CN105126111A - Preparation for improving bioavailability of sorafenib - Google Patents
Preparation for improving bioavailability of sorafenib Download PDFInfo
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- CN105126111A CN105126111A CN201510641732.3A CN201510641732A CN105126111A CN 105126111 A CN105126111 A CN 105126111A CN 201510641732 A CN201510641732 A CN 201510641732A CN 105126111 A CN105126111 A CN 105126111A
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
Abstract
The invention provides a sorafenib preparation. The sorafenib preparation includes active ingredients and macromolecular cosolvent. The active ingredients are selected from at least one of sorafenib, sorafenib salt, a sorafenib derivative or a prodrug of the sorafenib derivative. The macromolecular cosolvent is provided with vinyl acetate radical groups. The sorafenib preparation has the advantage that the bioavailability of the drug active ingredients is high.
Description
Technical field
The present invention relates to biomedicine field, particularly, the present invention relates to a kind of preparation improving Sorafenib bioavailability.
Background technology
Sorafenib is the inoperable hepatocarcinoma for the treatment of, renal cell carcinoma, and the tyrosine kinase inhibitor of thyroid carcinoma.Target site CRAF, BRAF, V600EBRAF, c-Kit, FLT-3 of Sorafenib inhibition tumor cell and CRAF, VEGFR-2, VEGFR-3, PDGFR-β of tumor vessel target site.RAF kinases is serine/threonine kinase, and c-Kit, FLT-3, VEGFR-2, VEGFR-3, PDGFR-β is TYR kinases, these zymogenesis are in tumor cell signal path, angiogenesis and apoptosis, therefore, Sorafenib has inhibition tumor cell propagation and opposing angiogenesis function.
At present, pharmaceutical arts be used for improving the common method of drug bioavailability have following these: salify, reduce diameter of aspirin particle, adopt non-aqueous solvent/cosolvent, be prepared into Emulsion or self-microemulsion agent, cyclodextrin inclusion compound, adopt the crystal formation of thermodynamic instability or be prepared into solid dispersion etc.
But the medicine composition of Sorafenib preparation need further research.
Summary of the invention
The present invention is intended to solve one of technical problem in correlation technique at least to a certain extent.
The present invention completes based on the discovery of inventor's following point:
Oral solution bioavailability compared by the Sorafenib preparation of current listing is 38%-49%, and bioavailability is lower, and said preparation oral dose is larger in addition, for 400mg/ time, and every day 2 times.Take this drug side effect in a large number for a long time obvious, so how to improve the bioavailability of Sorafenib preparation thus reduce its dosage, reduce toxic and side effects, food effect and pH effect, improve patient compliance and become extremely important with treatment effectiveness.
For the such highest dose of Sorafenib, the medicine that dissolubility is limited in oil-based solvent, the most feasible technological means improving its bioavailability is amorphous solid dispersion.But in actual experiment, inventor finds: because Sorafenib has thermal instability, so can not adopt hot-melt extruded to prepare; And its dissolubility is also limited so prepared by employing spraying dry be also not easy in conventional sprayable drying solvent, therefore preparing its solid dispersion suitability for industrialized production will have difficulties.In addition because solid dispersion itself belongs to upper state, it easily occurs aging in storage thus affects stability, thus increases difficulty to production and quality monitoring, and therefore preparing solid dispersion is not an optimum selection.
Based on the problems referred to above, inventors herein propose a kind of Sorafenib preparation comprising polymeric retention aid solvent, said preparation not only improves the bioavailability of Sorafenib by a relatively large margin compared to simulation listing preparation, and it is convenient to have suitability for industrialized production, drug substance stable, the plurality of advantages such as reliable.
In a first aspect of the present invention, the present invention proposes a kind of Sorafenib preparation, according to embodiments of the invention, this Sorafenib preparation comprises: active ingredient, and described active ingredient is at least one being selected from Sorafenib, Sorafenib salt, Sorafenib derivant or its prodrug; And polymeric retention aid solvent (in the present invention, sometimes also referred to as macromolecular compound), described polymeric retention aid solvent has vinyl acetate groups (VA group).According to embodiments of the invention, active ingredient is the compound of low solubility, the polymeric retention aid solvent added can improve the degree of super saturation of active ingredient in dissolution medium, the supersaturation that VA group maintains active ingredient for macromolecular compound is abnormal crucial, VA group can significantly improve the degree of supersaturation of active ingredient, thus effectively can improve the bioavailability of active ingredient.
