodiment, but be not limited to protection scope of the present invention.Preparation method and use instrument can be made improvements by those skilled in the art in right, and these improvement also should be regarded as protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.In preparation method, LEE011 and the MEK162 free form as raw material is prepared by known method.
In the preparation method of the crystal formation of the present invention:
Described " room temperature " refers to 15～25 DEG C.
Described " stirring ", adopts the conventional method of this area to complete, for instance magnetic agitation or mechanical agitation, mixing speed is 50～1800 revs/min, it is preferable that 300～900 revs/min.
Described " separation ", adopts the conventional method of this area to complete, for instance centrifugal or filtration.The operation " being centrifuged " is: the sample being intended to separate is placed in centrifuge tube, is centrifuged with the speed of 10000 revs/min, is all sink to bottom centrifuge tube to solid.
Unless stated otherwise, described " drying " can carry out at room temperature or at higher temperatures.Baking temperature room temperature～about 60 DEG C, or to 40 DEG C, or to 50 DEG C.Drying time can be 2～48 hours, or overnight.Dry and carry out in fume hood, convection oven or vacuum drying oven.
In the present invention, " crystal " or " crystal formation " refers to be characterized by shown X-ray diffractogram and confirms.It will be appreciated by those skilled in the art that physicochemical property discussed herein can be characterized, experimental error therein depends on the purity of the condition of instrument, the preparation of sample and sample.Particularly, as well known to those skilled in the art, X-ray diffractogram would generally change along with the condition of instrument.Special needs to be pointed out is, the relative intensity of X-ray diffractogram is likely to and changes along with the change of experiment condition, so the order of peak intensity cannot function as unique or deciding factor.It addition, the experimental error of peak angle degree is generally 5% or less, the error of these angles also should be considered into, allows generally for ± the error of 0.2 °.Further, since the impact of the empirical factors such as height of specimen, the overall offset of peak angle degree can be caused, allow generally for certain skew.Thus, it will be appreciated by persons skilled in the art that in the present invention, the x-ray diffraction pattern of a crystal formation need not be completely the same with the X-ray diffractogram in example referred herein.Any crystal formation having with the same or analogous figure of the characteristic peak in these collection of illustrative plates belongs within scope of the invention.The collection of illustrative plates of the collection of illustrative plates listed by the present invention and a unknown crystal formation can be compared by those skilled in the art, is identical or different crystal formation with what confirm this two groups of collection of illustrative plates reflection.
" crystal formation " and " polymorphic " and other relative words refer to solid chemical compound in the present invention to be existed with specific crystal form state in crystal structure.The difference of polymorphic physicochemical property can be embodied in the aspects such as storage stability, compressibility, density, dissolution rate.In extreme situations, the difference of dissolubility or dissolution rate can cause medicine poor efficiency, even toxicity.
Pharmaceutical co-crystals is the crystal in same crystal structure containing two kinds of molecules.Effect between two kinds of molecules is generally non-covalent bond (such as hydrogen bond, π-pi-conjugated, halogen key etc.).The formation of pharmaceutical co-crystals generally will not destroy the covalent bond of active constituents of medicine.The phrase " effective therapeutic dose " used in the present invention or " therapeutically effective amount " refer to the amount of reactive compound or the medicament causing biological respinse or the drug reaction sought in tissue, system, animal, individuality or people by research worker, veterinary, doctor or other clinicists.
The term " treatment " used in the present invention refers to one of the following or multiple: (1) prevention disease；Such as may tend to disease, disease or obstacle, preventing this disease, disease or obstacle but without suffering or show in the pathological changes of this disease or the individuality of symptom；(2) this disease is suppressed；Such as in just suffering or show the pathological changes of this disease, disease or obstacle or the individuality of symptom, suppress this disease, disease or obstacle；And (3) improve this disease；Such as, in suffering or show the pathological changes of this disease, disease or obstacle or the individuality of symptom, this disease, disease or obstacle (namely reversing pathological changes and/or symptom) are improved, for instance lower the severity of disease.
