CN110101668A - A kind of preparation method of Gefitinib composite particles - Google Patents
A kind of preparation method of Gefitinib composite particles Download PDFInfo
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- CN110101668A CN110101668A CN201910454802.2A CN201910454802A CN110101668A CN 110101668 A CN110101668 A CN 110101668A CN 201910454802 A CN201910454802 A CN 201910454802A CN 110101668 A CN110101668 A CN 110101668A
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- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
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- A61K9/1658—Proteins, e.g. albumin, gelatin
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Abstract
The invention discloses a kind of preparation methods of Gefitinib composite particles, comprising the following steps: Gefitinib dissolution is obtained good solvent phase by the first step in organic solvent；Second step in deionized water by zein dissolution adjusts pH to being completely dissolved, obtains water phase；Third step mixes the water phase of the good solvent phase of first step preparation and second step preparation, and separation obtains the Gefitinib composite particles after precipitating is precipitated.Gefitinib composite particles stable crystal form provided by the invention, partial size is small, and dissolution rate is high, improves the solubility of Gefitinib, and then improve its bioavilability, provides new selection for the exploitation of oral Geftinat solid pharmaceutical preparation.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of preparation method of Gefitinib composite particles.
Background technique
Gefitinib (Gefitinib, GTN), entitled N- (the chloro- 4- fluorophenyl of the 3-) -7- methoxyl group -6- (3- of chemistry
Quinoline -4- propoxyl group) quinazoline -4- amine, it is a kind of epidermal growth factor (EGFR) tyrosine kinase inhibitor, can interfere with tumour
Growth, transfer and angiogenesis, and increase the apoptosis of tumour cell, it is developed by Astrazeneca AB, Britain, trade name is easily auspicious
It is huskyThe first-line treatment of Patients with Non-small-cell Lung was used for by FDA approval in 2015.In clinical treatment, GTN
Required dosage it is larger, reached 250mg, higher dosage easily causes adverse reaction, such as nausea, diarrhea and vomiting,
It is unfavorable for the treatment of patient.
Gefitinib belongs to the II class drug in Biopharmaceutics Classification system (BCS), in the aqueous solution of pH > 7 almost
It is insoluble, because its extremely low water solubility limits the absorption of its oral preparation in the gastrointestinal tract, so as to cause lower biological utilisation
Degree.Therefore, the solubility for improving Gefitinib is of great significance for the exploitation of its oral solid formulation.
According to Noyes-Whitney equation, specific surface area is can be improved in the reduction of partial size, to improve the dissolution of drug
Degree.The method that tradition reduces diameter of aspirin particle includes micronization, medium milling or high pressure homogenization method, however these methods have consumption
When the problem of consuming energy, and mechanical force be easy to cause the degradation of drug during smashing particle, is particularly unsuitable for heat
Unstable drug.There is patent to disclose the method for improving Gefitinib dissolution rate.Wherein, Chinese patent
CN108309934A (" a kind of Gefitinib nano suspension and its preparation method and application ") is prepared for a kind of Gefitinib and receives
Rice suspension, but need to use the equipment such as high pressure homogenizer, freeze drier, higher cost in preparation process.
During dissolved, it is usually added into some stabilizers and crystallization process is controlled, such as polymer or surface-active
Agent etc..The present invention controls the crystallization process of Gefitinib by the way that zein (Zein) is added, so as to improve its physics and chemistry
Property achievees the purpose that improve bioavilability.
Zein because its abundance, biodegradable and safe and non-toxic feature in terms of drug and gene delivery at
For the biomaterial of great potential.Zein was approved by the FDA in the United States the auxiliary material as tablet and piller coating in 1985.
It, theoretically can be with drug molecule due to having hydrogen bond donor abundant, receptor and hydrophobic region in zein structure
Interaction is generated, influences the crystallization process of drug, and then influence final product form.
Therefore, develop that a kind of easy to operate, equipment requirement is low and the preparation method of the reduction diameter of aspirin particle of low energy consumption has
Very actual meaning.
Summary of the invention
The object of the present invention is to provide a kind of preparation methods of Gefitinib composite particles.
