CN108309934B - Gefitinib nanosuspension and preparation method and application thereof - Google Patents

Gefitinib nanosuspension and preparation method and application thereof Download PDF

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CN108309934B
CN108309934B CN201810412557.4A CN201810412557A CN108309934B CN 108309934 B CN108309934 B CN 108309934B CN 201810412557 A CN201810412557 A CN 201810412557A CN 108309934 B CN108309934 B CN 108309934B
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吴浩天
刘宇
韩佳婧
潘春娇
郭忠秋
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Abstract

The invention relates to a gefitinib nanosuspension, a preparation method and application thereof, belonging to the field of pharmaceutical formulation. The invention adopts a precipitation method combined with high-speed shearing and high-pressure homogenization to prepare the nano-suspension. The prescription is optimized by adopting a single-factor investigation method, the indexes of the preparation, such as particle size, PDI, Zeta potential, form and the like, are investigated, and the dissolution rate of the medicament is investigated by an in-vitro release experiment. The gefitinib nanosuspension is characterized in that: comprising gefitinib, lecithin and Sodium Dodecyl Sulfate (SDS). The particle size of the medicine in the suspension is 100-500 nm. The concentration of gefitinib in the suspension is 0.25-1 mg/ml. The nano suspension has the advantages of simple prescription, excellent effect and simple and controllable preparation method, improves the solubility of the medicine in water, is beneficial to improving the administration form of the medicine, and is beneficial to oral administration and absorption of the medicine.

Description

Gefitinib nanosuspension and preparation method and application thereof
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a gefitinib nanosuspension and a preparation method of lyophilized powder thereof.
Background
Nanosuspensions (NS) are submicron colloidal dispersions of pure drug nanoparticles prepared by homogenization, wet milling, etc., with a trace amount of surfactant as the suspending agent. The nano suspension is mainly applied to drugs with poor solubility. The preparation of the nanometer suspension from the insoluble medicine is not only beneficial to the stability, the solubility and the dissolution of the medicine, but also can improve the bioavailability of the medicine, and is more suitable for the clinical application of the pharmaceutical preparation.
Gefitinib (curcumol), a selective Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor, is commonly expressed in solid tumors of epithelial origin. Inhibition of EGFR tyrosine kinase activity can interfere with tumor growth, metastasis and angiogenesis, and increase apoptosis of tumor cells. Is suitable for treating locally advanced or metastatic non-small cell lung cancer (NSCLC) which has been treated by chemotherapy. In the currently clinically applied gefitinib tablet, after oral administration, cancer patients have slow absorption and an average terminal half-life of 41 hours, the plasma peak concentration of gefitinib appears 3 to 7 hours after administration, and reaches a steady state after 7 to 10 days of administration, and the average absorption bioavailability of the cancer patients is 59%. Therefore, other administration forms of gefitinib, such as nano suspension preparation, are developed, which are beneficial to improving the absorption rate and bioavailability of the medicament and are beneficial to clinical medication of the medicament.
Disclosure of Invention
The invention aims to provide a gefitinib nanosuspension and a preparation method thereof, so as to improve the dissolution rate of a medicament and improve the bioavailability of the medicament.
The invention adopts the following technical scheme: a gefitinib nanosuspension is prepared by gefitinib and a surfactant through high-speed shearing and high-pressure homogenization, wherein the surfactant is one or a mixture of more than two of lecithin, PVP, pluronic F68 and Sodium Dodecyl Sulfate (SDS).
Preferably, the surfactant is a mixture of lecithin and SDS.
More preferably, gefitinib to lecithin to SDS-1: 0.4 to 0.6:0.25 to 4 by mass ratio.
More preferably, gefitinib to lecithin to SDS is 1:0.5:0.5 by mass ratio.
The particle size of the gefitinib nanosuspension is 100-500 nm.