In some embodiments, the novel crystal forms of the present invention, including being pure, single, it is substantially free of any other crystal formation of mixing.In the present invention, " it is substantially free of " when being used to refer to novel crystal forms and refers to that this crystal formation contains other crystal formations less than 20% (weight), especially less than other crystal formations of 10% (weight), more refer to other crystal formations less than 5% (weight), more refer to other crystal formations less than 1% (weight).
It should be noted that, the numerical value mentioned in the present invention and numerical range should be narrowly interpreted as numerical value or numerical range itself, skilled artisan would appreciate that it can according to the difference of concrete technological accumulation and inheritance, float to some extent around concrete numerical value in basis without departing substantially from present invention spirit and principle, in the present invention, the foreseeable domain of walker of this those skilled in the art is many to be represented with term " about ".
The polymorphic of medicine can pass through to include but not limited to that following method obtains: melting recrystallization, melted cooling, solvent recrystallization, mistake solvent, quickly volatilization, fast cooling, at a slow speed cooling, steam diffusion and distillation.Sometimes, diverse ways is likely to and obtains identical crystallization.Polymorphic can pass through X-ray powder diffraction (XRPD), differential scanning calorimetric analysis (DSC), thermogravimetric analysis (TGA), light microscope technique, hygroscopicity etc. and detect, finds and sort out.And the crystallization mode that crystal formation of the present invention adopts be volatilization, stirring and cooling method.
Additionally, the present invention provides a kind of pharmaceutical composition, described pharmaceutical composition comprises the eutectic of the present invention for the treatment of and/or prevention effective dose and at least one pharmaceutically acceptable excipient, and above-mentioned eutectic is crystal form II I.Additionally, described pharmaceutical composition can also comprise the salt of other pharmaceutically useful eutectic, the crystal formation of its salt or amorphous article.Optionally, the crystal formation of the present invention can be used as independent activating agent, or they can with other activating agent combined administration, including there is same or similar therapeutic activity and being defined as other compound safe and efficient for this type of combined administration.In special embodiment, two kinds of (or multiple) activating agents jointly use the dosage allowing to significantly reduce every kind of activating agent used, thus reducing seen side effect.
Aforementioned pharmaceutical compositions can be made into certain dosage form, by applicable administration.The approach such as such as oral, parenteral (including subcutaneous, muscle, vein or Intradermal), rectum, transdermal, per nasal, vagina.The dosage form being suitable for oral administration includes tablet, capsule, granule, powder, pill, powder, lozenge, solution, syrup or suspensoid, as required, may be adapted to the quickly release of active constituents of medicine, postpones release or regulate release；The dosage form being suitable for parenteral includes aqueous or nonaqueous aseptic injectable solution, emulsion or suspension；The dosage form being suitable for rectally includes suppository or enema；The dosage form being suitable for transdermal administration includes ointment, cream, patch；The dosage form being suitable for nose administration includes aerosol, spray, nasal drop；The dosage form being suitable for vagina administration includes suppository, suppository, gel, paste or spray.Preferably due to the crystal formation of the present invention has beat all agent of low hygroscopicity and the stability in water or in ethanol water, therefore, be especially suitable for preparing into tablet, suspensoid, capsule, disintegrating tablet, namely release, slow release and controlled release tablet；More preferably tablet, suspensoid and capsule.