To achieve the goals above, The technical solution adopted by the invention is as follows:
The first aspect of the invention provides a kind of preparation method of Gefitinib composite particles, comprising the following steps:
Gefitinib dissolution is obtained good solvent phase by the first step in organic solvent；
Second step in deionized water by zein dissolution adjusts pH to being completely dissolved, obtains water phase；
Third step mixes the water phase of the good solvent phase of first step preparation and second step preparation, is precipitated to separate after precipitating and obtain
Obtain the Gefitinib composite particles.
The organic solvent is selected from least one of dimethyl sulfoxide, N,N-dimethylformamide.
The dosage of the organic solvent can be selected arbitrarily, and the dosage of the organic solvent can should be at least completely dissolved
Gefitinib, generally 5 of Gefitinib quality times or more, preferably 8-20 times.
Preferably, during by Gefitinib dissolution in organic solvent, it can be by heating (such as heating water bath)
Mode improves the solubility of Gefitinib, and temperature is 5-70 DEG C, preferably 30-70 DEG C, more preferably 40-60 DEG C.
The mass ratio of the Gefitinib and zein is 1:(0.5-10), preferably 1:(2-5).
The adjusting pH is 9-10.
During the dissolution in deionized water by zein, using stirring, ultrasound or it can be vortexed and adjust
The modes such as pH carry out hydrotropy, make system be uniformly mixed subject to.
Drug is precipitated completely by changing the degree of supersaturation of drug in dicyandiamide solution in the present invention, it is therefore desirable to control good
The volume ratio of solvent phase and water phase, in the third step, the body of the water phase of the good solvent phase and second step preparation of first step preparation
Product is than being 1:(40-200), preferably 1:(60-150).
In third step, the present invention by circulator bath control mixed solution temperature, preferably 15-35 DEG C, more preferably
18-25℃。
In the present invention, the separation can carry out lock out operation by conventional method in that art, generally filter, wash, filtering,
Dry, the washing can be carried out with deionized water, and the quality of each deionized water is 40-200 times of Gefitinib, preferably
It 80-150 times, washs and the number filtered is generally 1-6 times, preferably 2-5 times.The dry of this field routine can be used in the drying
Drying method carries out, such as static dry.The static dry such as temperature is dry under conditions of being 40-100 DEG C, and preferably 50-80 DEG C,
Time is 1~48h, preferably 1~for 24 hours；Or it is dried under reduced pressure 4-12h, preferably 5-8h, vacuum condition when decompression is 76mmHg-
450mmHg, preferably 150mmHg.
The second aspect of the invention provides a kind of Gefitinib composite particles of the method preparation.
The partial size of the Gefitinib composite particles is 1-10 μm.
Due to the adoption of the above technical scheme, the present invention has the following advantages and beneficial effects:
Gefitinib composite particles stable crystal form provided by the invention, partial size is small, and dissolution rate is high, improves Gefitinib
Solubility, and then improve its bioavilability, new selection is provided for the exploitation of oral Geftinat solid pharmaceutical preparation.
Usually, during dilution crystallization, the drug particle originally formed is largely unstable crystal form or is without fixed
Shape is easy to drive lower further growth in the degree of supersaturation of solution, so that partial size be made to become larger, screen by many experiments, discovery
Using zein, particle diameter distribution can be obtained during dissolved at 1-10 μm, and multiple for the Gefitinib of stable crystal form
Particle is closed, wherein albumen inhibits the growth of Gefitinib crystal, the generation of unstable crystal form is avoided, to the knot of Gefitinib
Brilliant process has carried out effective control, effectively improves the dissolution rate of drug.
Solventing-out process is a kind of effective ways for reducing diameter of aspirin particle, and basic ideas are that drug is dissolved in spy first
It in fixed good solvent, then is mixed with poor solvent, increases the degree of supersaturation of system to make drug be precipitated, the present invention will be beautiful
Rice gluten is first dissolved in poor solvent in advance, to control the crystallization process of drug, obtains that partial size is small, the drug of stable crystal form
Particle.Preparation process of the invention is simple, and equipment requirement is low, and low energy consumption, but has achieved the effect that traditional micronization, reduces life
Produce cost.
