CN112891349B - Apatinib oral pharmaceutical composition containing sedimentation inhibitor - Google Patents
Apatinib oral pharmaceutical composition containing sedimentation inhibitor Download PDFInfo
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- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
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Abstract
The present disclosure relates to an apatinib oral pharmaceutical composition comprising a sedimentation inhibitor. In particular, the present disclosure relates to pharmaceutical compositions comprising apatinib and hypromellose and/or copovidone. The disclosure also relates to a biphasic gastrointestinal simulation system constructed by adding n-octanol as an absorption phase in the duodenal cavity and the ileal cavity based on a gastrointestinal simulation system (GIS), and simultaneously applying a pion-line optical fiber ultraviolet detection system.
Description
Technical Field
The present disclosure pertains to the pharmaceutical field, and relates to a pharmaceutical composition comprising apatinib or a pharmaceutically acceptable salt thereof, wherein the composition further comprises a sedimentation inhibitor.
Background
Class II drugs in the Biopharmaceutical Classification System (BCS) have good permeability and poor solubility. For these drugs, solubility is a limitation of absorption. Weakly basic drugs in this class, also known as BCS IIB drugs, are capable of forming high concentrations in acidic gastric juice. The natural transition of pH from stomach to intestine automatically creates supersaturation. Oversaturation is thermodynamically unstable and it will precipitate very rapidly. The sedimentation inhibitors may extend the supersaturation state and may last long enough to increase bioavailability, but different sedimentation inhibitors exhibit different affinities for each Active Pharmaceutical Ingredient (API).
Screening and assessing the effect of precipitation inhibitors on supersaturation is critical for the efficient development of supersaturated drug delivery systems. Most studies have screened a precipitation inhibitor suitable for the drug by trial and error. Yamashita et al selected precipitation inhibitors by a high throughput screening method using a 96-well plate based microplate reader technique (Yamashita, t., ozaki, s., kushida, i.,2011.Int J Pharm 419,170-174.). Price et al developed a novel screening protocol for selecting precipitation inhibitors for supersaturated formulations by calculating enthalpy of drug-polymer mixing (Price, d.j., nair, a., kuentz, m., dressman, j., saal, c.,2019.European journal of pharmaceutical sciences 132,142-156.). However, physiological conditions are very complex, and these simple in vitro tests often suffer from contradictions in vivo results (Pestinau, A., evrard, B.,2017.European Journal of Pharmaceutical Sciences 102,203-219.).
Apatinib is a BCS class II weakly basic drug (pka=4.72; log p=4.51 (gasstroplus forecast); mw= 493.58 (apatinib mesylate), 397.48 (apatinib base)), which is an orally bioavailable small molecule inhibitor that selectively inhibits vascular endothelial growth factor receptor 2.
The oral intake bioavailability of apatinib is between 10% and 20% (Geng, r.,&Li,J.(2015).Expert opinion on pharmacotherapy,16(1),117-122.)。
disclosure of Invention
The present disclosure provides an oral pharmaceutical composition comprising apatinib or a pharmaceutically acceptable salt thereof, further comprising a sedimentation inhibitor.
In some embodiments, the apatinib or a pharmaceutically acceptable salt thereof is not in nanocrystalline form. In some embodiments, the apatinib or a pharmaceutically acceptable salt thereof has a particle size D90 value greater than 10 μm. In some embodiments, when the sedimentation inhibitor is hydroxypropyl methylcellulose, the D90 of apatinib or a pharmaceutically acceptable salt thereof is greater than 10 μm.
In some embodiments, the sedimentation inhibitor is a polymer, a surfactant, cyclodextrin, or the like.
The polymer may be selected from: cellulose derivatives such as HPMC, HPMCAS, methyl Cellulose (MC), ethyl Cellulose (EC), and hydroxypropyl cellulose (hydroxypropyl cellulose, HPC); vinyl polymers such as PVP, polyvinyl alcohol (PVA), polyvinylpyrrolidone copolymers (polyvinylpyrrolidone copolymer, coppp), and the like; ethylene oxide polymers such as PEG and the like. Some common surfactants are polyethylene glycol-15-hydroxystearate (Solutol HS 15), sodium dodecyl sulfate (sodium dodecyl sulfate, SDS), TPGS, and the like.