According to embodiments of the invention, above-mentioned Sorafenib preparation also comprises following additional technical feature one of at least further:
According to embodiments of the invention, the weight ratio of described active ingredient and described polymeric retention aid solvent is 1:0.1 ~ 10.According to embodiments of the invention, in the concentration range of above-mentioned polymeric retention aid solvent, the degree of supersaturation of active ingredient in simulated intestinal fluid solution (FaSSIF) and individuality significantly improves, and bioavailability significantly improves.
According to embodiments of the invention, described active ingredient is Sorafenib Tosylate.According to embodiments of the invention, Sorafenib Tosylate as the active ingredient of effective Sorafenib medicine, can be used in the pharmacy of Sorafenib.
According to embodiments of the invention, described polymeric retention aid solvent is polyvinylpyrrolidone vinyl acetate (PVP-VA).PVP-VA has VA group, and as previously mentioned, VA group is abnormal crucial for the supersaturation effect of PVP-VA, and the PVP-VA with VA group significantly increases the degree of supersaturation of Sorafenib, improves the bioavailability of Sorafenib.
According to embodiments of the invention, the weight ratio of described Sorafenib Tosylate and described polyvinylpyrrolidone vinyl acetate is 1:0.1 ~ 10, in one embodiment of the invention, the weight ratio of Sorafenib Tosylate and polyvinylpyrrolidone vinyl acetate is 1:3, in another one embodiment of the present invention, the weight ratio of Sorafenib Tosylate and polyvinylpyrrolidone vinyl acetate is 1:1.5, in yet another embodiment of the present invention, the weight ratio 1:1.1 of Sorafenib Tosylate and polyvinylpyrrolidone vinyl acetate.Inventor finds, the mass ratio of Sorafenib Tosylate and PVP-VA is not remarkable higher than 1:0.1, PVP-VA supersaturation effect, and weight ratio, lower than 1:10, is difficult to carry out from preparation angle, cannot meet patient compliance.According to embodiments of the invention, in the concentration range of above-mentioned PVP-VA, the degree of supersaturation of Sorafenib Tosylate in simulated intestinal fluid solution (FaSSIF) and individuality significantly improves, and bioavailability significantly improves.
According to embodiments of the invention, described Sorafenib preparation comprises sodium lauryl sulphate (SLS) further.According to embodiments of the invention, PVP-VA and SLS coupling can improve the dissolubility of Sorafenib, and the bioavailability of Sorafenib medicine significantly improves compared with existing preparation.
According to embodiments of the invention, the mass ratio of described active ingredient and described sodium lauryl sulphate is 1:0.01 ~ 3.According to embodiments of the invention, described active ingredient is Sorafenib Tosylate, and the mass ratio of described Sorafenib Tosylate and described sodium lauryl sulphate is 1:0.01 ~ 3.In one embodiment of the invention, the mass ratio of Sorafenib Tosylate and sodium lauryl sulphate is 1:1, in another one embodiment of the present invention, the mass ratio of Sorafenib Tosylate and sodium lauryl sulphate is 1:0.3, in yet another embodiment of the present invention, the mass ratio of Sorafenib Tosylate and sodium lauryl sulphate is 1:0.15.The discovery that inventor is surprised, under cosolvent PVP-VA existent condition, the mass ratio of Sorafenib Tosylate and SLS is higher than 1:0.01 or lower than 1:3, and the raising of Sorafenib Tosylate dissolubility is not remarkable.According to embodiments of the invention, under PVP-VA existent condition, the mass ratio of Sorafenib Tosylate and SLS is within the scope of 1:0.01 ~ 1:3, and the dissolubility of Sorafenib Tosylate has and significantly improves, and bioavailability also significantly improves compared with existing preparation.
According to embodiments of the invention, described Sorafenib preparation is peroral dosage form, comprises at least one of capsule, pill, tablet, granule, liquid oral or oral pastes, and preferably, described Sorafenib preparation is tablet.Described Sorafenib preparation exists with oral dosage form, and bioavailability in vivo significantly improves.