Detailed description of the invention
Fig. 1 is the x-ray diffraction pattern of the Gefitinib composite particles of preparation of the embodiment of the present invention.
Fig. 2 is the grain size distribution of the Gefitinib composite particles of preparation of the embodiment of the present invention.
Fig. 3 is the scanning electron microscope (SEM) photograph (20 μm) of the Gefitinib composite particles of preparation of the embodiment of the present invention.
Fig. 4 is the scanning electron microscope (SEM) photograph (5 μm) of the Gefitinib composite particles of preparation of the embodiment of the present invention.
Fig. 5 is that the Gefitinib composite particles of preparation of the embodiment of the present invention are molten in 0.1% lauryl sodium sulfate of 500ml
Dissolution curve in liquid.
Fig. 6 is the X-ray diffraction after the Gefitinib composite particles accelerated stability experiment of preparation of the embodiment of the present invention
Figure.
Specific embodiment
In order to illustrate more clearly of the present invention, below with reference to preferred embodiment, the present invention is described further.Ability
Field technique personnel should be appreciated that following specifically described content is illustrative and be not restrictive, this should not be limited with this
The protection scope of invention.
Drug and reagent used in the present invention: Gefitinib (purity >=99%, the limited public affairs of this reagent of Shanghai Adama
Department), zein (SILVER REAGENT, this reagent Co., Ltd of Shanghai Adama), sodium hydroxide (analysis it is pure, Shanghai Ling Feng chemistry examination
Agent Co., Ltd), lauryl sodium sulfate (biochemical reagents, Shanghai Yuan Ju Biotechnology Co., Ltd), dimethyl sulfoxide (analysis
Pure, the upper smooth Science and Technology Ltd. of Haitai), n,N-Dimethylformamide (analyzing pure, the upper smooth Science and Technology Ltd. of Haitai).
Embodiment 1
At room temperature, 100mg Gefitinib bulk pharmaceutical chemicals are dissolved in 1mL dimethyl sulfoxide, obtain good solvent phase.It will
300mg zein is dissolved in 100mL deionized water, and it is completely molten to zein to adjust pH=9 using 0.5M NaOH solution
Solution, obtains water phase.When temperature is 25 DEG C, good solvent is mutually injected in water phase, stirring filters after 30 minutes, filter cake is collected, with Ji
It is non-to be washed for 90 times of Buddhist nun's mass of deionized water, filter cake is placed in a vacuum drying oven 60 DEG C of dry 8h after suction filtration, obtains Ji Fei
For Buddhist nun's composite particles.Partial size is as shown in table 1, and table 1 is the particle size distribution parameters of Gefitinib composite particles.
Before collecting Gefitinib composite particles, good solvent is mutually injected to the suspension after stirring 30 minutes in water phase, is adopted
With 2000 particle size analyzer determination partial size of Malvern, D90 is 6.191 μm (being shown in Table 1), to the Gefitinib composite particles powder after drying
End carries out X-ray diffraction test, and result is metastable 7 crystal form, as shown in Figure 1, Fig. 1 is the Ji of preparation of the embodiment of the present invention
The non-x-ray diffraction pattern for Buddhist nun's composite particles, from figure 1 it appears that Gefitinib composite particles characteristic peak appears in
It is consistent with the map of 7 crystal forms through being compared with document at 6.42 ° and 15.36 °, 7 crystal forms are judged as with this.
The particle diameter distribution of Gefitinib composite particles is as shown in Figure 2.Fig. 2 is that the Gefitinib of preparation of the embodiment of the present invention is multiple
Close the grain size distribution of particle.Figure it is seen that zein can be obviously reduced compared with bulk pharmaceutical chemicals and blank control
The partial size of GTN, and uniform particle diameter distribution is kept, achieve the effect that conventional physical is ground.