Acceptable excipient on aforementioned pharmaceutical compositions Chinese materia medica, when solid oral dosage form, include but not limited to: diluent, for instance starch, pregelatinized Starch, lactose, Powderd cellulose, microcrystalline Cellulose, calcium hydrogen phosphate, tricalcium phosphate, mannitol, sorbitol, sugar etc.；Binding agent, for instance arabic gum, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, Polyethylene Glycol etc.；Disintegrating agent, for instance starch, sodium starch glycollate, pregelatinized Starch, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, silica sol etc.；Lubricant, for instance stearic acid, magnesium stearate, zinc stearate, sodium benzoate, sodium acetate etc.；Fluidizer, for instance silica sol etc.；Complex forming agents, for instance the cyclodextrin of various ranks and resin；Rate of release controlling agent, for instance hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, methylcellulose, methyl methacrylate, wax etc..Other available pharmaceutically acceptable excipient include but not limited to film former, plasticizer, coloring agent, flavoring agent, viscosity modifier, preservative, antioxidant etc..Optionally, tablet is coated with coatings, Lac isolation coat, sugar-coat or polymer coating are such as provided, polymer in coatings is hydroxypropyl methyl cellulose, polyvinyl alcohol, ethyl cellulose, methacrylic polymer, hydroxypropyl cellulose or starch such as, antitack agent such as silicon dioxide, Pulvis Talci can also be included, opacifiers is titanium dioxide such as, and coloring agent is iron oxides coloring agent such as.When liquid oral dosage form, suitable excipient includes water, oils, alcohols, glycols, flavoring agent, preservative, stabilizer, coloring agent etc.；The sterile suspensions of water or non-water can contain suspending agent and thickening agent；Excipient suitable in aqueous suspension includes rubber polymer or natural gums such as Radix Acaciae senegalis, Herba Xanthii natural gum, alginate, glucosan, sodium carboxymethyl cellulose, methylcellulose, polyvinylpyrrolidone or gelatin.When parenteral dosage forms, the excipient of the aseptic injectable solution of water or non-water is generally sterilized water, normal saline or D/W, it is possible to containing buffer agent, antioxidant, antibacterial with the isotonic solute of this pharmaceutical composition and blood can be made.Each excipient must be acceptable, can be compatible and harmless for patient with other compositions in formula.
Described pharmaceutical composition can use in prior art and well known to a person skilled in the art prepared by method.When preparing pharmaceutical composition, pharmaceutically acceptable to crystal formation of the present invention and one or more excipient is mixed mutually, optionally mix mutually with one or more other active constituents of medicine.Such as, tablet, capsule, granule can be prepared by techniques such as mixing, granulation, tabletting or filling capsules；Powder is prepared by the finely ground active constituents of medicine to suitable size and excipient being mixed；Solution and syrup can be prepared by being dissolved in suitably seasoned water or aqueous solution by active constituents of medicine；Suspensoid can be prepared by being scattered in pharmaceutically acceptable carrier by active constituents of medicine.
It is especially mentioned that the wet granulation technology of solid preparation, wet granulation for tablet, preparation technology is: the dry solids such as mixed active composition, filler, binding agent, with wetting agent such as water or alcohol moistening, the solid of this moistening is made condensation product or granule, continuing wet granulation, until obtaining required uniform grading, being subsequently dried this granular product.Then the dry granule obtained is mixed with disintegrating agent, lubricant, antitack agent etc., tabletting in pelleter；Alternatively, coating is carried out with suitable coating powder.
Additionally, also it is especially mentioned that oral suspensions, an advantage of this form of medication is that patient can swallow solid form, particularly with the patient swallowing the possible inconvenient old people of solid form, child or oral cavity, injury of throat.Suspensoid is the binary system formed in a liquid by solid particle dispersions, still keeps the crystal expection of its original solid form to would be even more beneficial to keep stablizing of drug products character in the water or aqueous carrier of suspensoid.Other components in oral suspensions can include buffer agent, surfactant, viscosity modifier, preservative, antioxidant, coloring agent, flavoring agent, taste masking agent etc..
Eutectic provided by the invention has the favorable property suitable in above-mentioned dosage form.
Additionally, the present invention provides eutectic purposes in preparing cancer drug.