According to embodiments of the invention, described Sorafenib preparation comprises pharmaceutically acceptable adjuvant further, optionally, described pharmaceutically acceptable adjuvant comprises at least one of microcrystalline Cellulose, starch, cross-linking sodium carboxymethyl cellulose, hydroxypropyl cellulose, hypromellose, sodium lauryl sulphate or magnesium stearate.Under the existence of above-mentioned adjuvant, described Sorafenib preparation is oral tablet, facilitates the bioavailability taking and improve Sorafenib of patient, improves the drug effect of described Sorafenib preparation.
In a second aspect of the present invention, the present invention proposes a kind of tablet, according to embodiments of the invention, described tablet contains the Sorafenib Tosylate of 137 weight portions; The polyvinylpyrrolidone vinyl acetate of 150 weight portions; The microcrystalline Cellulose of 500 weight portions; The cross-linking sodium carboxymethyl cellulose of 65 weight portions; And 20 sodium lauryl sulphates of weight portion.According to embodiments of the invention, the dissolution rate of above-mentioned tablet significantly improves, and significantly improves compared with existing Sorafenib preparation in the bioavailability of body active ingredient.
In a third aspect of the present invention, the present invention proposes a kind of tablet, according to embodiments of the invention, described tablet contains the Sorafenib Tosylate of 137 weight portions; The polyvinylpyrrolidone vinyl acetate of 150 weight portions; The microcrystalline Cellulose of 520 weight portions; And 65 cross-linking sodium carboxymethyl celluloses of weight portion.According to embodiments of the invention, fast and significantly improve, medicine supersaturation time lengthening, significantly improves in the bioavailability of body active ingredient for the drug-eluting speed of above-mentioned tablet.
Accompanying drawing explanation
Fig. 1 is the Sorafenib Tosylate according to the embodiment of the present invention, polyvinylpyrrolidone vinylacetate copolymers (PVP-VA), polyvinylpyrrolidone (PVP) and sodium lauryl sulphate (SLS) structural formula;
Fig. 2 be according to an embodiment of the invention in simulated intestinal fluid FaSSF PVP-VA and PVP on the oversaturated impact of Sorafenib (-initial supersaturation concentration;
pVP-VA;
pVP;
there is no macromolecular compound);
Fig. 3 is Sorafenib dissolubility in PVP-VA-SLS and PVP-SLSFaSSIF according to an embodiment of the invention;
Fig. 4 be according to an embodiment of the invention prescription A, prescription B and prescription C tablet in simulated intestinal fluid FaSSIF stripping curve (
prescription A tablet;
prescription B tablet;
prescription C tablet); And
Fig. 5 be different according to an embodiment of the invention Sorafenib Tosylate pharmaceutical formulation in Canis familiaris L. body pharmacokinetic curve result (
prescription A tablet;
prescription B tablet;
prescription C tablet).
Detailed description of the invention
The present invention completes based on the following discovery of inventor:
The bioavailability of Sorafenib preparation is lower, thus causes said preparation oral dose larger, and long-term taking this drug side effect a large amount of is obvious.In the present invention, inventors herein propose a kind of Sorafenib preparation comprising polymeric retention aid solvent, this Sorafenib preparation bioavailability is high.
Sorafenib preparation
In a first aspect of the present invention, the present invention proposes a kind of Sorafenib preparation, according to of the present invention be embodiment, this Sorafenib preparation comprises: active ingredient, and active ingredient is at least one being selected from Sorafenib, Sorafenib salt, Sorafenib derivant or its prodrug; And polymeric retention aid solvent, polymeric retention aid solvent has vinyl acetate groups (VA group).The compound that can form pharmaceutically-active ingredients Sorafenib all can as Sorafenib agent activity composition in the present invention, therefore in the present invention, the active component of Sorafenib preparation is selected from Sorafenib, Sorafenib salt, the at least one of Sorafenib derivant or its prodrug, but above-mentioned active ingredient is the compound of low solubility, need to add polymeric retention aid solvent so that active ingredient supersaturation in a liquid can be improved, thus improve the bioavailability of active ingredient at body, VA group can significantly improve active ingredient degree of supersaturation in a liquid, thus effectively can improve the bioavailability of active ingredient.
According to embodiments of the invention, the weight ratio of described active ingredient and described polymeric retention aid solvent is 1:0.1 ~ 10.According to embodiments of the invention, in the concentration range of above-mentioned polymeric retention aid solvent, the degree of supersaturation of active ingredient in simulated intestinal fluid solution (FaSSIF) and individuality significantly improves, and bioavailability significantly improves.