In some embodiments, the sedimentation inhibitor is hydroxypropyl methylcellulose and/or copovidone.
In some embodiments, the weight ratio of the sedimentation inhibitor to the apatinib or pharmaceutically acceptable salt thereof may be selected from 50:1-1:10, preferably 30:1-1:10, more preferably 20:1-1:1, more preferably 15:1-1:1, 10:1-1:1, 9:1-1:1, 8:1-1:1, 7:1-1:1, 6:1-1:1, 5:1-1:1, 4:1-1:1, 3:1-1:1, 2:1-1:1.
The present disclosure provides pharmaceutical compositions in a dosage form selected from the group consisting of tablets, capsules, minitablets, granules, or powders. In some embodiments, the composition is in the form of a tablet.
The pharmaceutical composition of the present disclosure may further comprise a disintegrant, which may be at least one selected from the group consisting of croscarmellose sodium, crospovidone, sodium carboxymethyl starch, calcium carboxymethyl cellulose, low substituted hydroxypropyl cellulose, starch, pregelatinized starch, and alginic acid.
The pharmaceutical composition of the present disclosure may further comprise a filler selected from microcrystalline cellulose, lactose, mannitol, pregelatinized starch, dextrin, sorbitol, sucrose, dibasic calcium phosphate, anhydrous dibasic calcium phosphate, calcium sulfate, and the like.
The pharmaceutical composition of the present disclosure may further comprise a binder, which may be selected from pregelatinized starch, povidone, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, and the like.
The pharmaceutical composition of the present disclosure may further comprise a lubricant selected from stearic acid, magnesium stearate, micro powder silica gel, talc, polyethylene glycol 4000, polyethylene glycol 6000, palmitic acid, calcium stearate, colloidal silica, carnauba wax, sodium stearyl fumarate, and the like.
In some embodiments, the daily dose of apatinib or a pharmaceutically acceptable salt thereof in a pharmaceutical composition described by the present disclosure is 50 to 700mg, preferably 300 to 600mg, more preferably 400 to 550mg, most preferably 500mg.
The present disclosure also provides the use of a sedimentation inhibitor in the preparation of a pharmaceutical composition comprising apatinib or a pharmaceutically acceptable salt thereof.
The present disclosure also provides a biphasic gastrointestinal simulation system comprising 3 containers 1, 2, 3, respectively, a simulated gastric chamber, a duodenal chamber and an ileal chamber, wherein the container 1 of the simulated gastric chamber is communicated with the container 2 of the simulated duodenal chamber through a tube, the container 2 of the simulated duodenal chamber is communicated with the container 3 of the simulated ileal chamber through a tube, further comprising 3 containers 4, 5, 6, respectively, filled with simulated gastric fluid or simulated intestinal fluid, the container 4 filled with simulated gastric fluid is communicated with the simulated gastric chamber through a tube, the container 5 filled with simulated intestinal fluid is communicated with the simulated duodenal chamber through a tube, the container 6 filled with simulated intestinal fluid is communicated with the simulated ileal chamber through a tube, peristaltic pumps are arranged on each tube, wherein the simulated duodenal chamber and the simulated ileal chamber are added with n-octanol as absorption phases to simulate the absorption of drugs in the intestinal tract, and the containers of the simulated gastric chamber, the duodenal chamber and the ileal chamber are applied with a pick-up on-line optical fiber ultraviolet detection system.
In some embodiments, the containers 1, 2, 3 are all dissolution cups.
In some embodiments, pH meters may also be used in containers simulating the gastric, duodenal and ileal compartments.
In some embodiments, the containers simulating the gastric, duodenal and ileal compartments are all in a 37 ℃ water bath.
