WO2017054741A1 - 提高索拉非尼生物利用度的制剂 - Google Patents

提高索拉非尼生物利用度的制剂 Download PDF

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WO2017054741A1
WO2017054741A1 PCT/CN2016/100651 CN2016100651W WO2017054741A1 WO 2017054741 A1 WO2017054741 A1 WO 2017054741A1 CN 2016100651 W CN2016100651 W CN 2016100651W WO 2017054741 A1 WO2017054741 A1 WO 2017054741A1
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sorafenib
weight
parts
pvp
active ingredient
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PCT/CN2016/100651
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French (fr)
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钱锋
刘程宇
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清华大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers

Definitions

  • the present invention relates to the field of biomedicine, and in particular, to a formulation for increasing the bioavailability of sorafenib.
  • Sorafenib is a tyrosine kinase inhibitor for the treatment of inoperable liver cancer, renal cell carcinoma, and thyroid cancer. Sorafenib inhibits the target sites of tumor cells CRAF, BRAF, V600EBRAF, c-Kit, FLT-3 and CRAF, VEGFR-2, VEGFR-3, PDGFR- ⁇ in tumor vascular target sites.
  • RAF kinase is a serine/threonine kinase
  • c-Kit, FLT-3, VEGFR-2, VEGFR-3, and PDGFR- ⁇ are tyrosine kinases that act on tumor cell signaling, angiogenesis, and apoptosis. Therefore, sorafenib has an inhibitory effect on tumor cell proliferation and resistance to angiogenesis.
  • the common methods used in the field of medicine to improve the bioavailability of drugs include the following: salt formation, reduction of drug particle size, preparation of emulsions or self-microemulsions using non-aqueous solvents/co-solvents, cyclodextrin inclusion, thermodynamics Unstable crystal form or prepared as a solid dispersion or the like.
  • sorafenib preparations remains to be further studied.
  • the present invention aims to solve at least one of the technical problems in the related art to some extent.
  • the bioavailability of the currently marketed sorafenib preparation is 38%-49% compared with the oral solution, and the bioavailability is relatively low.
  • the oral dose of the preparation is relatively large, 400 mg/time, twice a day. Long-term use of the drug in a large number of side effects is more obvious, so how to improve the bioavailability of sorafenib preparation, thereby reducing its dosage, reducing toxic side effects, food effects and pH effects, improving patient compliance and treatment effectiveness become very important.
  • sorafenib a drug with limited solubility in oily solvents
  • the most feasible technical means to increase its bioavailability is amorphous solid dispersion.
  • sorafenib is thermally unstable, it cannot be prepared by hot melt extrusion; and in the solvent which is commonly used for spray drying, its solubility is also limited, so spray drying is also used for preparation. It is not easy, so there will be difficulties in preparing industrial production of its solid dispersion.
  • the solid dispersion itself is in a high energy state, it is prone to aging in storage and affects stability. It is difficult to produce and quality supervision, so preparing a solid dispersion is not the best choice.
  • sorafenib preparation containing a polymer cosolvent which not only greatly improves the bioavailability of sorafenib compared to the simulated marketed preparation, but also has industrialized production convenience.
  • the drug is stable, reliable and many other advantages.
  • the invention provides a sorafenib formulation, according to an embodiment of the invention, the sorafenib formulation comprising: an active ingredient selected from the group consisting of sorafenib, At least one of sorafenib salt, sorafenib derivative or a prodrug thereof; and a polymer cosolvent (in the present invention, sometimes referred to as a polymer compound), the polymer cosolvent having vinyl acetate Ester group (VA group).
  • a polymer cosolvent in the present invention, sometimes referred to as a polymer compound
  • VA group vinyl acetate Ester group
  • the active ingredient is a low solubility compound
  • the added polymer cosolvent can increase the degree of supersaturation of the active ingredient in the dissolution medium
  • the VA group is essential for the polymer compound to maintain the supersaturation of the active ingredient.
  • the VA group can significantly increase the supersaturation of the active ingredient, thereby effectively increasing the bioavailability of the active ingredient.
  • the above sorafenib formulation further comprises at least one of the following additional technical features:
  • the weight ratio of the active ingredient to the polymer cosolvent is from 1:0.1 to 10.
  • the supersaturation of the active ingredient in the simulated intestinal fluid solution (FaSSIF) and the individual is greatly improved, and the bioavailability is greatly improved.
  • the active ingredient is sorafenib tosylate.
  • sorafenib tosylate can be used as an active ingredient of an effective sorafenib drug in the pharmaceutical of sorafenib.
  • the polymeric co-solvent is polyvinylpyrrolidone vinyl acetate (PVP-VA).
  • PVP-VA has a VA group.
  • VA group is extremely critical for the supersaturation effect of PVP-VA.
  • PVP-VA with VA group significantly increases the supersaturation of sorafenib and improves the cable. Rafini's bioavailability.
  • the weight ratio of the sorafenib tosylate to the polyvinylpyrrolidone vinyl acetate is 1:0.1 to 10, and in one embodiment of the present invention, the sorafibrate toluenesulfonate
  • the weight ratio of nicotine to polyvinylpyrrolidone vinyl acetate is 1:3.
  • the weight ratio of sorafenib tosylate to polyvinylpyrrolidone vinyl acetate is 1:1.5.
  • the weight ratio of sorafenib tosylate to polyvinylpyrrolidone vinyl acetate is 1:1.1.
  • the concentration range of the above PVP-VA in the concentration range of the above PVP-VA, the supersaturation of sorafenib tosylate in the simulated intestinal fluid solution (FaSSIF) and the individual is greatly improved, and the bioavailability is greatly improved.
  • the sorafenib formulation further comprises sodium lauryl sulfate (SLS).
  • SLS sodium lauryl sulfate
  • the combination of PVP-VA and SLS can improve the solubility of sorafenib, and the bioavailability of sorafenib is significantly improved compared to the existing preparation.
  • the mass ratio of the active ingredient to the sodium lauryl sulfate is from 1:0.01 to 3. Root According to an embodiment of the present invention, the active ingredient is sorafenib tosylate, and the mass ratio of the sorafenib toluenesulfonate to the sodium lauryl sulfate is 1:0.01 to 3. In one embodiment of the present invention, the mass ratio of sorafenib tosylate to sodium lauryl sulfate is 1:1, and in another embodiment of the present invention, sorafenib tosylate and ten The mass ratio of sodium dialkyl sulfate is 1:0.3.
  • the mass ratio of sorafenib tosylate to sodium lauryl sulfate is 1:0.15.
  • the inventors have surprisingly found that in the presence of the co-solvent PVP-VA, the mass ratio of sorafenib tosylate to SLS is higher than 1:0.01 or lower than 1:3, the solubility of sorafenib toluenesulfonate The improvement is not significant.
  • the mass ratio of sorafenib tosylate to SLS in the range of 1:0.01 to 1:3, and the solubility of sorafenib tosylate is greatly increased. Improved, bioavailability is also significantly improved compared to existing formulations.
  • the sorafenib preparation is in an oral dosage form, including at least one of a capsule, a pill, a tablet, a granule, an oral liquid or an internal ointment, preferably, the sorafenib preparation In the form of a tablet.
  • the sorafenib preparation is in the form of an oral dosage form, and the bioavailability in the living body is greatly improved.
  • the sorafenib formulation further comprises a pharmaceutically acceptable excipient, optionally, the pharmaceutically acceptable excipient comprises microcrystalline cellulose, starch, croscarmellose At least one of sodium, hydroxypropylcellulose, hypromellose, sodium lauryl sulfate or magnesium stearate.