The scanning electron microscope (SEM) photograph of Gefitinib composite particles is as shown in Figure 3.Fig. 3 is the Gefitinib of preparation of the embodiment of the present invention
The scanning electron microscope (SEM) photograph (20 μm) of composite particles.Fig. 4 is the scanning electron microscope of the Gefitinib composite particles of preparation of the embodiment of the present invention
Scheme (5 μm).From Fig. 3 and 4 as can be seen that the partial size majority of Gefitinib composite particles is less than 5 μm, after drying, Ji Fei is replaced
Although there is also certain crystal accumulation phenomenons for Buddhist nun's composite particles, but still with the presence of single crystal form.
The dissolution curve of Gefitinib composite particles is as shown in Figure 5.Fig. 5 is that the Gefitinib of preparation of the embodiment of the present invention is multiple
Close dissolution curve of the particle in 0.1% sodium dodecyl sulfate solution of 500ml.From fig. 5, it can be seen that Gefitinib raw material
Medicine only releases 20% or so within 60min, and after anti-solvent recrystallizes, Gefitinib composite particles are in 10min or so
The release for having reached 90% or more significantly improves the dissolution rate and dissolution rate of GTN.
This example demonstrates that using zein, available partial size is small and the Gefitinib composite particles of stable crystal form.
Dissolution determination: after taking Gefitinib composite particles to sieve with 100 mesh sieve, the powder for being equivalent to that main ingredient amount is 15mg is weighed
End takes dissolution medium (0.1% sodium dodecyl sulfate solution) 500ml, revolving speed 50rpm using paddle method, and medium temperature is 37 ±
It 0.5 DEG C, operates according to methods.3ml was sampled at 5,10,20,30,45,60 minutes respectively, while adding the synthermal dissolution of 3ml phase
Medium, sample solution use 0.45 μm of membrane filtration, take subsequent filtrate, and ultraviolet absorptivity is measured at 333nm, measures its content,
Dissolution rate is calculated, data are shown in Table 2.The result shows that Gefitinib composite particles are due to partial size very little and are metastable-state crystal, make table
Area increases, therefore dissolution rate improves, and the release at 10 minutes or so has reached 90% or more, significantly improved the molten of GTN
Rate and dissolution rate out.
Study on the stability: taking Gefitinib composite particles powder, simulates commercially available back, is put into the stabilization of 40 DEG C/75%RH
In property case, the sampling and testing after 1,3, June.The result shows that Gefitinib composite particles are still Asia after Acceleration study 6 months
7 type of stable state crystal form, stable product quality.As shown in fig. 6, the Gefitinib composite particles that Fig. 6 is preparation of the embodiment of the present invention add
X-ray diffraction pattern after fast stability experiment.From fig. 6, it can be seen that comparative example 1 and embodiment 1 are 7 type of meta-stable crystal form,
Comparative example 1 has gradually appeared the characteristic peak of I type under conditions of 40 DEG C/75%RH, and the composite particles that embodiment 1 obtains then can
Stablized 6 months with 7 types, stable product quality.
Comparative example 1
At room temperature, 100.2mg Gefitinib bulk pharmaceutical chemicals are dissolved in 1mL dimethyl sulfoxide, obtain good solvent phase.With
100mL deionized water is as water phase.When temperature is 25 DEG C, good solvent is mutually injected in water phase, stirring filters after 30 minutes, collects
Filter cake is washed with 90 times of deionized water of Gefitinib quality, and filter cake is placed in a vacuum drying oven 60 DEG C of dry 8h, obtains Ji
It is non-to replace Buddhist nun's composite particles.
Before collecting Gefitinib composite particles, good solvent is mutually injected to the suspension after stirring 30 minutes in water phase, is adopted
With 2000 particle size analyzer determination partial size of Malvern, D90 is 70.636 μm (being shown in Table 1), carries out X- to the fine-particle powder after drying and penetrates
The test of line diffraction, result are 7 crystal forms (see Fig. 1), the dissolution curve of the straight analysis particle control group of Gefitinib in deionized water
As shown in Figure 5.
It takes Gefitinib directly to analyse fine-particle powder, simulates commercially available back, be put into the stability case of 40 DEG C/75%RH, 1,
3, there is I crystal characteristic peak after accelerated test 6 months in sampling and testing after June (see Fig. 6).