The present disclosure also provides methods of predicting in vivo performance of a sedimentation inhibitor, comprising using a biphasic gastrointestinal modeling system.
The present disclosure also provides a method of predicting the behavior of an oral drug in vivo, comprising the use of a biphasic gastrointestinal modeling system.
The present disclosure also provides methods of predicting in vivo performance of a sedimentation inhibitor in an apatinib pharmaceutical composition, including the use of a biphasic gastrointestinal mimicking system.
Drawings
Fig. 1: dual phase gastrointestinal simulation system (BGIS) schematic
Fig. 2: solubility-pH diagram
Fig. 3: results of monitoring drug concentration in each chamber of biphasic gastrointestinal simulation system
Fig. 4A: supersaturation degree variation of duodenal chamber
Fig. 4B: jejunal chamber supersaturation variation
Fig. 5: microscopic image of apatinib precipitation process
Fig. 6: apatinib precipitate electron microscope image
Fig. 7: DSC thermogram of apatinib precipitate
Fig. 8: x-ray diffraction pattern of apatinib precipitate
Fig. 9: time profile of apatinib groups
Fig. 10: in vitro dissolution-time curve
Fig. 11: in vivo absorption score-time curve
Fig. 12: levy diagram
Fig. 13: correlation between in vitro dissolution fraction and in vivo absorption fraction
Fig. 14: predicted and measured plasma concentration-time curve
Detailed Description
Example 1: solubility determination
Preparation of dissolution medium:
disodium hydrogen phosphate-citric acid buffer solution
300ml of 0.2mol/L Na 2 HPO 4 And 0.1mol/L citric acid solution, adding standard FaSSIF powder, adding 1000mg of CoPVP into 100ml, adding 1000mg of HPMC into 100ml to obtain three groups of buffer solutions (i.e. a sedimentation inhibitor-free group, a CoPVP group and an HPMC group), and mixing the groups according to different proportions to prepare disodium hydrogen phosphate-citric acid buffer solutions with pH values of 2, 3, 4, 4.7, 5, 6 and 6.5.
Saturated solubility sample preparation:
taking a small amount of apatinib mesylate, respectively adding 3ml of each buffer solution (n=3), carrying out ultrasonic treatment for 20min to ensure that the API is dispersed and is beneficial to dissolution, shaking for 24h at 37 ℃, centrifuging at 4500rpm, taking 200 μl of supernatant, uniformly mixing with 800 μl of mobile phase diluent, and carrying out sample injection to detect the content.
HPLC content determination:
preparing a standard substance: taking 25.00mg of apatinib free base in a 25ml volumetric flask and diluting to the concentration of 1, 3, 10, 30, 100, 300 and 1000 mug/ml respectively by acetonitrile to fix the volume.
Chromatographic conditions: at 10mmol/L KH 2 PO 4 (10% H3PO4 to 3.0) mobile phase A, acetonitrile mobile phase B, mobile phase A: mobile phase b=60: 40, flow rate 1.0mL/min, isocratic elution 10min, column temperature 30 ℃, detection wavelength 260nm, sample injection 10 μl, chromatographic column Kromasil 100-5C18 (250×4.6mm,5 um).
As a result, square ■ indicates no PI (sedimentation inhibitor), triangle ∈ indicates coppp, and circle ∈ indicates HPMC, as shown in fig. 2. The solid line is a fitted curve.
Example 2: dissolution detection based on biphasic gastrointestinal simulation system
The device is shown in figure 1, and has 3 dissolution cups for respectively representing stomach, duodenum and jejunum; 5 peristaltic pumps simulate gastrointestinal transport of the liquid medicine and secretion of gastric juice and intestinal juice; n-octanol above the physiological-related medium aqueous solution is used as an absorption phase to simulate the absorption of the intestinal wall to the medicine in the intestinal tract; probes of a nylon online optical fiber ultraviolet detection system are respectively arranged in two-phase solutions of a stomach cavity, a duodenum cavity and an ileum cavity so as to monitor the drug concentration of each cavity in real time; in addition, pH probes are placed in the aqueous phases of the duodenal and ileal compartments to monitor pH changes during gastrointestinal transit.