  • the sorafenib preparation is an oral tablet, which is convenient for the patient to take and improve the bioavailability of sorafenib, and improves the efficacy of the sorafenib preparation.
  • the invention provides a tablet comprising 137 parts by weight of sorafenib tosylate and 150 parts by weight of polyvinylpyrrolidone vinyl acetate according to an embodiment of the invention Ester; 500 parts by weight of microcrystalline cellulose; 65 parts by weight of croscarmellose sodium; and 20 parts by weight of sodium lauryl sulfate.
  • the dissolution rate of the above-mentioned tablet is remarkably improved, and the bioavailability of the active ingredient is remarkably improved as compared with the existing sorafenib preparation.
  • the invention provides a tablet comprising 137 parts by weight of sorafenib tosylate and 150 parts by weight of polyvinylpyrrolidone vinyl acetate according to an embodiment of the invention Ester; 520 parts by weight of microcrystalline cellulose; and 65 parts by weight of croscarmellose sodium.
  • the drug dissolution rate of the above tablet is rapidly and significantly increased, the drug supersaturation time is prolonged, and the bioavailability of the active ingredient is remarkably improved.
  • the invention provides a method of treating cancer.
  • the method comprises administering to the patient a sorafenib formulation as described above or a tablet as described above.
  • the dissolution rate of the sorafenib preparation or tablet described above in the patient is increased, and the availability of the active ingredient in the patient is significantly increased.
  • the dosage of the drug can be effectively reduced, thereby effectively reducing the toxic side effects, the food effect, and the pH effect, and improving patient compliance and therapeutic effectiveness.
  • the treatment of a cancer patient is safer and more effective than the prior art.
  • the above method for treating cancer may further comprise at least one of the following additional technical features:
  • the cancer comprises at least one selected from the group consisting of liver cancer, renal cell carcinoma, and thyroid cancer.
  • treatment includes cancer selected from at least one of liver cancer, renal cell cancer, and thyroid cancer, and the therapeutic effectiveness is further improved.
  • PVP-VA polyvinylpyrrolidone vinyl acetate copolymer
  • PVP polyvinylpyrrolidone
  • SLS sodium dodecyl sulfate
  • FIG. 2 is a graph showing the effect of PVP-VA and PVP on sorafenib supersaturation in a simulated intestinal fluid FaSSF (-initial supersaturation concentration, in accordance with one embodiment of the present invention; PVP-VA; PVP; No polymer compound);
  • FIG. 4 is a dissolution profile of Formulation A, Formulation B, and Formula C tablets in simulated intestinal fluid FaSSIF, in accordance with one embodiment of the present invention ( Prescription A tablets; Prescription B tablets; Prescription C tablets);
  • Figure 5 is a graph showing the pharmacokinetic profile of different sorafenib toluene formulations in dogs according to one embodiment of the present invention ( Prescription A tablets; Prescription B tablets; Prescription C tablets).
  • the bioavailability of the sorafenib preparation is relatively low, resulting in a relatively large oral dose of the preparation, and the long-term use of a large amount of the drug has obvious side effects.
  • the inventors have proposed a sorafenib preparation comprising a polymer cosolvent, which has high bioavailability.
  • the invention provides a sorafenib formulation, according to an embodiment of the invention, the sorafenib formulation comprises: an active ingredient selected from the group consisting of sorafenib, sora At least one of a non-salt salt, a sorafenib derivative or a prodrug thereof; and a polymer co-solvent having a vinyl acetate group (VA group).
  • an active ingredient selected from the group consisting of sorafenib, sora At least one of a non-salt salt, a sorafenib derivative or a prodrug thereof.
  • VA group vinyl acetate group
  • the compound which can form the pharmacologically active ingredient sorafenib can be used as the active ingredient of the sorafenib preparation in the present invention, and therefore the active ingredient of the sorafenib preparation in the present invention is selected from the group consisting of sorafenib, sorafenib salt, At least one of a sorafenib derivative or a prodrug thereof, but the above active ingredient is a low solubility compound, and a polymer cosolvent is required to increase supersaturation of the active ingredient in the liquid, thereby enhancing the active ingredient in the body.
  • the VA group can significantly increase the supersaturation of the active ingredient in the liquid, thereby effectively increasing the bioavailability of the active ingredient.
  • the weight ratio of the active ingredient to the polymer cosolvent is from 1:0.1 to 10.
  • the supersaturation of the active ingredient in the simulated intestinal fluid solution (FaSSIF) and the individual is greatly improved, and the bioavailability is greatly improved.
  • the active ingredient is sorafenib tosylate.
  • sorafenib tosylate can be used as an active ingredient of an effective sorafenib drug in the pharmaceutical of sorafenib.
  • the polymeric co-solvent is polyvinylpyrrolidone vinyl acetate (PVP-VA).
  • PVP-VA has a VA group.
  • the VA group of PVP-VA is related to the supersaturation parameter of sorafenib, and the VA group of PVP-VA can significantly increase the supersaturation parameter of sorafenib, prolonging the sorafenib Supersaturation reduces the decrease in sorafenib supersaturation, so that the VP group of PVP-VA significantly increases the degree of supersaturation of sorafenib and improves the bioavailability of sorafenib.
  • the weight ratio of sorafenib tosylate to polyvinylpyrrolidone vinyl acetate is 1:0.1 to 10, and in one embodiment of the present invention, sorafenib toluene and polyethylene
  • the weight ratio of pyrrolidone vinyl acetate is 1:3.
  • the weight ratio of sorafenib tosylate to polyvinylpyrrolidone vinyl acetate is 1:1.5, in yet another embodiment of the present invention.
  • the weight ratio of sorafenib tosylate to polyvinylpyrrolidone vinyl acetate was 1:1.1.
  • Patient compliance According to the embodiment of the present invention, in the concentration range of the above PVP-VA, the supersaturation of sorafenib toluenesulfonate in the simulated intestinal fluid solution Fassif and the individual is greatly improved, and the bioavailability is greatly improved.
  • the sorafenib formulation further comprises sodium lauryl sulfate (SLS).
  • SLS sodium lauryl sulfate
  • the combination of PVP-VA and SLS can improve the solubility of sorafenib, and the bioavailability of sorafenib is significantly improved compared to the existing preparation.
  • the mass ratio of the active ingredient to the sodium lauryl sulfate is 1:0.01 to 3, wherein the active ingredient is sorafenib toluenesulfonate.
  • the mass ratio of the sorafenib tosylate to the sodium lauryl sulfate is 1:0.01 to 3.
  • the mass ratio of sorafenib tosylate to sodium lauryl sulfate is 1:1, and in another embodiment of the invention, sorafenib tosylate and ten
  • the mass ratio of sodium dialkyl sulfate is 1:0.3.
  • the mass ratio of sorafenib tosylate to sodium lauryl sulfate is 1:0.15.
  • the inventors have surprisingly found that in the presence of the co-solvent PVP-VA, the mass ratio of sorafenib tosylate to SLS is higher than 1:0.01 or lower than 1:3, the solubility of sorafenib toluenesulfonate The improvement is not significant.
  • the mass ratio of sorafenib tosylate to SLS in the range of 1:0.01 to 1:3, and the solubility of sorafenib tosylate is short. The rapid increase in time and the bioavailability are also significantly improved compared to the existing formulations.
  • the inventors have found that in a mixed system of PVP-VA and SLS, the VP of PVP-VA The hydrophobic interaction of the group is strong and the interaction with SLS is strong.