According to embodiments of the invention, active ingredient is Sorafenib Tosylate.According to embodiments of the invention, Sorafenib Tosylate as the active ingredient of effective Sorafenib medicine, can be used in the pharmacy of Sorafenib.
According to embodiments of the invention, polymeric retention aid solvent is polyvinylpyrrolidone vinyl acetate (PVP-VA).PVP-VA has VA group.According to embodiments of the invention, the VA group of PVP-VA is relevant to the supersaturation parameter of Sorafenib, the VA group of PVP-VA can significantly improve the supersaturation parameter of Sorafenib, extend the supersaturation of Sorafenib, slow down the oversaturated decline of Sorafenib, thus the VA group of PVP-VA significantly increases the degree of super saturation of Sorafenib, improves the bioavailability of Sorafenib.
According to embodiments of the invention, the weight ratio of Sorafenib Tosylate and polyvinylpyrrolidone vinyl acetate is 1:0.1 ~ 10, in one embodiment of the invention, the weight ratio of Sorafenib Tosylate and polyvinylpyrrolidone vinyl acetate is 1:3, in another one embodiment of the present invention, the weight ratio of Sorafenib Tosylate and polyvinylpyrrolidone vinyl acetate is 1:1.5, in yet another embodiment of the present invention, the weight ratio of Sorafenib Tosylate and polyvinylpyrrolidone vinyl acetate is 1:1.1.Inventor finds, the mass ratio of Sorafenib Tosylate and PVP-VA is higher than 1:0.1, and Sorafenib supersaturation effect is not remarkable, and weight ratio, lower than 1:10, is difficult to carry out from preparation angle, cannot meet patient compliance.According to embodiments of the invention, in the concentration range of above-mentioned PVP-VA, the supersaturation of Sorafenib Tosylate in simulated intestinal fluid solution Fassif and individuality significantly improves, and bioavailability significantly improves.
According to embodiments of the invention, described Sorafenib preparation comprises sodium lauryl sulphate (SLS) further.According to embodiments of the invention, PVP-VA and SLS coupling can improve the dissolubility of Sorafenib, and the bioavailability of Sorafenib medicine significantly improves compared with existing preparation.
According to embodiments of the invention, the mass ratio of described active ingredient and described sodium lauryl sulphate is 1:0.01 ~ 3, and wherein said active ingredient is Sorafenib Tosylate.According to embodiments of the invention, the mass ratio of described Sorafenib Tosylate and described sodium lauryl sulphate is 1:0.01 ~ 3.In one embodiment of the invention, the mass ratio of Sorafenib Tosylate and sodium lauryl sulphate is 1:1, in another embodiment of the present invention, the mass ratio of Sorafenib Tosylate and sodium lauryl sulphate is 1:0.3, in yet another embodiment of the present invention, the mass ratio of Sorafenib Tosylate and sodium lauryl sulphate is 1:0.15.The discovery that inventor is surprised, under cosolvent PVP-VA existent condition, the mass ratio of Sorafenib Tosylate and SLS is higher than 1:0.01 or lower than 1:3, and the raising of Sorafenib Tosylate dissolubility is not remarkable.According to embodiments of the invention, under PVP-VA existent condition, the mass ratio of Sorafenib Tosylate and SLS is within the scope of 1:0.01 ~ 1:3, and the dissolubility of Sorafenib Tosylate significantly improves at short notice fast, and bioavailability also significantly improves compared with existing preparation.
According to embodiments of the invention, inventor finds, in the mixed system of PVP-VA and SLS, the hydrophobic forces of the VA group of PVP-VA is strong, and SLS interaction force is strong; In the mixed system of Sorafenib, PVP-VA, SLS, VA group and the hydrophobic tail end of SLS are the main action sites of Sorafenib.Above-mentioned discovery may be the reason that PVP-VA-SLS significantly can increase Sorafenib dissolubility.The synergism of PVP-VA and SLS, the dissolubility of Sorafenib is significantly improved at short notice fast, and bioavailability also significantly improves compared with existing preparation.
According to embodiments of the invention, Sorafenib preparation is peroral dosage form, comprises at least one of capsule, pill, tablet, granule, liquid oral or oral pastes, and preferably, Sorafenib preparation is tablet.Sorafenib preparation exists with oral dosage form, and bioavailability in vivo significantly improves.