The preparation method of the gefitinib nanosuspension is a precipitation method combined with a high-speed shearing and high-pressure homogenization method, and comprises the following steps:
1) dissolving gefitinib raw material medicine in methanol to obtain an organic phase;
2) dissolving surfactant in purified water to obtain water phase;
3) slowly dropping the organic phase into the water phase in a water bath under stirring to uniformly disperse the gefitinib in the aqueous solution of the surfactant, and performing rotary evaporation to remove methanol to obtain a crude suspension;
4) and sequentially carrying out high-speed shearing treatment and high-pressure homogenization treatment on the coarse suspension to obtain the gefitinib nano suspension.
Preferably, the amount of methanol used in step 1) is 1-5ml per 50mg of gefitinib; the temperature of the water bath in the step 3) is 0-80 ℃; the step 4) is that the high-speed shearing treatment is as follows: the shearing speed is 10000-; the high-pressure homogenization treatment comprises the following steps: the homogenization pressure is 58015-133568psi, and the number of homogenization times is 3-20.
More preferably, the amount of methanol used in step 1) is 1-5ml per 50mg of gefitinib; the temperature of the water bath in the step 3) is 0 ℃; the step 4) is that the high-speed shearing treatment is as follows: the shearing speed is 20000rpm, and the shearing time is 2 min; the high-pressure homogenization treatment comprises the following steps: homogenization pressure was 87022psi, and the number of homogenizations was 15.
The gefitinib nanosuspension freeze-dried powder is prepared by mixing the gefitinib nanosuspension with a freeze-drying protective agent and freeze-drying the mixture.
Preferably, the lyoprotectant is one or a combination of more than two of mannitol, lactose and glucose.
The gefitinib nanosuspension is applied to preparation of antitumor drugs.
The invention has the beneficial effects that:
1. the gefitinib nanosuspension reduces the particle size of the medicament, increases the specific surface area and obviously improves the solubility of the raw material medicament.
2. In vitro dissolution tests show that the gefitinib nanosuspension can greatly improve the dissolution rate of the raw material medicaments.
3. The gefitinib nanosuspension has the advantages of simple prescription process, small dosage of a surfactant, no organic solvent residue, good preparation safety, lower cost and easy industrialization.
4. The gefitinib nanosuspension can be further freeze-dried, and the freeze-dried powder has good stability and is easy to store and transport.
5. The gefitinib nanosuspension overcomes the defect of insufficient solubility of raw material medicines, improves the dissolution rate of the medicine, can accelerate the absorption rate of the medicine after oral administration, can improve the bioavailability, and is beneficial to promoting the further research and development of the application of gefitinib preparations.
Drawings
Figure 1 is a particle size distribution plot of gefitinib nanosuspension of example 4, formulation 2.
Figure 2 is a transmission electron micrograph of gefitinib nanosuspension of example 4, formulation 2.
Figure 3 is a liquid chromatogram of gefitinib of example 5.
Figure 4 is the in vitro cumulative release profile of the gefitinib nanosuspension of example 5.
Detailed Description
The invention is further illustrated by the following specific examples, but it should be noted that the scope of protection of the invention should not be limited in any way by these examples.
Example 1
The preparation method of the gefitinib nanosuspension comprises the following steps:
1) 50mg of gefitinib was completely dissolved in 1ml of methanol to obtain an organic phase.
2) 25mg of SDS and 25mg of lecithin were dissolved in 50ml of purified water to obtain an aqueous phase.
3) In an ice-water bath (0 ℃ C.) with stirring (3X 10)3r.min-1), slowly dropping the organic phase into the aqueous phase to uniformly disperse the organic phase. And after the dropwise addition is finished, removing the methanol by rotation to obtain a crude mixed suspension.
4) The resulting crude suspension was suspended at 2X 104Shearing at high speed for 2min at rpm, and homogenizing for 15 times at 87022psi pressure to obtain Gefitinib nanosuspension.