  • the VA group and the hydrophobic tail of SLS are the main sites of action of sorafenib.
  • the above findings may be the reason why PVP-VA-SLS can significantly increase the solubility of sorafenib.
  • the synergistic effect of PVP-VA and SLS makes the solubility of sorafenib increase rapidly and in a short time, and the bioavailability is also significantly improved compared with the existing preparation.
  • the sorafenib preparation is an oral dosage form comprising at least one of a capsule, a pill, a tablet, a granule, an oral liquid or an internal ointment, and preferably, the sorafenib preparation is a tablet.
  • the sorafenib preparation is in the form of an oral dosage form, and the bioavailability in the living body is greatly improved.
  • the sorafenib formulation further comprises a pharmaceutically acceptable adjuvant
  • the pharmaceutically acceptable adjuvant comprises microcrystalline cellulose, starch, croscarmellose fiber At least one of sodium, hydroxypropylcellulose, hypromellose, sodium lauryl sulfate or magnesium stearate.
  • the sorafenib preparation is an oral tablet, which is convenient for the patient to take and improve the bioavailability of sorafenib, and improves the efficacy of the sorafenib preparation.
  • the invention provides a tablet comprising, according to an embodiment of the invention, (1) 137 parts by weight of sorafenib tosylate, 150 parts by weight of polyvinylpyrrolidone Vinyl acetate, 500 parts by weight of microcrystalline cellulose, 65 parts by weight of croscarmellose sodium, and 20 parts by weight of sodium lauryl sulfate; or (2) 137 parts by weight of toluenesulfonic acid Lafini, 150 parts by weight of polyvinylpyrrolidone vinyl acetate, 520 parts by weight of microcrystalline cellulose, and 65 parts by weight of croscarmellose sodium.
  • the dissolution rate of the tablet of the above formula in the solvent is greatly increased, the tablet of the formula 2 is rapidly dissolved in the dissolution medium and reaches the supersaturated platform, and the supersaturation of the drug after the platform is lowered slowly, the formula 1 tablet It rapidly dissolves in the dissolution medium and reaches a peak, and the dissolution rate of the above-mentioned tablets is also greatly improved compared with the existing preparation, and the bioavailability is correspondingly increased.
  • the invention provides a method of treating cancer.
  • the method comprises administering to the patient a sorafenib formulation as described above or a tablet as described above.
  • the inventors have experimentally verified that the dissolution rate of the above-mentioned sorafenib preparation or tablet in the patient is increased, and the availability of the active ingredient in the patient is remarkably improved.
  • the amount of the sorafenib preparation described above or the tablet described above can be effectively reduced, thereby effectively reducing the toxic side effects, food effects and pH effects of the drug, and improving patient compliance. Sex and therapeutic effectiveness.
  • the treatment of a cancer patient is safer and more effective than the prior art.
  • the cancer comprises at least one selected from the group consisting of liver cancer, renal cell carcinoma and thyroid cancer.
  • Sorafenib can effectively inhibit the target sites of liver cancer, renal cell carcinoma and thyroid cancer tumor cells CRAF, BRAF, V600EBRAF, c-Kit, FLT-3 and CRAF, VEGFR of vascular target sites of liver cancer, renal cell carcinoma and thyroid cancer -2, VEGFR-3, PDGFR- ⁇ .
  • RAF kinase is a serine/threonine kinase
  • c-Kit, FLT-3, VEGFR-2, VEGFR-3, and PDGFR- ⁇ are tyrosine kinases that act on liver cancer, renal cell carcinoma, and thyroid cancer tumor cells.
  • the signaling pathway, angiogenesis and apoptosis, sorafenib has significant inhibition of liver cancer, renal cell carcinoma and thyroid cancer tumor cell proliferation and anti-angiogenesis.
  • treatment includes cancer selected from at least one of liver cancer, renal cell cancer, and thyroid cancer, and the therapeutic effectiveness is further improved.
  • the term "administering" as used herein refers to introducing a predetermined amount of a substance into a patient in some suitable manner.
  • the sorafenib formulation or tablet of the present invention can be administered by any conventional route as long as it can reach the intended tissue.
  • the sorafenib formulation or tablet of the invention can be administered orally.
  • the sorafenib preparation or tablet of the present invention can be administered using a specific device that delivers the active ingredient to the target cells.
  • the frequency and dose of the sorafenib formulation or tablet of the present invention can be determined by a number of relevant factors including the type of disease to be treated, the route of administration, the age of the patient, the sex, the weight, and the severity of the disease.
  • the degree and type of drug as the active ingredient may be divided into 1 dose, 2 doses or multiple doses in a suitable form for administration once, twice or more times throughout the time period, as long as a therapeutically effective amount is achieved. .
  • terapéuticaally effective amount means an amount of a sorafenib formulation or tablet sufficient to significantly ameliorate certain symptoms associated with a disease or condition, that is, an amount that provides a therapeutic effect for a given condition and dosage regimen.
  • a drug that reduces, prevents, delays, inhibits, or blocks any symptoms of a disease or condition should be therapeutically effective.
  • a therapeutically effective amount of a drug does not require a cure for the disease or condition, but will provide a treatment for the disease or condition such that the onset of the disease or condition of the individual is delayed, prevented or prevented, or the symptoms of the disease or condition are alleviated, or the disease or condition The period is changed, or for example, the disease or condition becomes less severe, or the recovery is accelerated.
  • treatment is used to mean obtaining the desired pharmacological and/or physiological effect.
  • the effect may be prophylactic in terms of completely or partially preventing the disease or its symptoms, and/or may be therapeutic in terms of partially or completely curing the disease and/or the adverse effects caused by the disease.
  • treatment encompasses the treatment of diseases in mammals, particularly humans (mainly inoperable liver cancer, renal cell carcinoma, and thyroid cancer), including: (a) inhibiting the disease, such as arresting disease progression; or (b) Relieve diseases, such as alleviating symptoms associated with the disease.
  • treatment encompasses any administration of a medicament to a subject to treat, cure, ameliorate, ameliorate, ameliorate or inhibit the disease of the individual, including but not limited to the administration of a sorafenib formulation or tablet as described herein. Individual.
  • the sorafenib formulation or tablet of the invention may be used in combination with conventional methods of treatment and/or therapy, or may be used separately from conventional methods of treatment and/or therapy.
  • sorafenib preparations or tablets of the present invention are administered in combination therapy with other drugs, they can be administered to the individual sequentially or simultaneously.
  • other therapeutic or prophylactic combinations known in the art can be included.
  • Sorafenib tosylate used in the examples of the present invention is provided by Qilu Pharmaceutical Co., Ltd. (Shandong, China); polyvinylpyrrolidone PVP (Kollidon 30) and polyvinylpyrrolidone vinyl acetate PVP-VA (Kollidon VA64) Presented by BASF Chemical Reagent Company of Germany. All salts used to dissolve the solution and methanol for spray drying (analytical grade) were supplied by Beijing Chemical Plant. The chemical structures and key features of the complexes and compounds mentioned in the present invention are shown in Figure 1.
  • the polymer compound PVP-VA or PVP was dissolved in the simulated intestinal fluid FaSSIF at a concentration of 0.3 and 3 mg/mL, toluenesulfonic acid.
  • Sorafenib was dissolved in DMSO at a concentration of 100 or 20 mg/mL.
  • 100 ⁇ l of the sorafenib drug solution was added to 10 mL of the polymer compound solution.