According to embodiments of the invention, Sorafenib preparation comprises pharmaceutically acceptable adjuvant further, in some embodiments of the invention, pharmaceutically acceptable adjuvant comprises microcrystalline Cellulose, starch, cross-linking sodium carboxymethyl cellulose, at least one of hydroxypropyl cellulose, hypromellose, sodium lauryl sulphate or magnesium stearate.Under the existence of above-mentioned adjuvant, Sorafenib preparation is oral tablet, facilitates the bioavailability taking and improve Sorafenib of patient, improves the drug effect of Sorafenib preparation.
Tablet
In a second aspect of the present invention, the present invention proposes a kind of tablet, according to embodiments of the invention, tablet comprises: the Sorafenib Tosylate of (1) 137 weight portion, the polyvinylpyrrolidone vinyl acetate of 150 weight portions, the microcrystalline Cellulose of 500 weight portions, the cross-linking sodium carboxymethyl cellulose of 65 weight portions, and the sodium lauryl sulphate of 20 weight portions; Or (2) 137 Sorafenib Tosylates of weight portion, the polyvinylpyrrolidone vinyl acetate of 150 weight portions, the microcrystalline Cellulose of 520 weight portions, the cross-linking sodium carboxymethyl cellulose of 65 weight portions.According to embodiments of the invention, the tablet dissolution rate in a solvent of above-mentioned formula significantly improves, formula 2 tablet rapid solution reach supersaturation platform in dissolution medium, after platform, the supersaturation of medicine reduces slowly, formula 1 tablet Fast Stripping reach peak value in dissolution medium, above-mentioned tablet also significantly improves compared with existing preparation at body dissolution rate simultaneously, and bioavailability is also corresponding significantly to be improved.
Embodiments of the invention are described below in detail.Embodiment described below is exemplary, only for explaining the present invention, and can not be interpreted as limitation of the present invention.Unreceipted concrete technology or condition in embodiment, according to the technology described by the document in this area or condition or carry out according to product description.Agents useful for same or the unreceipted production firm person of instrument, being can by the conventional products of commercial acquisition.
Embodiment 1 material
The Sorafenib Tosylate used in embodiments of the invention is provided (Shandong Province of China) by Qilu Pharmaceutical Co., Ltd.; Polyvinylpyrrolidone PVP (Kollidon30) and polyvinylpyrrolidone vinyl acetate PVP-VA (KollidonVA64) is given by German BASF chemical reagents corporation.All salt for solvent soln, to provide by Beijing Chemical Plant for spray-dired methanol (analytical pure).The complex mentioned in the present invention and the chemical constitution of compound and key feature are as shown in Figure 1.
Embodiment 2PVP-VA and PVP is on Sorafenib oversaturated impact in FaSSIF
In embodiments of the invention, inventor is in order to assessing compound is on the impact keeping Sorafenib hypersaturated state, macromolecular compound PVP-VA or PVP is dissolved in simulated intestinal fluid FaSSIF with the concentration of 0.3 and 3mg/mL, and Sorafenib Tosylate is dissolved in DMSO with the concentration of 100 or 20mg/mL.In dissolution medium, the Sorafenib drug solution of 100 microlitres joins in the macromolecular compound solution of 10mL.Gained mixture solution earthquake device (brand: Tianjin Ou Nuo, model: WE-2) shakes dissolving, and concussion speed is 100rpm, and temperature is 37 degrees Celsius.After 0.3,1,2 and 4 hour, solution is centrifugal 3min on 15000rpm centrifuge, high performance liquid chromatography (HPLC) (brand: ShimadzuLC-20AT; The place of production: kyoto, Japan) analyze the concentration of medicine in supernatant.
In order to comparative analysis, in the present embodiment, have detected the dissolubility of lenticular medicine in FaSSIF.Method is as follows: with the resuspended excessive lenticular medicine of FaSSIF solution, then vortex 1min, ultrasonic 15min, concussion dissolving 24 hours.Rear suspension liquid with the centrifugal 3min of the centrifugal speed of 15,000rpm, detect the concentration of supernatant by HPLC/UV detection method.
The result that PVP-VA and PVP affects Sorafenib supersaturation as shown in Figure 2 and Table 1, wherein macromolecular compound concentration and the impact of kind on Sorafenib supersaturation parameter as shown in table 1,
Table 1
It should be noted that: supersaturation parameter (definition of supersaturation parameter see YuejieChen, etcl.Mol.Pharmaceutics.2015,12,576-589) is between 0-1, and it is used for characterizing macromolecular compound and maintains oversaturated ability.Numerical value more levels off to 1, shows that maintenance supersaturation ability is stronger otherwise it is more weak to maintain supersaturation ability.