Described " cancer " includes the pernicious or benign growths of cell in skin or biological organs, and described organ includes but not limited to breast, prostate, lung, kidney, pancreas, stomach or intestinal.Cancer is prone to invade adjacent tissue and spread (transfer) arrive organ farther out, for instance bone, liver, lung or brain.Cancer of the present invention includes metastatic tumour cellular type, such as but not limited to melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma and mastocytoma, and tissue cancer type, for instance but it is not limited to colorectal carcinoma, carcinoma of prostate, small cell lung cancer and nonsmall-cell lung cancer, breast carcinoma, cancer of pancreas, bladder cancer, renal carcinoma, gastric cancer, glioblastoma multiforme, primary hepatocarcinoma, ovarian cancer, carcinoma of prostate and leiomyosarcoma of uterus.
In following embodiment, the condition of described test method generally conventionally condition or manufacturer's suggestion is implemented.
Being explained as follows of abbreviation used in the present invention:
XRPD:X ray powder diffraction
DSC: differential scanning calorimetric analysis
TGA: thermogravimetric analysis
DVS: dynamic water is adsorbed
X-ray powder diffraction figure of the present invention gathers on PanalyticalEmpyreanX ray powder diffractometer, and test temperature is ordinary temperature, for instance 25 DEG C.The method parameter of X-ray powder diffraction of the present invention is as follows:
X ray reflection parameter: Cu, K α
1.540598；1.544426
K α 2/K α 1 intensity: 0.50
Voltage: 45 KVs (kV)
Electric current: 40 milliamperes (mA)
Sweep limits: spend from 3.0 to 40.0
Differential scanning calorimetric analysis of the present invention (DSC) figure gathers on TAQ2000.The method parameter of differential scanning calorimetric analysis of the present invention (DSC) is as follows:
Sweep speed: 10 DEG C/min
Protective gas: nitrogen
Thermogravimetric analysis of the present invention (TGA) figure gathers on TAQ5000.The method parameter of thermogravimetric analysis of the present invention (TGA) is as follows:
Sweep speed: 10 DEG C/min
Protective gas: nitrogen
Dynamic water of the present invention absorption (DVS) figure gathers on the Intrinsic dynamic water adsorption instrument produced by SMS company (SurfaceMeasurementSystemsLtd.).The method parameter of described dynamic water adsorption instrument is as follows:
Temperature: 25 DEG C
Carrier gas, flow velocity: N2, 200 ml/min
Unit interval mass change: 0.002%/minute
RH range: 0%RH-95%RH
Preparation example 1
The preparation method of eutectic crystal formation I:
MEK162 and the 4mL of 26.6mg acetonitrile/water (v:v=19:1) being placed at 50 DEG C and stir 30 minutes, add 16.0mgLEE011, overnight also slow cooling is to 20 DEG C to continue stirring, and collecting solid can obtain.
These X-ray powder diffraction data preparing the crystal formation that example obtains are as shown in table 1.
Table 1
| 2theta | D interval | Relative intensity % |
| 7.46 | 11.85 | 15.77 |
| 8.29 | 10.67 | 20.26 |
| 10.37 | 8.53 | 54.57 |
| 11.37 | 7.79 | 52.73 |
| 12.48 | 7.10 | 5.21 |
| 13.00 | 6.81 | 18.91 |
| 13.35 | 6.63 | 45.08 |
| 14.11 | 6.28 | 9.89 |
| 14.57 | 6.08 | 18.05 |
| 15.84 | 5.60 | 18.04 |
| 16.67 | 5.32 | 13.53 |
| 16.87 | 5.26 | 15.95 |
| 17.88 | 4.96 | 6.10 |
| 19.29 | 4.60 | 100.00 |
| 19.55 | 4.54 | 19.83 |
| 20.26 | 4.38 | 11.23 |
| 21.59 | 4.12 | 39.45 |
| 22.39 | 3.97 | 16.48 |
| 22.67 | 3.92 | 60.10 |
| 22.94 | 3.88 | 19.18 |
| 23.55 | 3.78 | 46.10 |
| 23.79 | 3.74 | 13.16 |
| 25.22 | 3.53 | 19.81 |
| 25.97 | 3.43 | 25.44 |
| 26.80 | 3.33 | 15.49 |
| 28.04 | 3.18 | 11.25 |
| 29.21 | 3.06 | 10.34 |
| 30.64 | 2.92 | 8.17 |
| 32.85 | 2.73 | 2.68 |
| 34.60 | 2.59 | 7.79 |
Embodiment 1
The preparation method of crystal form II I:
327mg being prepared the crystal formation I that example 1 prepares and adds in 20mL vial, add and molten under the MeOH room temperature (25 ± 3 DEG C) of 15mL cross leaching 4.0ml filtrate to 20ml vial clearly, room temperature (25 ± 3 DEG C) is slowly evaporated completely solvent, can obtain.