  • the resulting mixture solution was shaken and dissolved on an oscillator (brand: Tianjin Uno, model: WE-2), the oscillation speed was 100 rpm, and the temperature was 37 degrees Celsius. After 0.3, 1, 2 and 4 hours, the solution was centrifuged on a 15,000 rpm centrifuge for 3 min, and the concentration of the drug in the supernatant was analyzed by high performance liquid chromatography (HPLC) (brand: Shimadzu LC-20AT; origin: Kyoto, Japan).
  • HPLC high performance liquid chromatography
  • the solubility of the crystalline drug in FaSSIF was examined in this example.
  • the procedure was as follows: Excess crystalline drug was resuspended in FaSSIF solution, then vortexed for 1 min, sonicated for 15 min, and lysed for 24 hours. Thereafter, the suspension was centrifuged at a centrifugal speed of 15,000 rpm for 3 minutes, and the concentration of the supernatant was measured by HPLC/UV detection.
  • the supersaturation parameter (for definition of supersaturation parameters, see Yuejie Chen, et cl. Mol. Pharmaceutics. 2015, 12, 576-589) is between 0-1, which is used to characterize the maintenance of polymer compounds.
  • the ability to saturate The closer the value is to 1, the stronger the ability to maintain supersaturation or the weaker the ability to maintain supersaturation.
  • Figure 2 (ordinate drug concentration is the concentration of sorafenib) shows that in FaSSIF, regardless of whether the concentration of PVP is high or low, the effect of PVP in maintaining sorafenib supersaturation is not significant.
  • the results show that after joining PVP In FaSSIF, the supersaturation parameter of sorafenib is very low and does not increase with increasing concentration of polymer compounds.
  • PVP-VA PVP-VA has great potential to maintain the supersaturation of sorafenib in FaSSIF, because the supersaturation parameters of sorafenib are very large and with PVP- under the conditions of PVP-VA.
  • the VA concentration increases significantly.
  • the main difference between PVP-VA and PVP is the VA group, so the inventors can conclude that the main mechanism for maintaining sorafenib supersaturation is related to the VA group of PVP-VA.
  • the inventors examined the effects of PVP-VA, PVP-VA+SLS, PVP, PVP+SLS, and SLS on the dissolution behavior of sorafenib.
  • the results of the study are shown in Figure 3 (the concentration of sorafenib on the ordinate indicates the concentration of sorafenib).
  • the solubility of sorafenib in FaSSIF is 3.3 ⁇ g/mL.
  • the concentration of SLS is increased to 3 mg/mL alone, the solubility of sorafenib can be It reached 29.4 ⁇ g/mL.
  • sorafenib solubility was only 43.3 ⁇ g/mL.
  • PVP-VA and PVP are mainly due to the difference of VA groups, so it can be explained that the VA group is critical for the synergistic solubilization of sorafenib in the polymer and SLS mixed system.
  • composition A B C Sorafenib tosylate 137 137 137 PVP-VA 150 150 -- MCC 500 520 650 CCNa 65 65 65 65 SLS 20 -- 20 Total weight 872 872 872
  • Sorafenib tosylate and microcrystalline cellulose (MCC), croscarmellose sodium (CCNa), PVP-VA, and the like were uniformly mixed, and compressed into tablets under a pressure of 400 kgf.
  • the dissolution conditions of USPII were as follows, dissolution medium: 300 ml FaSSIF; rotation speed: 75 rpm; temperature: 37 °C.