Fig. 2 (vertical coordinate drug level refers to Sorafenib concentration) result shows, and in FaSSIF, no matter the concentration of PVP is high or low, the effect of PVP in the supersaturation of maintenance Sorafenib is not remarkable.Result shows, and in the FaSSIF adding PVP, the supersaturation parameter of Sorafenib is very low and do not increase along with the increase of macromolecular compound concentration.Have very large potential to maintain the supersaturation of Sorafenib in FaSSIF for PVP-VA, PVP-VA, because under the condition adding PVP-VA, the supersaturation parameter of Sorafenib is very large and significantly increase along with the increase of PVP-VA concentration.
The main difference of PVP-VA and PVP is VA group, so inventor can reach a conclusion: maintain the oversaturated main mechanism of Sorafenib relevant to the VA group of PVP-VA.
Embodiment 3SLS is on the impact of Sorafenib solubility behavior
In the present embodiment, inventor has investigated PVP-VA, PVP-VA+SLS, PVP, PVP+SLS and the SLS impact on the solubility behavior of Sorafenib.Investigate result as shown in Fig. 3 (vertical coordinate sorafenib concentration represents Sorafenib concentration), Sorafenib dissolubility in FaSSIF is 3.3 micrograms/mL, when independent increase SLS concentration is to 3mg/mL, Sorafenib dissolubility can reach 29.4 micrograms/mL.During independent increase Macromolecule PVP-VA or PVP to 3mg/mL, Sorafenib dissolubility does not have significant change.But when 3mg/mLSLS and 3mg/mLPVP-VA exists jointly, Sorafenib dissolubility brings up to 164.6 micrograms/mL.But this collaborative solubilising phenomenon is not obvious when PVP and SLS exists jointly.When 3mg/mLPVP and 3mg/mLSLS exists jointly, Sorafenib dissolubility is only 43.3 micrograms/mL.PVP-VA and PVP is mainly the difference of VA group, therefore can illustrate that VA group is very crucial for the collaborative solubilising of Sorafenib in macromolecule and SLS mixed system.
Embodiment 4 tablet USP II stripping is tested
Three kinds of tablet tablet machine make tablet according to the composition shown in table 2, and three kinds of tablets are used for stripping experiment and pharmacokinetic studies.
Table 2
| Composition | A | B | C |
| Sorafenib Tosylate | 137 | 137 | 137 |
| PVP-VA | 150 | 150 | -- |
| MCC | 500 | 520 | 650 |
| CCNa | 65 | 65 | 65 |
| SLS | 20 | -- | 20 |
| Gross weight | 872 | 872 | 872 |
By mix homogeneously such as Sorafenib Tosylate and microcrystalline Cellulose (MCC), cross-linking sodium carboxymethyl cellulose (CCNa), PVP-VA, and make tablet at the pressure of 400kgf.USP II leaching condition is as follows, dissolution medium: 300mlFaSSIF; Rotating speed: 75rpm; Temperature: 37 DEG C.Filter with 0.45 micrometer syringe filter membrane at predetermined point of time sampling 0.5mL respectively, get after filtrate is suitably diluted with methanol and analyze medicament contg with HPLC/UV.
USP II stripping result is as shown in Fig. 4 (vertical coordinate drug level represents Sorafenib Tosylate concentration).Result shows: after not adding the prescription C tablet stripping of PVP-VA, sedimentation is at once separated out.The prescription B tablet being added with PVP-VA keeps a long hypersaturated state, and sedimentation velocity is very slow.The dissolution rate of prescription A tablet (adding a small amount of SLS in prescription B tablet) significantly improves, and reaches a higher peak value, but its sedimentation precipitation rate is also very fast.
Pharmacokinetic in embodiment 5 Canis familiaris L. body
In the present embodiment, inventor have evaluated the bioavailability of kind of the tablet of three shown in table 2 in Canis familiaris L. body.