The X-ray powder diffraction data of the crystal formation that the present embodiment obtains are as shown in table 2.Its XRPD figure schemes such as Fig. 3 such as Fig. 1, its DSC figure such as Fig. 2, its TGA.As can be seen from Figure 2, the crystal form II I that the present embodiment provides starts first endothermic peak occur near heating to 70～78 DEG C, starts second endothermic peak occur near heating to 114～126 DEG C.As can be seen from Figure 3, when the crystal form II I that the present embodiment provides is near heating is to 114 DEG C, there is the loss in weight gradient of about 4.4～4.8%.
In the present embodiment, from Fig. 2, Fig. 3, Fig. 7 it can be seen that be not detected by solvent peak nuclear magnetic data, the content that can deduce the water in crystal form II I according to TGA weightlessness is about 2 moles.
Table 2
Embodiment 2
The preparation method of crystal form II I:
16.1mg is prepared the crystal formation I addition 5mL bottle that example 1 prepares, and the MeOH adding 2.0mL under room temperature (25 ± 3 DEG C) crosses leaching 0.5mL filtrate to 1.5mL vial clearly to molten, and room temperature (25 ± 3 DEG C) is slowly evaporated completely solvent, can obtain.
The X-ray powder diffraction data of the crystal formation that the present embodiment obtains are as shown in table 3.
Table 3
Embodiment 3
The preparation method of crystal form II I:
The LEE011 of MEK162 and the 49.3mg of 50.0mg is added in 20mL vial, 8.0mLMeOH solvent is added extremely molten clearly under room temperature (25 ± 3 DEG C), crossing leaching 4.0mL filtrate to 20mL vial, room temperature (25 ± 3 DEG C) is slowly evaporated completely solvent, can obtain.
The X-ray powder diffraction data of the crystal formation that the present embodiment obtains are as shown in table 4.
Table 4
| 2theta | D interval | Relative intensity % |
| 4.31 | 20.51 | 88.46 |
| 6.95 | 12.71 | 19.46 |
| 8.22 | 10.76 | 61.59 |
| 10.63 | 8.33 | 26.74 |
| 12.67 | 6.99 | 60.62 |
| 13.07 | 6.77 | 40.81 |
| 14.03 | 6.31 | 35.47 |
| 14.21 | 6.23 | 38.51 |
| 14.70 | 6.03 | 64.45 |
| 15.36 | 5.77 | 37.63 |
| 16.50 | 5.37 | 33.24 |
| 17.48 | 5.07 | 35.31 |
| 18.34 | 4.84 | 41.49 |
| 18.83 | 4.71 | 97.35 |
| 19.60 | 4.53 | 37.68 |
| 20.46 | 4.34 | 100.00 |
| 20.73 | 4.29 | 45.38 |
| 21.17 | 4.20 | 36.02 |
| 21.63 | 4.11 | 70.32 |
| 22.65 | 3.93 | 91.83 |
| 23.10 | 3.85 | 85.91 |
| 23.34 | 3.81 | 51.75 |
| 23.70 | 3.75 | 44.02 |
| 24.71 | 3.60 | 72.82 |
| 25.29 | 3.52 | 34.34 |
| 26.20 | 3.40 | 83.77 |
| 28.33 | 3.15 | 40.73 |
| 28.71 | 3.11 | 45.12 |
| 31.21 | 2.87 | 19.49 |
Embodiment 4
The research of MEK162 and LEE011 component molar ratio in crystal form II I:
Weighing the crystal form II I addition vial that the 1.504mg embodiment of the present invention 1 prepares, addition 10mLMeOH solvent is molten clearly, tests and calculate the mol ratio of MEK162 and LEE011 in solution with high performance liquid chromatograph device.Result is table 5 such as.