  • a sample of 0.5 mL was sampled at a predetermined time point and filtered through a 0.45 micron syringe filter membrane, and the filtrate was appropriately diluted with methanol to analyze the drug content by HPLC/UV.
  • the inventors evaluated the bioavailability of the three tablets shown in Table 2 in dogs.
  • the interaction sites of PVP-VA and sorafenib were mainly VA groups by infrared spectroscopy; NOESY experiments, 1D 13 C NMR experiments and fluorescence spectroscopy experiments showed that in the mixed system of SLS and PVP-VA, SLS and VA group interaction of PVP-VA; 1D 13 C NMR chromatographic results show that in the mixed system of sorafenib, SLS and PVP-VA, VA group and SLS hydrophobic tail are the main of sorafenib The site of action.
  • the inventors believe that the VA group is a key factor for improving the supersaturation and solubility of sorafenib.
  • the introduction of a VA group in a sorafenib formulation can significantly increase the supersaturation of sorafenib; the interaction between the VA group and SLS and sorafenib can significantly increase the solubility of sorafenib, thereby Compared with the existing preparations, the bioavailability of sorafenib can be significantly improved by adding PVP-VA alone or simultaneously with PVP-VA and SLS.

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Abstract

本发明提出了一种索拉非尼制剂，该索拉非尼制剂包含活性成份和高分子助溶剂，所述活性成份为选自索拉非尼、索拉非尼盐、索拉非尼衍生物或其前药的至少一种，所述高分子助溶剂具有乙酸乙烯酯基团。

Description

提高索拉非尼生物利用度的制剂
优先权信息
本申请请求2015年09月30日向中国国家知识产权局提交的、专利申请号为201510641732.3的专利申请的优先权和权益，并且通过参照将其全文并入此处。
技术领域
本发明涉及生物医药领域，具体地，本发明涉及一种提高索拉非尼生物利用度的制剂。
背景技术
索拉非尼是治疗不能手术的肝癌，肾细胞癌，以及甲状腺癌的酪氨酸激酶抑制剂。索拉非尼抑制肿瘤细胞的靶部位CRAF、BRAF、V600EBRAF、c-Kit、FLT-3和肿瘤血管靶部位的CRAF、VEGFR-2、VEGFR-3、PDGFR-β。RAF激酶是丝氨酸/苏氨酸激酶，而c-Kit、FLT-3、VEGFR-2、VEGFR-3、PDGFR-β为络氨酸激酶，这些激酶作用于肿瘤细胞信号通路、血管生成和凋亡，因此，索拉非尼具有抑制肿瘤细胞增殖和抵抗血管生成作用。
目前，药剂领域用来提高药物生物利用度的常用方法有以下这些：成盐，降低药物粒径，采用非水性溶剂/共溶剂，制备成乳剂或自微乳剂，环糊精包合，采用热力学不稳定的晶型或制备成固体分散体等。
然而，索拉非尼制剂的药物组成还有待进一步研究。
发明内容
本发明旨在至少在一定程度上解决相关技术中的技术问题之一。
本发明是基于发明人下列问题的发现而完成的：
目前上市的索拉非尼制剂相比口服溶液剂生物利用度为38％-49％，生物利用度比较低，另外该制剂口服剂量比较大，为400mg/次，每日2次。长期大量服用该药物副作用比较明显，所以如何提高索拉非尼制剂的生物利用度、从而降低其剂量，降低毒副作用、食物效应以及pH效应，提高病人顺应性和治疗有效性变得非常重要。
对于索拉非尼这样一个剂量极大，在油性溶剂中溶解度有限的药物，提高其生物利用度的最可行的技术手段为非晶固体分散体。但是在实际实验中，发明人发现：由于索拉非尼具有热不稳定性，所以不能采用热熔挤出来制备；而且在常用可喷雾干燥用溶剂中其溶解度也有限所以采用喷雾干燥来制备也不容易，因此制备其固体分散体工业化生产将存在困难。另外由于固体分散体本身属于高能态，其在存储中容易发生老化从而影响稳定性，从 而给生产以及质量监管增加难度，因此制备固体分散体不是一个最佳选择。
基于上述问题，发明人提出了一种包含高分子助溶剂的索拉非尼制剂，该制剂不仅相比于模拟上市制剂较大幅度提高了索拉非尼的生物利用度，而且具有工业化生产方便，药物稳定、可靠等诸多优点。
在本发明的第一方面，本发明提出了一种索拉非尼制剂，根据本发明的实施例，该索拉非尼制剂包含：活性成份，所述活性成份为选自索拉非尼、索拉非尼盐、索拉非尼衍生物或其前药的至少一种；以及高分子助溶剂(在本发明中，有时也称为高分子化合物)，所述高分子助溶剂具有乙酸乙烯酯基团(VA基团)。根据本发明的实施例，活性成份是低溶解度的化合物，加入的高分子助溶剂能够提高活性成份在溶出介质中的过饱和程度，VA基团对于高分子化合物维持活性成份的过饱和异常关键，VA基团能够显著提高活性成份的过饱和度，从而能够有效提高活性成份的生物利用度。
根据本发明的实施例，上述索拉非尼制剂还进一步包括下列附加技术特征至少之一：
根据本发明的实施例，所述活性成份与所述高分子助溶剂的重量比是1：0.1～10。根据本发明的实施例，在上述高分子助溶剂的浓度范围内，活性成份在模拟肠液溶液(FaSSIF)和个体中的过饱和度大幅提高，生物利用度大幅提高。
根据本发明的实施例，所述活性成份是甲苯磺酸索拉非尼。根据本发明的实施例，甲苯磺酸索拉非尼可以作为有效的索拉非尼药物的活性成份，被用在索拉非尼的制药中。
根据本发明的实施例，所述高分子助溶剂是聚乙烯吡咯烷酮乙酸乙烯酯(PVP-VA)。PVP-VA具有VA基团，如前所述，VA基团对于PVP-VA的过饱和效应异常关键，具有VA基团的PVP-VA显著增加了索拉非尼的过饱和度，提高了索拉非尼的生物利用率。
根据本发明的实施例，所述甲苯磺酸索拉非尼与所述聚乙烯吡咯烷酮乙酸乙烯酯的重量比是1：0.1～10，在本发明的一个实施例中，甲苯磺酸索拉非尼与聚乙烯吡咯烷酮乙酸乙烯酯的重量比是1：3，在本发明的另外一个实施例中，甲苯磺酸索拉非尼与聚乙烯吡咯烷酮乙酸乙烯酯的重量比是1：1.5，在本发明的再一个实施例中，甲苯磺酸索拉非尼与聚乙烯吡咯烷酮乙酸乙烯酯的重量比1：1.1。发明人发现，甲苯磺酸索拉非尼与PVP-VA的质量比高于1：0.1，PVP-VA过饱和效果不显著，重量比低于1：10，从制剂角度难以实施，无法满足病人顺应性。根据本发明的实施例，在上述PVP-VA的浓度范围内，甲苯磺酸索拉非尼在模拟肠液溶液(FaSSIF)和个体中的过饱和度大幅提高，生物利用度大幅提高。