Pharmacokinetic is carried out in 4 male beagle dogs' (body weight is about 10kg).The flush period of 1 week is had between twice administration.Before each administration, Canis familiaris L. is by overnight fasting.20mL water is fed immediately after administration 137mg.10min, 0.5h, 1h, 2h, 4h, 6h, 8h, 24h, 48h before administration, after administration get blood 2mL, and the blood of taking-up is placed in the blood taking tube containing EDTA.Blood sample on the centrifuge of 4 degrees Celsius with 400 × g centrifugal speed centrifugal 15 minutes.Blood plasma after centrifugal through suitably process after with HPLCLC/MS analysed for plasma drug content.Drug-time curve in Canis familiaris L. body is as shown in Fig. 5 (vertical coordinate drug level represents Sorafenib Tosylate concentration).
Fig. 5 result shows: compared with prescription C (simulating the preparation that goes on the market), the maximum plasma concentration (C of prescription B medicine
max) and area under the drug-time curve (AUC) improve about 85% and 78%, the C of prescription A medicine
maximprove about 30% and 26% with AUC, two kinds of form preparations have been significantly increased the bioavailability of Sorafenib.
It should be noted that, inventor has also carried out the research of the interaction mechanism of related compound.VA group is mainly by infrared spectroscopic study PVP-VA and Sorafenib interaction sites; NOESY experiment, 1D
13cNMR experiment and fluorescence spectrum experiments research show: in the mixed system of SLS and PVP-VA, the VA Interaction of substituents of SLS and PVP-VA; 1D
13cNMR chromatography experiment result shows, in the mixed system of Sorafenib, SLS and PVP-VA, VA group and the hydrophobic tail end of SLS are the main action sites of Sorafenib.
Based on above-mentioned result of the test, inventor thinks, VA group is the key factor improving Sorafenib degree of supersaturation and dissolubility.The degree of supersaturation that VA group can significantly improve Sorafenib is introduced in Sorafenib preparation; Interaction between VA group and SLS and Sorafenib can significantly improve the dissolubility of Sorafenib, thus, compared with existing preparation, no matter be add separately PVP-VA or add the bioavailability that PVP-VA and SLS all can significantly improve Sorafenib simultaneously.
In the description of this description, specific features, structure, material or feature that the description of reference term " embodiment ", " some embodiments ", " example ", " concrete example " or " some examples " etc. means to describe in conjunction with this embodiment or example are contained at least one embodiment of the present invention or example.In this manual, to the schematic representation of above-mentioned term not must for be identical embodiment or example.And the specific features of description, structure, material or feature can combine in one or more embodiment in office or example in an appropriate manner.In addition, when not conflicting, the feature of the different embodiment described in this description or example and different embodiment or example can carry out combining and combining by those skilled in the art.
Although illustrate and describe embodiments of the invention above, be understandable that, above-described embodiment is exemplary, can not be interpreted as limitation of the present invention, and those of ordinary skill in the art can change above-described embodiment within the scope of the invention, revises, replace and modification.
Claims (10)
1. a Sorafenib preparation, is characterized in that, comprises:
Active ingredient, described active ingredient is at least one being selected from Sorafenib, Sorafenib salt, Sorafenib derivant or its prodrug; And
Polymeric retention aid solvent, described polymeric retention aid solvent has vinyl acetate groups.
2. Sorafenib preparation according to claim 1, is characterized in that, the weight ratio of described active ingredient and described polymeric retention aid solvent is 1:0.1 ~ 10.
3. Sorafenib preparation according to claim 2, is characterized in that, described active component is Sorafenib Tosylate.
4. Sorafenib preparation according to claim 2, is characterized in that, described polymeric retention aid solvent is polyvinylpyrrolidone vinyl acetate.
5. Sorafenib preparation according to claim 1, is characterized in that, described Sorafenib preparation comprises sodium lauryl sulphate further.
6. Sorafenib preparation according to claim 5, is characterized in that, the mass ratio of described active ingredient and described sodium lauryl sulphate is 1:0.01 ~ 3.
7. Sorafenib preparation according to claim 1, is characterized in that, described Sorafenib preparation is peroral dosage form, comprises at least one of capsule, pill, tablet, granule, liquid oral or oral pastes,
Preferably, described Sorafenib preparation is tablet.
8. Sorafenib preparation according to claim 1, is characterized in that, described Sorafenib preparation comprises pharmaceutically acceptable adjuvant further,
Optionally, described pharmaceutically acceptable adjuvant comprises at least one of microcrystalline Cellulose, starch, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, hydroxypropyl cellulose, hypromellose, sodium lauryl sulphate or magnesium stearate.