Table 5
| Compound | MEK162/LEE011 component |
| MEK162 concentration (mmol/L) | 0.157 |
| LEE011 concentration (mmol/L) | 0.153 |
| Mol ratio | 1:1 |
Embodiment 5
Crystal form II I draws moist research:
Take the prepared crystal form II I of the about 10mg embodiment of the present invention 1 and carry out dynamic water absorption (DVS) test.Result such as table 6, DVS is schemed such as Fig. 4.
Table 6
About draw moist feature description with draw moist weightening finish define (Chinese Pharmacopoeia version annex XIXJ medicine in 2010 draws moist test direction principle):
Deliquescence: absorb the fractal one-tenth liquid of enough water；
Great draw moist: draw wet weightening finish and be not less than 15%；
Have draw moist: drawing wet weightening finish and less than 15% but being not less than 2%；
Slightly draw moist: draw wet weightening finish and less than 2% but be not less than 0.2%；
Nothing or moist almost without drawing: drawing wet weightening finish less than 0.2%.
It is shown that the crystal form II I of the present invention from 10% relative humidity to 80% relative humidity balance after weightening finish 1.12%, slightly draw moist.And weightening finish 1.93% after balance from 10% relative humidity to 95% relative humidity, illustrate that being susceptible to high humility affects and deliquescence.
Embodiment 6
The stability study of crystal form II I:
Taking that two parts of samples of crystal form II I that the embodiment of the present invention 1 prepares are uncovered is positioned over 25 DEG C/60%RH, 40 DEG C/75%RH, after 30 days, XRPD is surveyed in sampling.Experimental result is table 7 below such as.
Table 7
| Initial crystal formation | Placement condition | Standing time | Crystal formation changes |
| Crystal form II I | 25 DEG C/60%RH | 30 days | Crystal form II I remains unchanged (such as Fig. 5) |
| Crystal form II I | 40 DEG C/75%RH | 30 days | Crystal form II I remains unchanged (such as Fig. 6) |
It is shown that the crystal form II I of the present invention places 30 days under two kinds of conditions of 25 DEG C/60%RH, 40 DEG C/75%RH, crystal formation does not change.
Above-described embodiment only for technology design and the feature of the present invention are described, its object is to allow person skilled in the art will appreciate that present disclosure and to implement according to this, can not limit the scope of the invention with this.All equivalences made according to spirit of the invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (18)
1. the eutectic of a CDK inhibitor and mek inhibitor, it is characterised in that: shown in the structural formula of described eutectic such as formula (I):
Wherein, x is the number between 0～3.
2. eutectic according to claim 1, it is characterised in that: x is 0,1,2 or 3.
3. eutectic according to claim 1, it is characterized in that: described eutectic is crystal form II I, the X-ray powder diffraction figure that described crystal form II I records with CuK alpha ray has characteristic peak in 2theta value for 18.8 ° ± 0.2 °, 20.5 ° ± 0.2 °, 23.1 ° ± 0.2 ° place.
4. eutectic according to claim 3, it is characterised in that: the X-ray powder diffraction figure of described crystal form II I is also the place in 22.6 ° ± 0.2 °, 4.3 ° ± 0.2 °, 12.7 ° ± 0.2 ° or many places have characteristic peak in 2theta value.
5. eutectic according to claim 4, it is characterised in that: the X-ray powder diffraction figure of described crystal form II I is also that 22.6 ° ± 0.2 °, 4.3 ° ± 0.2 °, 12.7 ° ± 0.2 ° place has characteristic peak in 2theta value.