根据本发明的实施例，所述索拉非尼制剂进一步包括十二烷基硫酸钠(SLS)。根据本发明的实施例，PVP-VA与SLS联用可以提高索拉非尼的溶解度，索拉非尼药物的生物利用度与现有制剂相比显著提高。
根据本发明的实施例，所述活性成份与所述十二烷基硫酸钠的质量比是1：0.01～3。根 据本发明的实施例，所述活性成份是甲苯磺酸索拉非尼，所述甲苯磺酸索拉非尼与所述十二烷基硫酸钠的质量比是1：0.01～3。在本发明的一个实施例中，甲苯磺酸索拉非尼与十二烷基硫酸钠的质量比是1：1，在本发明的另外一个实施例中，甲苯磺酸索拉非尼与十二烷基硫酸钠的质量比是1：0.3，在本发明的再一个实施例中，甲苯磺酸索拉非尼与十二烷基硫酸钠的质量比是1：0.15。发明人惊奇的发现，在助溶剂PVP-VA存在的条件下，甲苯磺酸索拉非尼与SLS的质量比高于1：0.01或低于1：3，甲苯磺酸索拉非尼溶解度的提高不显著。根据本发明的实施例，在PVP-VA存在的条件下，甲苯磺酸索拉非尼与SLS的质量比在1：0.01～1：3范围内，甲苯磺酸索拉非尼的溶解度有大幅提高，生物利用度与现有制剂相比也显著提高。
根据本发明的实施例，所述索拉非尼制剂呈口服剂型，包括胶囊剂、丸剂、片剂、颗粒剂、口服液体或内服膏剂的至少一种，优选地，所述索拉非尼制剂呈片剂。所述索拉非尼制剂以口服剂型形式存在，在生物体内的生物利用度大幅提高。
根据本发明的实施例，所述索拉非尼制剂进一步包括药物上可接受的辅料，任选地，所述药物上可接受的辅料包括微晶纤维素、淀粉、交联羧甲基纤维素钠、羟丙基纤维素、羟丙甲纤维素、十二烷基硫酸钠或硬脂酸镁的至少一种。在上述辅料的存在下，所述索拉非尼制剂呈口服片剂，方便患者的服用和提高索拉非尼的生物利用度，提高所述索拉非尼制剂的药效。
在本发明的第二方面，本发明提出了一种片剂，根据本发明的实施例，所述片剂含有137重量份的甲苯磺酸索拉非尼；150重量份的聚乙烯吡咯烷酮乙酸乙烯酯；500重量份的微晶纤维素；65重量份的交联羧甲基纤维素钠；以及20重量份的十二烷基硫酸钠。根据本发明的实施例，上述片剂的溶出速率显著提高，在体活性成份的生物利用度与现有索拉非尼制剂相比显著提高。
在本发明的第三方面，本发明提出了一种片剂，根据本发明的实施例，所述片剂含有137重量份的甲苯磺酸索拉非尼；150重量份的聚乙烯吡咯烷酮乙酸乙烯酯；520重量份的微晶纤维素；以及65重量份的交联羧甲基纤维素钠。根据本发明的实施例，上述片剂的药物溶出速率快速并显著提高，药物过饱和时间延长，在体活性成份的生物利用度显著提高。
在本发明的第四方面，本发明提出了一种治疗癌症的方法。根据本发明的实施例，所述方法包括：为患者给药前面所述的索拉非尼制剂或前面所述的片剂。前面所述的索拉非尼制剂或片剂在患者体内的溶出速率提高，活性成份在患者体内的利用度显著提高。利用根据本发明实施例的治疗癌症的方法，可有效降低药物的用量，从而有效降低药物毒副作用、食物效应以及pH效应，提高病人顺应性和治疗有效性。利用根据本发明实施例的治疗癌症的方法，相比于现有技术，对癌症患者的治疗更加安全，效果更加显著。
根据本发明的实施例，上述治疗癌症的方法还可以进一步包括如下附加技术特征至少之一：
根据本发明的实施例，所述癌症包括选自肝癌、肾细胞癌和甲状腺癌的至少之一。利用根据本发明实施例的治疗癌症的方法，治疗包括选自肝癌、肾细胞癌和甲状腺癌的至少之一的癌症，治疗有效性进一步提高。
附图说明
图1是根据本发明实施例的甲苯磺酸索拉非尼，聚乙烯吡咯烷酮醋酸乙烯酯共聚物(PVP-VA)，聚乙烯吡咯烷酮(PVP)以及十二烷基硫酸钠(SLS)结构式；
图2是根据本发明一个实施例的模拟肠液FaSSF中PVP-VA以及PVP对索拉非尼过饱和的影响(-初始过饱和浓度；
Figure PCTCN2016100651-appb-000001
PVP-VA；
Figure PCTCN2016100651-appb-000002
PVP；
Figure PCTCN2016100651-appb-000003
没有高分子化合物)；
图3是根据本发明一个实施例的索拉非尼在PVP-VA-SLS以及PVP-SLS FaSSIF中溶解度；
图4是根据本发明一个实施例的处方A，处方B以及处方C片剂在模拟肠液FaSSIF中溶出曲线(
Figure PCTCN2016100651-appb-000004
处方A片剂；
Figure PCTCN2016100651-appb-000005
处方B片剂；
Figure PCTCN2016100651-appb-000006
处方C片剂)；以及
图5是根据本发明一个实施例的不同甲苯磺酸索拉非尼药物配方在狗体内药代动力学曲线结果(
Figure PCTCN2016100651-appb-000007
处方A片剂；
Figure PCTCN2016100651-appb-000008
处方B片剂；
Figure PCTCN2016100651-appb-000009
处方C片剂)。
具体实施方式
本发明是基于发明人的下列发现而完成的：
索拉非尼制剂的生物利用度比较低，从而导致该制剂口服剂量比较大，长期服用大量该药物副作用明显。在本发明中，发明人提出了一种包含高分子助溶剂的索拉非尼制剂，该索拉非尼制剂生物利用度高。
索拉非尼制剂
在本发明的一方面，本发明提出了一种索拉非尼制剂，根据本发明的是实施例，该索拉非尼制剂包含：活性成份，活性成份为选自索拉非尼、索拉非尼盐、索拉非尼衍生物或其前药的至少一种；以及高分子助溶剂，高分子助溶剂具有乙酸乙烯酯基团(VA基团)。可以形成药理活性成份索拉非尼的化合物均可以作为本发明中索拉非尼制剂活性成份，因此本发明中索拉非尼制剂的活性成分选自索拉非尼、索拉非尼盐、索拉非尼衍生物或其前药的至少一种，但上述活性成份是低溶解度的化合物，需要加入高分子助溶剂以能够提高活性成份在液体中的过饱和，从而提高活性成份在体的生物利用度，VA基团可显著提高活性成份在液体中的过饱和度，从而能够有效提高活性成份的生物利用度。
根据本发明的实施例，所述活性成份与所述高分子助溶剂的重量比是1：0.1～10。根据本发明的实施例，在上述高分子助溶剂的浓度范围内，活性成份在模拟肠液溶液(FaSSIF)和个体中的过饱和度大幅提高，生物利用度大幅提高。
根据本发明的实施例，活性成份是甲苯磺酸索拉非尼。根据本发明的实施例，甲苯磺酸索拉非尼可以作为有效的索拉非尼药物的活性成份，被用在索拉非尼的制药中。
根据本发明的实施例，高分子助溶剂是聚乙烯吡咯烷酮乙酸乙烯酯(PVP-VA)。PVP-VA具有VA基团。根据本发明的实施例，PVP-VA的VA基团与索拉非尼的过饱和参数相关，PVP-VA的VA基团能够显著提高索拉非尼的过饱和参数，延长索拉非尼的过饱和，减缓索拉非尼过饱和的下降，从而PVP-VA的VA基团显著增加了索拉非尼的过饱和程度，提高了索拉非尼的生物利用率。
根据本发明的实施例，甲苯磺酸索拉非尼与聚乙烯吡咯烷酮乙酸乙烯酯的重量比是1：0.1～10，在本发明的一个实施例中，甲苯磺酸索拉非尼与聚乙烯吡咯烷酮乙酸乙烯酯的重量比是1：3，在本发明的另外一个实施例中，甲苯磺酸索拉非尼与聚乙烯吡咯烷酮乙酸乙烯酯的重量比是1：1.5，在本发明的再一个实施例中，甲苯磺酸索拉非尼与聚乙烯吡咯烷酮乙酸乙烯酯的重量比是1：1.1。发明人发现，甲苯磺酸索拉非尼与PVP-VA的质量比高于1：0.1，索拉非尼过饱和效果不显著，重量比低于1：10，从制剂角度难以实施，无法满足病人顺应性。据本发明的实施例，在上述PVP-VA的浓度范围内，甲苯磺酸索拉非尼在模拟肠液溶液Fassif和个体中的过饱和大幅提高，生物利用度大幅提高。
根据本发明的实施例，所述索拉非尼制剂进一步包括十二烷基硫酸钠(SLS)。根据本发明的实施例，PVP-VA与SLS联用可以提高索拉非尼的溶解度，索拉非尼药物的生物利用度与现有制剂相比显著提高。