Specific operation parameters:
the gastric chamber simulates the stomach, initially 300ml of drug-containing FaSSGF, the a pump simulates gastric emptying, which is pumped into the duodenal chamber with a pump speed of v over time t out =ln (2) 300 xe (-ln (2) t/8)/8+1, c pump mimics gastric secretion pumping 1ml/min FaSSGF;
the duodenal chamber simulates the duodenum, initially 50ml simulated intestinal fluid and 100ml n-octanol, receiving FaSSGF transported by pump a, pump B pumps the aqueous phase into the ileum chamber, the pump speed changing over time t to v=ln (2) 300 xe (-ln (2) t/8)/8+2, while peristaltic pump D simulates intestinal fluid secretion pumping v=1 ml/min;
jejunal compartments simulate jejunum, initially 100ml simulated intestinal fluid and 100ml n-octanol, receiving simulated intestinal fluid transported by the B pump, while the E pump simulated intestinal fluid is secretively pumped into v=1 ml/min.
A. And B, controlling the two pumps by a singlechip programmed by Arduino software, so that the liquid in the gastric cavity is emptied to meet the first-level kinetic speed, and simultaneously, the constant volume of the duodenal cavity is met. The pump run time was 40min after which the solution volume in each chamber remained constant.
Each chamber was magnetically stirred at 100rpm in a 37℃water bath.
The change in the volume V of the aqueous phase of each chamber over time t can be described by the following formula:
V g ＝V s，0 ×e -(ln(2)×t/GE)
V d ＝V d，0
V j ＝V j，0 +V s，0 x(1-e -(ln(2)×t/GE) )+(v g +v d +v j )×t
here V g 、V d And V j Representing the volumes of the stomach, duodenum and jejunum chambers, respectively, at time t; v (V) (s，0) 、V (d，0) And V (j，0) Representing the initial volumes of physiologically relevant medium in the gastric (300 ml), duodenal (50 ml) and jejunal (100 ml) chambers, respectively; GE indicates the half-gastric emptying period (8 min); v g 、v d And v j The secretion pumping speeds of the gastric cavity, the duodenal cavity and the jejunum cavity are respectively shown (all are 1 ml/min).
Absorption test of apatinib in a biphasic gastrointestinal simulation system simulating the gastrointestinal tract of a mouse
Preparing a solution:
because the pH value of the gastrointestinal tract of the mice and the pH value of the gastrointestinal tract of the human body are different to a certain extent, the pH has great influence on the process of super-dissolution and precipitation of BCS II B medicaments, and great deviation is generated when the correlation between the inside and the outside of the three-dimensional body is established. Reference data, therefore, were obtained by adjusting the pH of simulated duodenal fluid and empty intestinal fluid to the physiological values of mice used in vivo experiments, respectively: 4.7 and 5.0.
Simulated duodenal fluid (Mouse Fasted State Simulated Duodenal Fluid, mfaassdf): the pH was adjusted to 4.70 by mixing 0.2mol/L disodium hydrogen phosphate with 0.1mol/L citric acid solution.
Simulated jejunal fluid (Mouse Fasted State Simulated Jejunal Fluid, mfacssjf): mixing disodium hydrogen phosphate 0.2mol/L and citric acid 0.1mol/L at a proper ratio, adjusting pH to 5.00, adding FaSSIF powder 2.240g, dissolving, and standing for 2 hr.
Simulated duodenal secretions (Mouse Fasted State Simulated Duodenal Secretion, mfacsds): formulated at 4-fold concentration according to mfaassdf method.
Jejunal secretion (Mouse Fasted State Simulated Jejunal Secretion, mfacsjs) was simulated: formulated at 4-fold concentration according to mfacssjf method.
The content determination method comprises the following steps:
BGIS on-line monitoring: pion online optical fiber ultraviolet detection system
The second-order guide range 335-340 probe optical path is 2mm and 1mm respectively establishes standard curves,
after the blank is deducted from the corresponding non-drug containing medium, the change of the drug content is monitored on line.