9. a tablet, is characterized in that, contains:
The Sorafenib Tosylate of 137 weight portions;
The polyvinylpyrrolidone vinyl acetate of 150 weight portions;
The microcrystalline Cellulose of 500 weight portions;
The cross-linking sodium carboxymethyl cellulose of 65 weight portions; And
The sodium lauryl sulphate of 20 weight portions.
10. a tablet, is characterized in that, contains:
The Sorafenib Tosylate of 137 weight portions;
The polyvinylpyrrolidone vinyl acetate of 150 weight portions;
The microcrystalline Cellulose of 520 weight portions; And
The cross-linking sodium carboxymethyl cellulose of 65 weight portions.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510641732.3A CN105126111A (en) | 2015-09-30 | 2015-09-30 | Preparation for improving bioavailability of sorafenib |
| PCT/CN2016/100651 WO2017054741A1 (en) | 2015-09-30 | 2016-09-28 | Preparation for improving bioavailability of sorafenib |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510641732.3A CN105126111A (en) | 2015-09-30 | 2015-09-30 | Preparation for improving bioavailability of sorafenib |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017054741A1 (en) * | 2015-09-30 | 2017-04-06 | 清华大学 | Preparation for improving bioavailability of sorafenib |
| CN110339173A (en) * | 2018-04-08 | 2019-10-18 | 北京化工大学 | A kind of Sorafenib Tosylate nanometer tablet |
| WO2022120512A1 (en) * | 2020-12-07 | 2022-06-16 | 天津睿创康泰生物技术有限公司 | Sorafenib pharmaceutical composition having high bioavailability and application |
| CN115192540A (en) * | 2018-06-15 | 2022-10-18 | 汉达癌症医药责任有限公司 | Salts of kinase inhibitors and compositions thereof |
| WO2023155307A1 (en) | 2022-02-21 | 2023-08-24 | 北京睿创康泰医药研究院有限公司 | Sorafenib or donafenib oral preparation with low dose and high drug exposure, and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101594851A (en) * | 2006-11-09 | 2009-12-02 | 阿伯特有限及两合公司 | The pharmaceutical dosage form that is used for the tyrosine kinase inhibitor of oral administration |
| WO2015119848A1 (en) * | 2014-02-05 | 2015-08-13 | Merck Sharp & Dohme Corp. | Tablet formulation for cgrp-active compounds |
| CN104888228A (en) * | 2015-05-29 | 2015-09-09 | 连云港杰瑞药业有限公司 | Sorafenib tosylate solid dispersion body and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20130172375A1 (en) * | 2011-12-13 | 2013-07-04 | Hoffmann-La Roche Inc. | Pharmaceutical composition |
| CN105126111A (en) * | 2015-09-30 | 2015-12-09 | 清华大学 | Preparation for improving bioavailability of sorafenib |
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- 2015-09-30 CN CN201510641732.3A patent/CN105126111A/en active Pending
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101594851A (en) * | 2006-11-09 | 2009-12-02 | 阿伯特有限及两合公司 | The pharmaceutical dosage form that is used for the tyrosine kinase inhibitor of oral administration |
| WO2015119848A1 (en) * | 2014-02-05 | 2015-08-13 | Merck Sharp & Dohme Corp. | Tablet formulation for cgrp-active compounds |
| CN104888228A (en) * | 2015-05-29 | 2015-09-09 | 连云港杰瑞药业有限公司 | Sorafenib tosylate solid dispersion body and preparation method thereof |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017054741A1 (en) * | 2015-09-30 | 2017-04-06 | 清华大学 | Preparation for improving bioavailability of sorafenib |
| CN110339173A (en) * | 2018-04-08 | 2019-10-18 | 北京化工大学 | A kind of Sorafenib Tosylate nanometer tablet |
| CN115192540A (en) * | 2018-06-15 | 2022-10-18 | 汉达癌症医药责任有限公司 | Salts of kinase inhibitors and compositions thereof |
| WO2022120512A1 (en) * | 2020-12-07 | 2022-06-16 | 天津睿创康泰生物技术有限公司 | Sorafenib pharmaceutical composition having high bioavailability and application |
| WO2023155307A1 (en) | 2022-02-21 | 2023-08-24 | 北京睿创康泰医药研究院有限公司 | Sorafenib or donafenib oral preparation with low dose and high drug exposure, and application thereof |
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| Publication number | Publication date |
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| WO2017054741A1 (en) | 2017-04-06 |
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