6. the eutectic according to claim 3 or 4 or 5, it is characterised in that: the X-ray powder diffraction figure of described crystal form II I is also the place in 26.2 ° ± 0.2 °, 24.7 ° ± 0.2 °, 21.6 ° ± 0.2 ° or many places have characteristic peak in 2theta value.
7. eutectic according to claim 6, it is characterised in that: the X-ray powder diffraction figure of described crystal form II I is also that 26.2 ° ± 0.2 °, 24.7 ° ± 0.2 °, 21.6 ° ± 0.2 ° place has characteristic peak in 2theta value.
8. the eutectic according to claim 3 or 4 or 5, it is characterised in that: described crystal form II I contains the water of 2～3 moles.
9. the preparation method of the eutectic as according to any one of claim 3 to 8, it is characterised in that: the preparation method of crystal form II I includes method one or method two:
Method one: being mixed with the mixed solvent system of water, organic solvent of ketone, ether organic solvent or nitrile organic solvent in alcohol organic solvent or alcohol organic solvent by LEE011 and MEK162 eutectic crystal formation I, the method then passing through volatilization obtains crystal form II I；
Method two: mixed in alcohol organic solvent by LEE011 and MEK162, the method then passing through volatilization obtains crystal form II I.
10. the preparation method of eutectic according to claim 9, it is characterized in that: in method one, the volume ratio that feeds intake of the mixed solvent system of feed intake quality and described alcohol organic solvent or alcohol organic solvent and water, organic solvent of ketone, ether organic solvent or the nitrile organic solvent of described crystal formation I is 8～25mg/mL.
11. the preparation method of eutectic according to claim 9, it is characterised in that: in method one, being mixed by described crystal formation I in alcohol organic solvent, the method then passing through volatilization obtains crystal form II I.
12. the preparation method of the eutectic according to claim 9 to 11, it is characterised in that: described alcohol organic solvent includes methanol.
13. the preparation method of the eutectic according to claim 9 to 11, it is characterised in that: in method two, the mass ratio that feeds intake of described LEE011 and described MEK162 is 1:0.9～1.1.
14. the preparation method of eutectic according to claim 9, it is characterised in that: in method two, the volume ratio that feeds intake of feed intake quality and the described alcohol organic solvent of described MEK162 is 6～7mg/mL.
15. a Pharmaceutical composition, including active component and pharmaceutically acceptable excipient, it is characterised in that: described active component includes the eutectic as according to any one of claim 1 to 8.
16. a Pharmaceutical composition, including active component and pharmaceutically acceptable excipient, it is characterised in that: described active component includes being selected from the eutectic according to any one of claim 3 to 8.
17. the eutectic as according to any one of claim 1 to 8 treats the purposes in cancer drug preparation in preparation.
18. the method treating cancer, it is characterised in that: it includes applying the eutectic as according to any one of claim 1 to 8 or the Pharmaceutical composition as described in claim 15 or 16 to patient.
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| WO2014018725A1 (en) * | 2012-07-26 | 2014-01-30 | Novartis Ag | Pharmaceutical combinations of a cdk4/6 inhibitor and a b-raf inhibitor |
| WO2014097125A1 (en) * | 2012-12-20 | 2014-06-26 | Novartis Ag | Pharmaceutical combination comprising binimetinib |
| WO2014147573A2 (en) * | 2013-03-21 | 2014-09-25 | Novartis Ag | Combination therapy |
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| WO2014018725A1 (en) * | 2012-07-26 | 2014-01-30 | Novartis Ag | Pharmaceutical combinations of a cdk4/6 inhibitor and a b-raf inhibitor |
| WO2014097125A1 (en) * | 2012-12-20 | 2014-06-26 | Novartis Ag | Pharmaceutical combination comprising binimetinib |
| WO2014147573A2 (en) * | 2013-03-21 | 2014-09-25 | Novartis Ag | Combination therapy |
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