Evaluation of Settlement inhibition efficacy
In fig. 3, a is the gastric compartment, B is the duodenal compartment, C is the jejunal compartment, D is the duodenal absorption compartment, E is the jejunal absorption compartment, and F is the drug absorption percentage f_vitro; squares represent apatinib-only groups, triangles represent coppp-containing groups, circles represent HPMC-containing groups, stars represent pH values, and dashed lines represent saturated solubility for the corresponding color group at the current pH value. (n=3)
Percentage of drug in vitro absorption F/u Vitro ％＝(C DO ×V DO +C JO ×V JO )/((C 0 ×V (s，0) ))×100％
C DO C (C) JO Is the duodenumChamber, jejunum absorption Chamber drug concentration, V DO V (V) JO The volume of n-octanol of the phase solvent is absorbed by the duodenum and jejunum.
Fig. 4A and 4B show changes in supersaturation in the duodenal and jejunal compartments, respectively.
Since the apparent solubility of the drug changes with the addition of the sedimentation inhibitor, the super-solubility (Supersaturation Degree) should be the ratio of the measured concentration to the solubility of the corresponding group when evaluating the sedimentation inhibition effect, i.e
SD＝S x，t /S x，0
Although the concentration of HPMC group is smaller than that of CoPVP group, coPVP has the effect of improving the solubility of apatinib, the sedimentation inhibition effect is higher than that of HPMC, and the super-solubility maximum value of HPMC group SD is in the duodenal chamber D，H，Max =9.82, copp group SD D，C，Max =6.98, apatinib group SD D，A，Max =3.98, more pronounced in jejunum, super solubility maximum HPMC group SD J，H，Max =3.6, copp group SD J，C，Max =1.6, apatinib group SD J，A，Max ＝1.1。
SD Max The maximum effect of the sedimentation inhibitor on the super-dissolution can be evaluated, and to evaluate the continuous effect of the sedimentation inhibitor on the super-dissolution, the area under the super-solubility curve (Area Under Curve of SD, AUC) SD )
The evaluation results are shown in the following table:
TABLE 1 evaluation of CoPVP and HPMC Settlement inhibition efficacy index results
Example 3 polarized light microscope and electron microscope observation
The apatinib and the solutions of each group are prepared according to the method, and are evenly mixed with the simulated intestinal juice according to the ratio of 1:2, 1 drop is taken on the glass slide with the groove, the glass slide carefully covers the drop, and the precipitation process is continuously observed under the same visual field.
The precipitate obtained from each in vitro sedimentation simulation experiment was centrifuged at 3800r/min for 10min and dried under vacuum at 30℃overnight. And taking a proper amount of precipitate on the copper plate, and shooting the precipitate form by a scanning electron microscope.
Device information: japan electronics, scanning electron microscope, model: JSM-6510.
The experimental operation process comprises the following steps: and (3) a proper amount of dried sample is adhered to a sample table, and a layer of gold film with the thickness of about 20nm is plated on the surface of the sample by an ion sputtering instrument. And then the sample is moved to a sample bin of a scanning electron microscope for vacuumizing, after the vacuum meets the test requirement, electrons are emitted under high pressure, the focused electron beam interacts with the sample, secondary electron emission is excited, the secondary electron emission quantity changes along with the change of the surface morphology of the sample, and secondary electrons are collected through a detector to obtain a secondary electron image reflecting the surface morphology of the sample. The accelerating voltage is selected to be 10kV or 15kV.
Fig. 5 is a micrograph of an apatinib precipitation process. The A apatinib group, the B group containing CoPVP and the C group containing HPMC are respectively 5min, 60min and 120min. The results show that apatinib can form crystals rapidly, and CoPVP and HPMC can inhibit the generation of crystals obviously.