Influence of (A) reaction temperature
Changing the temperature in the step 3) without changing other conditions, and examining the influence of the temperature change in the preparation process on the results, wherein the temperature is respectively ice water bath (0 ℃), room temperature (25 ℃) and 60 ℃ water bath, and the results are shown in Table 1.
TABLE 1 Effect of temperature
Figure BDA0001648442980000031
As can be seen from Table 1, in the preparation process of the nanosuspension, when the temperature is high, the particle movement rate is accelerated, the collision probability is increased, the aggregation among the particles is increased, the nanosuspension is easy to grow into crystals and particles, so that the particles grow up, and the temperature needs to be reduced to prevent the particles from fusing with each other, thereby improving the stability. The result shows that the particle size and the polydispersity index are smaller during ice-water bath, so the invention adopts an ice-bath method to reduce the temperature to prepare the nano suspension.
(II) Effect of high shear time
Changing the high-speed shearing time in the step 4) to be 0, 2, 4, 6 and 8min respectively without changing other conditions, and investigating the influence of the shearing time on the nano suspension, wherein the results are shown in a table 2.
TABLE 2 Effect of high shear time
Figure BDA0001648442980000032
Figure BDA0001648442980000041
As can be seen from Table 2, the particle size of the coarse suspension is reduced by high-speed shearing, the risk of blocking a high-pressure homogenizing pipeline is reduced, the particle size of the nano suspension is smaller when the nano suspension is sheared for 2min, the influence on the final particle size change is not large when the shearing time is continuously increased, the emulsification phenomenon is aggravated and is not suitable for the next reaction, and the high-speed shearing for 2min is ideal time.
Influence of (III) homogenizing pressure
The effect of high-pressure homogenization pressure on the particle size was examined while keeping other conditions unchanged, and the particle size of the nanosuspension was measured under different pressures by homogenizing the suspension obtained after high-speed shearing in step 4) for 15 times under 58015psi, 72518psi, 87022psi, 101526psi and 133568psi, and the results are shown in table 3.
TABLE 3 Effect of high pressure homogenization pressure on particle size
Figure BDA0001648442980000042
As can be seen from Table 3, when the homogenization pressure is greater than 87022psi, the particle sizes are all small, and the PDI is less than 0.3, which meets the requirement of relatively uniform particle size. The homogenizing pressure, increased after 87022psi, experienced little change, and was finally selected to be 87022psi in view of instrument losses.
(IV) Effect of number of homogenizers
And (3) keeping other conditions unchanged, examining the influence of the high-pressure homogenization times on the particle size, changing the step 4), homogenizing the suspension after high-speed shearing under 87022psi pressure for 3, 9, 15 and 20 times respectively, and measuring the particle size of the nano suspension under different homogenization times. The results are shown in Table 4.
TABLE 4 influence of number of high-pressure homogenizers on particle size
Figure BDA0001648442980000043
As can be seen from table 4, the particle size is smaller when the number of homogenization times is 15, the distribution is more uniform, and the degree of particle size increase is not obvious with increasing the number of homogenization times, which is an ideal number of homogenization times, and is 15.
Example 2 Gefitinib nanosuspension
The preparation method of the gefitinib nanosuspension comprises the following steps:
1) 50mg of gefitinib was completely dissolved in 1ml of methanol to obtain an organic phase.
2) 25mg of SDS and 25mg of lecithin were dissolved in 50ml of purified water to obtain an aqueous phase.
3) In an ice-water bath (0 ℃ C.) with stirring (3X 10)3r·min-1) And slowly dripping the organic phase into the water phase to uniformly disperse the organic phase. And after the dropwise addition is finished, removing the methanol by rotation to obtain a crude mixed suspension.
4) The resulting crude suspension was suspended at 2X 104Shearing at high speed for 2min at rpm, and homogenizing for 15 times at 87022psi pressure to obtain Gefitinib nanosuspension.