根据本发明的实施例，所述活性成份与所述十二烷基硫酸钠的质量比是1：0.01～3，其中所述活性成份是甲苯磺酸索拉非尼。根据本发明的实施例，所述甲苯磺酸索拉非尼与所述十二烷基硫酸钠的质量比是1：0.01～3。在本发明的一个实施例中，甲苯磺酸索拉非尼与十二烷基硫酸钠的质量比是1：1，在本发明的另一个实施例中，甲苯磺酸索拉非尼与十二烷基硫酸钠的质量比是1：0.3，在本发明的再一个实施例中，甲苯磺酸索拉非尼与十二烷基硫酸钠的质量比是1：0.15。发明人惊奇的发现，在助溶剂PVP-VA存在的条件下，甲苯磺酸索拉非尼与SLS的质量比高于1：0.01或低于1：3，甲苯磺酸索拉非尼溶解度的提高不显著。根据本发明的实施例，在PVP-VA存在的条件下，甲苯磺酸索拉非尼与SLS的质量比在1：0.01～1：3范围内，甲苯磺酸索拉非尼的溶解度在短时间内快速大幅提高，生物利用度与现有制剂相比也显著提高。
根据本发明的实施例，发明人发现，在PVP-VA和SLS的混合体系中，PVP-VA的VA 基团的疏水作用力强，和SLS相互作用力强；在索拉非尼、PVP-VA、SLS的混合体系中，VA基团和SLS疏水尾端是索拉非尼的主要的作用位点。上述发现可能是PVP-VA-SLS能够显著增加索拉非尼溶解度的原因。PVP-VA与SLS的协同作用，使得索拉非尼的溶解度在短时间内快速大幅提高，生物利用度与现有制剂相比也显著提高。
根据本发明的实施例，索拉非尼制剂为口服剂型，包括胶囊剂、丸剂、片剂、颗粒剂、口服液体或内服膏剂的至少一种，优选地，索拉非尼制剂呈片剂。索拉非尼制剂以口服剂型形式存在，在生物体内的生物利用度大幅提高。
根据本发明的实施例，索拉非尼制剂进一步包括药学上可接受的辅料，在本发明的一些实施例中，药学上可接受的辅料包括微晶纤维素、淀粉、交联羧甲基纤维素钠，羟丙基纤维素、羟丙甲纤维素、十二烷基硫酸钠或硬脂酸镁的至少一种。在上述辅料的存在下，索拉非尼制剂呈口服片剂，方便患者的服用和提高索拉非尼的生物利用度，提高索拉非尼制剂的药效。
片剂
在本发明的另一方面，本发明提出了一种片剂，根据本发明的实施例，片剂包含：(1)137重量份的甲苯磺酸索拉非尼，150重量份的聚乙烯吡咯烷酮乙酸乙烯酯，500重量份的微晶纤维素，65重量份的交联羧甲基纤维素钠，以及20重量份的十二烷基硫酸钠；或(2)137重量份的甲苯磺酸索拉非尼，150重量份的聚乙烯吡咯烷酮乙酸乙烯酯，520重量份的微晶纤维素，65重量份的交联羧甲基纤维素钠。根据本发明的实施例，上述配方的片剂在溶剂中的溶出速率大幅提高，配方2片剂在溶出介质中快速溶解并达到过饱和平台，平台后药物的过饱和降低缓慢，配方1片剂在溶出介质中快速溶出并达到峰值，同时上述片剂在体溶出速率与现有制剂相比也大幅提高，生物利用度也相应大幅提高。
治疗癌症的方法
在本发明的再一方面，本发明提出了一种治疗癌症的方法。根据本发明的实施例，所述方法包括：为患者给药前面所述的索拉非尼制剂或前面所述的片剂。发明人通过实验验证，前面所述的索拉非尼制剂或片剂在患者体内的溶出速率提高，活性成份在患者体内的利用度显著提高。利用根据本发明实施例的治疗癌症的方法，可有效降低前面所述的索拉非尼制剂或前面所述的片剂的用量，从而有效降低药物毒副作用、食物效应以及pH效应，提高病人顺应性和治疗有效性。利用根据本发明实施例的治疗癌症的方法，相比于现有技术，对癌症患者的治疗更加安全，效果更加显著。
根据本发明的具体实施例，所述癌症包括选自肝癌、肾细胞癌和甲状腺癌的至少之一。索拉非尼可有效抑制肝癌、肾细胞癌和甲状腺癌肿瘤细胞的靶部位CRAF、BRAF、V600EBRAF、c-Kit、FLT-3和肝癌、肾细胞癌和甲状腺癌肿瘤血管靶部位的CRAF、VEGFR-2、 VEGFR-3、PDGFR-β。RAF激酶是丝氨酸/苏氨酸激酶，而c-Kit、FLT-3、VEGFR-2、VEGFR-3、PDGFR-β为络氨酸激酶，这些激酶作用于肝癌、肾细胞癌和甲状腺癌肿瘤细胞的信号通路、血管生成和凋亡，索拉非尼具有显著的抑制肝癌、肾细胞癌和甲状腺癌肿瘤细胞增殖和抵抗血管生成作用。利用根据本发明实施例的治疗癌症的方法，治疗包括选自肝癌、肾细胞癌和甲状腺癌的至少之一的癌症，治疗有效性进一步提高。
在本文中所使用的术语“给药”指将预定量的物质通过某种适合的方式引入病人。本发明的索拉非尼制剂或片剂可以通过任何常见的途径被给药，只要它可以到达预期的组织。优选地，本发明的索拉非尼制剂或片剂可以口服被给药。此外，本发明的索拉非尼制剂或片剂可以使用将活性成分传送到靶细胞的特定器械来给药。
本发明的索拉非尼制剂或片剂的给药频率和剂量可以通过多个相关因素被确定，该因素包括要被治疗的疾病类型，给药途径，病人年龄，性别，体重和疾病的严重程度以及作为活性成分的药物类型。根据本发明的一些实施例，日剂量可分为适宜形式的1剂、2剂或多剂，以在整个时间段内以1次、2次或多次给药，只要达到治疗有效量即可。
术语“治疗有效量”是指索拉非尼制剂或片剂足以显著改善某些与疾病或病症相关的症状的量，也即为给定病症和给药方案提供治疗效果的量。例如，在不能手术的肝癌、肾细胞癌和甲状腺癌的治疗中，减少、预防、延缓、抑制或阻滞疾病或病症的任何症状的药物应当是治疗有效的。治疗有效量的药物不需要治愈疾病或病症，但将为疾病或病症提供治疗，使得个体的疾病或病症的发作被延缓、阻止或预防，或者疾病或病症的症状得以缓解，或者疾病或病症的期限被改变，或者例如疾病或病症变得不严重，或者加速康复。
术语“治疗”用于指获得期望的药理学和/或生理学效果。所述效果就完全或部分预防疾病或其症状而言可以是预防性的，和/或就部分或完全治愈疾病和/或疾病导致的不良作用而言可以是治疗性的。本文使用的“治疗”涵盖哺乳动物、特别是人的疾病(主要指不能手术的肝癌，肾细胞癌以及甲状腺癌)的治疗，包括：(a)抑制疾病，例如阻滞疾病发展；或(b)缓解疾病，例如减轻与疾病相关的症状。本文使用的“治疗”涵盖将药物给予个体以治疗、治愈、缓解、改善、减轻或抑制个体的疾病的任何用药，包括但不限于将含本文所述索拉非尼制剂或片剂给予有需要的个体。
根据本发明的具体实施例，本发明的索拉非尼制剂或片剂可与常规治疗方法和/或疗法相结合使用，或者可与常规治疗方法和/或疗法分开使用。当本发明的索拉非尼制剂或片剂在采用与其它药物的联合疗法中给药时，它们可序贯地或同时地给予个体。或者，可包括本领域已知的其它治疗药或预防药的组合。
下面详细描述本发明的实施例。下面描述的实施例是示例性的，仅用于解释本发明，而不能理解为对本发明的限制。实施例中未注明具体技术或条件的，按照本领域内的文献所 描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
实施例1材料
本发明的实施例中用到的甲苯磺酸索拉非尼由齐鲁制药有限公司提供(中国山东)；聚乙烯吡咯烷酮PVP(Kollidon 30)和聚乙烯吡咯烷酮乙酸乙烯酯PVP-VA(Kollidon VA64)由德国BASF化学试剂公司赠送。所有用于溶解溶液的盐、用于喷雾干燥的甲醇(分析纯)均由北京化工厂提供。本发明中所提到的复合物和化合物的化学结构和关键特征由图1所示。
实施例2PVP-VA和PVP对索拉非尼在FaSSIF中过饱和的影响
本发明的实施例中，发明人为了评价化合物对保持索拉非尼过饱和状态的影响，高分子化合物PVP-VA或PVP以0.3和3mg/mL的浓度溶解在模拟肠液FaSSIF中，甲苯磺酸索拉非尼以100或20mg/mL的浓度溶解在DMSO中。在溶出介质中，100微升的索拉非尼药物溶液加入到10mL的高分子化合物溶液中。所得混合物溶液在震荡器(品牌：天津欧诺，型号：WE-2)上震荡溶解，震荡速度是100rpm，温度是37摄氏度。0.3，1，2和4小时后，溶液在15000rpm离心机上离心3min，高效液相色谱(HPLC)(品牌：Shimadzu LC-20AT；产地：日本京都)分析上清液中药品的浓度。