Fig. 6 is an electron microscope image of apatinib pellet. A is apatinib group; b is a CoPVP-containing group; and C is HPMC-containing group. The apatinib precipitates to form cluster crystals, the CoPVP is isolated from the precipitates by a high molecular network structure, so that the formation of larger crystals is avoided by fine particles, HPMC has a certain inhibition effect, and the precipitated particles are smaller square crystals. Each set of results corresponds to a polarized microscope result.
EXAMPLE 4 XRD and DSC analysis
The precipitate obtained from each in vitro sedimentation simulation experiment was centrifuged at 3800r/min for 10min and dried under vacuum at 30℃overnight. And taking a proper amount of precipitate on a monocrystalline silicon plate for XRD analysis.
About 2mg of the precipitate was taken out in a 5mm aluminum crucible, and the crucible was closely weighed and capped for DSC analysis.
XRPD test conditions: BRUKER D8 DISCOVERY XRPD (40 KV,40mA,2-Theta mode, start10 °, increment19 °, end48 °)
DSC test conditions: METTLER TOLEDO DSC 3+ (25-300 ℃,10 ℃ C./min, N2 50ml/min purgegas)
FIG. 7 shows DSC thermograms of apatinib API, apatinib mesylate and precipitate samples collected by solvent transfer experiments, without sedimentation inhibitor (PI) (a), with CoPVP (b), with HPMC (c), apatinib mesylate (d) and apatinib base (e) endothermic peaks at 153.15 ℃, 152.70 ℃, 152.70 ℃, 201.62 ℃ and 167.99 ℃, respectively. The melting point of the precipitate is about 50 ℃ lower than that of the apatinib mesylate powder, and even 15 ℃ lower than that of the common apatinib base crystal form.
FIG. 8 is an X-ray diffraction pattern of apatinib precipitate without PI (a), coPVP (b), HPMC (c), naCl (d), apatinib free base (e), apatinib mesylate (f), coPVP (g) and HPMC (h).
EXAMPLE 5 in vivo absorption test of apatinib in mice
Experimental animals:
c57BL/6 male mice were purchased from Kvins laboratory animal Co., ltd., license number SCXK (Su) 2016-0010, SPF grade.
Preparing a solvent:
and weighing 10.2mg of apatinib, dissolving in 8ml of propylene glycol, adding 12ml of physiological saline, and uniformly mixing to obtain solution A containing 0.5mg/ml of apatinib for injection. Weighing 50.6mg of apatinib, and dissolving in 50ml of pH 2HCl solution acid liquor to obtain a B solution containing 1mg/ml of apatinib for stomach irrigation; taking 20ml of solution B and 200mg of dissolved CoPVP to obtain a gastric lavage C solution containing 1% CoPVP and 1mg/ml of apatinib; and taking 20ml of solution B to dissolve 200mg of HPMC, thus obtaining the gastric lavage solution D containing 1% HPMC and 1mg/ml of apatinib.
C57BL/6 mice are male, weight 20+ -2 g, after fasted and water-free for one night, the mice are randomly divided into 4 groups, and intravenous injection groups are injected with 5ml/kg (namely 2.5 mpk) of A liquid by tail vein; the remaining lavage 10ml/kg (i.e. 10 mpk) was the sedimentation inhibitor free group, the CoPVP containing group, and the HPMC containing group, respectively. 0.083, 0.25, 0.5, 1, 2, 4, 6h after administration, about 50. Mu.l of blood was collected from the orbit, and the supernatant was collected by centrifugation at 4000rpm for 10min in an EDTA-K2-type EP tube.
And (3) measuring the blood medicine content:
instrument for measuring and controlling the intensity of light
High performance liquid chromatography-mass spectrometry system: shimadzu CBM30Alite liquid phase system (containing Shimadzu LC30AD pump, DGU-20A3 in-line vacuumA degasser, shimadzu SIL30AC thermostated autosampler, shimadzu CTO20AC column incubator); SCIEX Triple Quad TM QTRAP 5500Mass Spectrometer system (ESI interface ion source); G560E vortex mixer (U.S. Scientific Industries, inc.), legend Micro 21R refrigerated high speed centrifuge (Thermo Fisher Co.); meltretolidox XSE204 electronic balance; milli-QA10 ultra-pure water machine (Millipore Co., U.S.A.).