(one) Effect of the type of active agent
The other conditions were not changed, the surfactant type in step 2) was changed, and the effect of different surfactant types on the nanosuspensions was examined, with the results shown in table 5.
TABLE 5 Effect of surfactant classes
Figure BDA0001648442980000051
And no surfactant is added.
As can be seen from table 5, the type of surfactant has a large influence on the particle size and stability of the nanosuspension. When lecithin and SDS are mixed to be used as the surfactant, the nano suspension has small particle size and good stability.
(II) Effect of dose ratio of active Agents
The amount of SDS as a surfactant in step 2) was varied under otherwise unchanged conditions, and the effect of different surfactant ratios on the nanosuspensions was examined, with the results shown in Table 6.
TABLE 6 Effect of surfactant ratio
Figure BDA0001648442980000052
As can be seen from table 6, the particle size was minimized for the optimum surfactant dosage when gefitinib lecithin SDS is 1:0.5: 0.5.
Example 3 Gefitinib nanosuspension lyophilized powder
The preparation method of the gefitinib nanosuspension freeze-dried powder comprises the following steps:
1) 50mg of gefitinib was completely dissolved in 1ml of methanol to obtain an organic phase.
2) 25mg of SDS and 25mg of lecithin were dissolved in 50ml of purified water to obtain an aqueous phase.
3) In an ice-water bath (0 ℃ C.) with stirring (3X 10)3r·min-1) And slowly dripping the organic phase into the water phase to uniformly disperse the organic phase. And after the dropwise addition is finished, removing the methanol by rotation to obtain a crude mixed suspension.
4) The resulting crude suspension was suspended at 2X 104Shearing at high speed for 2min at rpm, and homogenizing for 15 times at 87022psi pressure to obtain Gefitinib nanosuspension.
5) Adding the freeze-dried powder into the prepared gefitinib suspension as shown in Table 7, shaking uniformly, freezing for 24h in a refrigerator at-80 ℃, and freeze-drying for 8h in a freeze-drying machine to obtain the gefitinib nanosuspension freeze-dried powder with compact, glossy and cake-shaped surface. The results are shown in Table 7.
TABLE 7 Gefitinib nanosuspension lyophilized powder prepared from different lyoprotectants
Figure BDA0001648442980000061
And injection, wherein a freeze-drying protective agent is not added.
As shown in Table 7, after 5% and 10% mannitol is added for freeze-drying, the freeze-dried powder is loose and uniform in texture, purified water is added for ultrasonic redissolution, the freeze-dried powder can be dispersed uniformly quickly, the particle size change is small after the redissolution is determined, the stability is good, and the effect of 10% mannitol is better than that of 5% mannitol, so that 10% mannitol is selected to be added as a freeze-drying protective agent for preparing the freeze-dried powder.
Example 4
And (3) detecting the particle size distribution of the gefitinib nanosuspension by adopting a Nano-ZS (Nano-zero-scanning with zero) nanometer particle size and zeta potential analyzer. Figure 1 is example 2 table 6, gefitinib: lecithin: SDS 1:0.5: particle size distribution diagram of nanosuspension prepared from 0.5 (formulation No. 2), it can be seen from fig. 1 that the average particle size of gefitinib nanosuspension prepared is 140.4 nm.
And observing the form of the gefitinib nanosuspension by adopting a transmission electron microscope. Fig. 2 is a transmission electron microscope image of lyophilized powder of gefitinib nanosuspension prepared with lyophilized powder of 10% mannitol (sample No. 3) in table 7 of example 3. As can be seen from figure 2, the prepared gefitinib nanosuspension particles are uniform spherical, and the particle size is less than 500 nm.
Example 5 in vitro dissolution of Gefitinib nanosuspension
In-vitro dissolution rate comparison tests are carried out on gefitinib raw material medicines and gefitinib nanosuspension freeze-dried powder of a sample No. 3 in example 3, and at different time points, the sample is subjected to content detection and the cumulative release percentage is calculated.