为了比较分析，本实施例中检测了晶体状药物在FaSSIF中的溶解度。方法如下：用FaSSIF溶液重悬过量的晶体状药物，然后涡旋1min，超声15min，震荡溶解24小时。之后悬浮液以15，000rpm的离心速度离心3min，用HPLC/UV检测法检测上清液的浓度。
PVP-VA和PVP对索拉非尼过饱和影响的结果如图2和表1所示，其中高分子化合物浓度和种类对索拉非尼过饱和参数的影响如表1所示，
表1：
Figure PCTCN2016100651-appb-000010
需要说明的是：过饱和参数(过饱和参数的定义参见Yuejie Chen，et cl.Mol.Pharmaceutics.2015，12，576-589)介于0-1之间，其用来表征高分子化合物维持过饱和的能力。数值越趋近于1，表明维持过饱和能力越强否则维持过饱和能力越弱。
图2(纵坐标药物浓度是指索拉非尼浓度)结果显示，在FaSSIF中，不论PVP的浓度是高还是低，PVP在维持索拉非尼过饱和中的作用不显著。结果显示，在加入了PVP的 FaSSIF中，索拉非尼的过饱和参数非常低而且不随着高分子化合物浓度的增加而增加。对于PVP-VA，PVP-VA有很大的潜能维持索拉非尼在FaSSIF中的过饱和，因为在加入PVP-VA的条件下，索拉非尼的过饱和参数很大而且随着PVP-VA浓度的增加而大幅增加。
PVP-VA和PVP的主要不同在于VA基团，所以发明人可得出结论：维持索拉非尼过饱和的主要机制与PVP-VA的VA基团相关。
实施例3SLS对索拉非尼溶解行为的影响
在本实施例中，发明人考察了PVP-VA，PVP-VA+SLS，PVP，PVP+SLS以及SLS对索拉非尼的溶解行为的影响。考察结果如图3(纵坐标sorafenib浓度表示索拉非尼浓度)所示，索拉非尼在FaSSIF中溶解度为3.3微克/mL，单独增加SLS浓度至3mg/mL时，索拉非尼溶解度可以达到29.4微克/mL。单独增加高分子PVP-VA或PVP至3mg/mL时索拉非尼溶解度没有明显变化。但是3mg/mL SLS与3mg/mL PVP-VA共同存在时，索拉非尼溶解度提高到164.6微克/mL。但是PVP与SLS共同存在时这种协同增溶现象却不明显。3mg/mL PVP与3mg/mL SLS共同存在时，索拉非尼溶解度仅为43.3微克/mL。PVP-VA与PVP主要在于VA基团的差别，因此可以说明VA基团对于索拉非尼在高分子和SLS混合体系中的协同增溶非常关键。
实施例4片剂USPⅡ溶出实验
三种片剂用压片机根据表2所示的组成制成片剂，三种片剂用于溶出实验和药代动力学实验。
表2：
组成 A B C
甲苯磺酸索拉非尼 137 137 137
PVP-VA 150 150 --
MCC 500 520 650
CCNa 65 65 65
SLS 20 -- 20
总重 872 872 872
将甲苯磺酸索拉非尼和微晶纤维素(MCC)、交联羧甲基纤维素钠(CCNa)、PVP-VA等混合均匀，并在400kgf的压力下压制成片剂。USPⅡ溶出条件如下，溶出介质：300ml FaSSIF；转速：75rpm；温度：37℃。分别在预定时间点取样0.5mL以0.45微米注射器过滤膜过滤，取滤液以甲醇适当稀释后以HPLC/UV分析药物含量。
USPⅡ溶出结果如图4(纵坐标药物浓度表示甲苯磺酸索拉非尼浓度)所示。结果显示：不加PVP-VA的处方C片剂溶出后立刻沉降析出。加有PVP-VA的处方B片剂保持一个长 时间的过饱和状态，并且沉降速度很慢。处方A片剂(向处方B片剂中添加少量的SLS)的溶出速率显著提高，并且达到一个更高的峰值，然而，其沉降析出速率也很快。
实施例5狗体内药代动力学研究
在本实施例中，发明人评估了表2中所示的三种片剂在狗体内的生物利用度。
在4个雄性比格犬(体重约为10kg)中进行药代动力学研究。两次给药之间有1周的冲洗期。每次给药前，狗被禁食过夜。给药137mg后立即喂20mL水。给药前、给药后的10min、0.5h、1h、2h、4h、6h、8h、24h、48h取血2mL，取出的血放在含有EDTA的采血管中。血样在4摄氏度的离心机上以400×g离心速度离心15分钟。离心后的血浆经过适当处理后以HPLC LC/MS分析血浆中药物含量。狗体内的药时曲线如图5(纵坐标药物浓度表示甲苯磺酸索拉非尼浓度)所示。
图5结果表明：与处方C(模拟上市制剂)相比，处方B药物的最大血药浓度(Cmax)和药时曲线下面积(AUC)提高大约85％和78％，处方A药物的Cmax和AUC提高大约30％和26％，两种形式制剂均显著提高了索拉非尼的生物利用度。
需要说明的是，发明人还进行了相关化合物的相互作用机制的研究。通过红外光谱研究PVP-VA与索拉非尼相互作用位点主要为VA基团；NOESY实验、1D13C NMR实验和荧光光谱实验研究表明：在SLS和PVP-VA的混合体系中，SLS与PVP-VA的VA基团相互作用；1D13C NMR色谱实验结果表明，在索拉非尼、SLS和PVP-VA的混合体系中，VA基团以及SLS疏水尾端是索拉非尼的主要的作用位点。
基于上述试验结果，发明人认为，VA基团是提高索拉非尼过饱和度和溶解度的关键因素。在索拉非尼制剂中引入VA基团能够显著提高索拉非尼的过饱和度；VA基团与SLS以及索拉非尼之间的相互作用可以显著提高索拉非尼的溶解度，从而，与现有制剂相比，不论是单独加入PVP-VA还是同时加入PVP-VA和SLS均可以显著提高索拉非尼的生物利用度。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的， 不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (12)

  1. 一种索拉非尼制剂，其特征在于，包含：
    活性成份，所述活性成份为选自索拉非尼、索拉非尼盐、索拉非尼衍生物或其前药的至少一种；以及
    高分子助溶剂，所述高分子助溶剂具有乙酸乙烯酯基团。
  2. 根据权利要求1所述的索拉非尼制剂，其特征在于，所述活性成份与所述高分子助溶剂的重量比是1：0.1～10。
  3. 根据权利要求2所述的索拉非尼制剂，其特征在于，所述活性成分是甲苯磺酸索拉非尼。
  4. 根据权利要求2所述的索拉非尼制剂，其特征在于，所述高分子助溶剂是聚乙烯吡咯烷酮乙酸乙烯酯。
  5. 根据权利要求1所述的索拉非尼制剂，其特征在于，所述索拉非尼制剂进一步包括十二烷基硫酸钠。
  6. 根据权利要求5所述的索拉非尼制剂，其特征在于，所述活性成份与所述十二烷基硫酸钠的质量比是1：0.01～3。
  7. 根据权利要求1所述的索拉非尼制剂，其特征在于，所述索拉非尼制剂呈口服剂型，包括胶囊剂、丸剂、片剂、颗粒剂、口服液体或内服膏剂的至少一种，
    优选地，所述索拉非尼制剂呈片剂。
  8. 根据权利要求1所述的索拉非尼制剂，其特征在于，所述索拉非尼制剂进一步包括药物上可接受的辅料，
    任选地，所述药物上可接受的辅料包括微晶纤维素、淀粉、交联羧甲基纤维素钠、羧甲基淀粉钠、羟丙基纤维素、羟丙甲纤维素、十二烷基硫酸钠或硬脂酸镁的至少一种。
  9. 一种片剂，其特征在于，含有：
    137重量份的甲苯磺酸索拉非尼；
    150重量份的聚乙烯吡咯烷酮乙酸乙烯酯；
    500重量份的微晶纤维素；
    65重量份的交联羧甲基纤维素钠；以及
    20重量份的十二烷基硫酸钠。
  10. 一种片剂，其特征在于，含有：
    137重量份的甲苯磺酸索拉非尼；
    150重量份的聚乙烯吡咯烷酮乙酸乙烯酯；
    520重量份的微晶纤维素；以及
    65重量份的交联羧甲基纤维素钠。
  11. 一种治疗癌症的方法，其特征在于，包括：
    为患者给药权利要求1～8任一项所述的索拉非尼制剂或权利要求9～10任一项所述的片剂。
  12. 根据权利要求11所述的方法，其特征在于，所述癌症包括选自肝癌、肾细胞癌和甲状腺癌的至少之一。
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