Preparation of test article
Control solution: apatinib 10.13mg was precisely weighed, dissolved in 10ml of methanol to prepare a stock solution of 1mg/ml, and diluted with 50% methanol-water to prepare a series of standard solutions of 10, 30, 100, 300, 1000, 3000 ng/ml.
Quality control solution: apatinib 10.15mg was precisely weighed, dissolved in 10ml of methanol to prepare a stock solution of 1mg/ml, and diluted with 50% methanol-water to prepare a series of quality control solutions of 20, 200, 2400ng concentration.
Internal standard solution: gefitinib 10.18mg was precisely weighed, dissolved in 10ml of methanol to prepare a stock solution of 1mg/ml, and diluted with 50% methanol-water to prepare an internal standard solution of 10 ng.
Standard curve solution: sequentially adding 50 μl of internal standard solution, 10 μl of blank plasma and 10 μl of each reference solution, mixing by vortex, adding 430 μl of acetonitrile, mixing by vortex, centrifuging at 10000rpm for 10min, and placing appropriate amount of supernatant into sample bottle for insertion tube.
Replacing the control solution with a quality control sample to obtain 3 concentration quality control samples; replacing the standard solution with 50% methanol-water to obtain a Blank liquid; replacing the internal standard solution and the reference substance solution with 50% methanol-water, and Double Blank solution; and replacing blank plasma with each plasma to be detected, and replacing the reference substance solution with 50% methanol-water to obtain each sample.
Chromatographic conditions
Chromatographic column Hypersil GOLD (50 mm. Times.2.1 mm,3 μm), 5mmol/L aqueous ammonium acetate: acetonitrile=40:60 (V/V), flow rate 0.4mL/min, column temperature 40 ℃, sample injection amount 5 μl.
Mass spectrometry conditions
The ion source is an electrospray ionization source (ESI), and the Mass-to-charge ratio (m/z) Q1 Mass (Da) is selectively monitored by positive ion mode detection, capillary voltage, drying gas temperature, drying gas flow rate and atomization gas pressure: 398.3 Q3 Mass (Da) 184.3 (apatinib) and Q1 Mass (Da): 447.1 Ion peak of Q3 Mass (Da) 128.1 (internal standard gefitinib), fragment voltage CE (volts) of 32 and 50, time:100msec.
Fig. 9 is a graph of the drug time profile (bioavailability for each group of figures) for each group of apatinib, ■ for the PI-free group (Blank), for the PI-containing group (i.e., c-containing group (i.v.)), for the c-containing group (i.e., c-containing group (i.c.).
TABLE 3 pharmacokinetic parameters of apatinib
The results show that the CoPVP and HPMC can obviously improve the bioavailability of the apatinib, and the bioavailability of the apatinib is increased from 39% to 60% and 52%, namely, the relative bioavailability is improved by 151% and 133%. Can obviously inhibit the generation of crystals. (P <0.05, P < 0.001)
EXAMPLE 6IVIVC construction
Obtaining a pK parameter through a static injection time curve based on GastroPlus software, substituting the pK parameter into an oral administration time curve and deconvolving to obtain an in vivo absorption fraction-time curve Fa-t of the oral administration medicine; taking the in vitro absorption percentage-time curve M-t and Fa-t of the medicine as levy plot to obtain scaling parameters, and scaling the M-t according to the scaling parameters; and carrying out convolution operation on the scaled M-t to obtain a predicted drug time curve (C-t).
Fig. 10 is the in vitro solubility over time of the sum of two organic phases: square ■ shows no PI, triangle shows coppp, circle shows HPMC; the solid line is a fitted curve of the dicarb model.
FIG. 11 is a fraction absorbed over time by Loo-Riegelman deconvolution.
Fig. 12 is a Levy diagram: square ■ represents no PI, triangle represents coppp, and the dashed line is regression.