The dissolution test method comprises the following steps: and (3) inspecting the in-vitro dissolution characteristics of the gefitinib nanosuspension and the bulk drug by using a dialysis bag release method. The dissolution temperature is (37 +/-0.5) DEG C, the rotation speed is 100r min－1. Weighing a proper amount of gefitinib raw material drug, putting the gefitinib raw material drug into a dialysis bag, putting the gefitinib raw material drug into 1% SDS-Na PBS (pH 7.4, 20mL), putting another gefitinib nano suspension agent which is equivalent to the same amount of the gefitinib raw material drug into the dialysis bag, and putting the gefitinib nano suspension agent into a PBS (pH 7.4, 20mL) containing 1% SDS-Na by mass fraction. 1mL of the solution was sampled at 0, 5, 10, 15, 20, 30, 60, 90, 120, 150 and 180min and filtered through a 0.45 μm microfiltration membrane. Immediately after sampling, 1mL of isothermal fresh medium was replenished.
Measuring the absorption peak area (A) of the sample at 343nm by using a high performance liquid chromatograph; the mobile phase is methanol: 10mM ammonium acetate solution 80: 20 (V); the temperature of the chromatographic column is 30 ℃, the sample injection flow rate is 1mL/min, and the sample injection amount is 20 mu L; the chromatographic column is as follows: Inertsustatin-C18(4.6X 250nm, 5 μm). The liquid chromatogram of gefitinib is shown in figure 3.
The regression equation of the standard curve of gefitinib is as follows: Y-26.401X +52.151 (r-0.9997). The content of gefitinib is 2.5-160 mu g/mL-1With a good linear relationship in the range. And measuring the absorption peak area of the sample and calculating the concentration of the drug. The drug concentrations measured at different times were plotted against time. The result is shown in fig. 4, and the in vitro accumulative release rate of the gefitinib nanosuspension prepared by the invention is obviously higher than that of the bulk drug.
Example 6 stability of Gefitinib nanosuspensions
The gefitinib nanosuspension lyophilized powder prepared by using 10% mannitol (sample No. 3) as lyophilized powder in Table 7 of example 3 was dispensed into 2mL penicillin bottles, placed at room temperature, sampled at 0, 2, 4, 6 and 8 weeks, and the appearance of the lyophilized powder was observed and the particle size and polydispersity were measured. The results are shown in Table 8.
TABLE 8 stability testing of Gefitinib nanosuspensions
Figure BDA0001648442980000071
As can be seen from Table 8, the samples were allowed to stand at room temperature and maintained good system stability for a long period of time.

Claims (2)

1. A preparation method of gefitinib nanosuspension freeze-dried powder is characterized by comprising the following steps: the method comprises the following steps:
1) dissolving gefitinib raw material medicine in methanol to obtain an organic phase;
2) dissolving surfactant in purified water to obtain water phase; the surfactant is a mixture of lecithin and SDS;
3) slowly dropping the organic phase into the water phase under stirring at the water bath temperature of 0 ℃ to uniformly disperse the gefitinib in the aqueous solution of the surfactant, and removing the methanol by rotary evaporation to obtain a coarse suspension; according to the mass ratio, gefitinib and lecithin are SDS = 1:0.5: 0.5;
4) sequentially carrying out high-speed shearing treatment and high-pressure homogenization treatment on the coarse suspension to obtain gefitinib nano suspension; the high-speed shearing treatment comprises the following steps: the shearing speed is 20000rpm, and the shearing time is 2 min; the high-pressure homogenization treatment comprises the following steps: homogenization pressure 87022psi, 15 homogenization times;
5) mixing the gefitinib nanosuspension with 5-10% mannitol, and freeze-drying to obtain the gefitinib nanosuspension freeze-dried powder.
2. The use of gefitinib nanosuspension lyophilized powder prepared according to the method of claim 1 in the preparation of an anti-tumor medicament.
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