Figure 13 is a correlation between the fraction dissolved in vitro and the fraction absorbed in vivo, square ■ shows no PI, triangle is fig. d, coppp is indicated, and the dashed line is regression.
Fig. 14 is a graph of predicted and actual drug plasma concentration versus time: square ■ shows no PI, triangle shows coppp, and circle shows HPMC. Solid lines with three colors represent the corresponding predicted plasma concentrations of apatinib in each group.
TABLE 4 prediction error of Cmax and AUC values based on correlation model
From Table 4, it can be seen that both internally and externally validated PEs are less than 10% and meet the class A IVIVC standard. The results indicate that BGIS is a suitable device for assessing the supersaturation of apatinib in vitro while screening PI. The IVIVC can be used to establish a specification for assessing the effect of precipitation inhibitors on apatinib supersaturation by predicting in vivo performance through in vitro experiments. Selecting the appropriate PI and even screening the appropriate formulation will save cost and time. The observed AUC obtained with Gastroplus is slightly higher than the average AUC obtained with WinNonlin due to internal integration method differences.
Claims (8)
1. An oral pharmaceutical composition comprising apatinib or a pharmaceutically acceptable salt thereof, further comprising a sedimentation inhibitor, wherein the sedimentation inhibitor is hydroxypropyl methylcellulose and/or copovidone, and the weight ratio of the sedimentation inhibitor to the apatinib or the pharmaceutically acceptable salt thereof can be selected from 20:1-1:10.
2. The pharmaceutical composition of claim 1, wherein when the sedimentation inhibitor is hydroxypropylmethyl cellulose, the D90 of apatinib or a pharmaceutically acceptable salt thereof is greater than 10 μm.
3. The pharmaceutical composition of claim 1, in a dosage form selected from the group consisting of tablets, capsules, granules, or powders.
4. A pharmaceutical composition according to claim 3, which is a tablet.
5. The pharmaceutical composition of claim 1, further comprising a disintegrant selected from at least one of croscarmellose sodium, crospovidone, sodium carboxymethyl starch, calcium carboxymethyl cellulose, low substituted hydroxypropyl cellulose, starch, pregelatinized starch, alginic acid.
6. The pharmaceutical composition of claim 1, further comprising a filler selected from the group consisting of microcrystalline cellulose, lactose, mannitol, pregelatinized starch, dextrin, sorbitol, sucrose, dibasic calcium phosphate, anhydrous dibasic calcium phosphate, calcium sulfate.
7. The pharmaceutical composition of claim 1, further comprising a lubricant selected from stearic acid, magnesium stearate, aerosil, talc, polyethylene glycol 4000, polyethylene glycol 6000, palmitic acid, calcium stearate, colloidal silica, carnauba wax, sodium stearyl fumarate.
8. A method of predicting the in vivo performance of hydroxypropylmethyl cellulose and/or copovidone in an oral pharmaceutical composition of apatinib or a pharmaceutically acceptable salt thereof, comprising using a biphasic gastrointestinal simulation system comprising 3 containers 1, 2, 3, respectively, simulating gastric, duodenal and ileal chambers, the container 1 of the simulated gastric chamber being in communication with the container 2 of the simulated duodenal chamber via a tube, the container 2 of the simulated duodenal chamber being in communication with the container 3 of the simulated ileal chamber via a tube, and further comprising 3 further containers 4, 5, 6, containing simulated gastric fluid or simulated intestinal fluid, the container 4 of the simulated gastric fluid being in communication with the simulated gastric chamber via a tube, the container 5 of the simulated intestinal fluid being in communication with the simulated duodenal chamber via a tube, peristaltic pumps being provided on each tube, wherein the simulated duodenal chamber and the simulated ileal chamber are supplemented with octanol as an absorption phase to simulate the absorption of a drug in the intestinal wall, and the simulated gastric chamber, the duodenal chamber and the ultraviolet chamber being detected in an on-line ultraviolet optical fiber system.
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