The embodiment is that the blank control experiment of the aqueous solution of any polymer and albumen is not added, the results showed that the Ji of precipitation
Non- for Buddhist nun is high 7 crystal forms of Crystal, but I crystal characteristic peak is transited out of after acceleration for stabilization is tested 6 months, and partial size compared with
Greatly, it is therefore desirable to albumen be added and inhibit crystallization process.
Comparative example 2
At room temperature, 99.8mg Gefitinib bulk pharmaceutical chemicals are dissolved in 1mL dimethyl sulfoxide, obtain good solvent phase.It will
25.6mg zein is dissolved in 100mL deionized water, and it is completely molten to zein to adjust pH=9 using 0.5M NaOH solution
Solution, obtains water phase.When temperature is 25 DEG C, good solvent is mutually injected in water phase, stirring filters after 30 minutes, filter cake is collected, with Ji
It is non-to be washed for 90 times of Buddhist nun's mass of deionized water, filter cake is placed in a vacuum drying oven 60 DEG C of dry 8h, it is multiple to obtain Gefitinib
Close particle.
Before collecting Gefitinib composite particles, good solvent is mutually injected to the suspension after stirring 30 minutes in water phase, is adopted
With 2000 particle size analyzer determination partial size of Malvern, D90 is 26.142 μm (being shown in Table 1), carries out X- to the fine-particle powder after drying and penetrates
The test of line diffraction, result are 7 crystal forms.
The embodiment is that control experiment of the preferred mass than outer zein is added, the results showed that if zein is added
It can control the crystal form of Gefitinib, but be unable to get particle of the particle diameter distribution at 1-10 μm.
Therefore, only using the zein in preferred mass ratio, it can just obtain that partial size is small and the Ji of stable crystal form is non-
For Buddhist nun's composite particles.
Embodiment 2
99.7mg Gefitinib bulk pharmaceutical chemicals are dissolved in 1mLN, in dinethylformamide, 45 DEG C of ultrasonic dissolutions is heated to, obtains
To good solvent phase.501.3mg zein is dissolved in 100mL deionized water, using 0.5M NaOH solution adjust pH=9 to
Zein is completely dissolved, and obtains water phase.When temperature is 25 DEG C, good solvent mutually to be injected in water phase, stirring filters after 30 minutes,
Filter cake is collected, is washed with 90 times of deionized water of Gefitinib quality, filter cake is placed in a vacuum drying oven 60 DEG C after suction filtration and is done
Dry 7h obtains Gefitinib composite particles.
Before collecting Gefitinib composite particles, good solvent is mutually injected to the suspension after stirring 30 minutes in water phase, is adopted
With 2000 particle size analyzer determination partial size of Malvern, D90 is 8.287 μm, carries out X-ray diffraction survey to the fine-particle powder after drying
Examination, result are 7 crystal forms.
Embodiment 3
Under conditions of temperature is 40 DEG C, 102.2mg Gefitinib bulk pharmaceutical chemicals are dissolved in 1mL dimethyl sulfoxide, are obtained good
Solvent phase.300.2mg zein is dissolved in 100mL deionized water, adjusts pH=9 to corn using 0.5M NaOH solution
Albumen is completely dissolved, and obtains water phase.When temperature is 20 DEG C, good solvent is mutually injected in water phase, stirring filters after 30 minutes, collects
Filter cake is washed with 90 times of deionized water of Gefitinib quality, and filter cake is placed in a vacuum drying oven 70 DEG C of dry 8h after suction filtration,
Obtain Gefitinib composite particles.
Before collecting Gefitinib composite particles, good solvent is mutually injected to the suspension after stirring 30 minutes in water phase, is adopted
With 2000 particle size analyzer determination partial size of Malvern, D90 is 9.846 μm, carries out X-ray diffraction survey to the fine-particle powder after drying
Examination, result are 7 crystal forms.
Table 1
Table 2
Embodiment 4
At room temperature, 100mg Gefitinib bulk pharmaceutical chemicals are dissolved in 0.5mL dimethyl sulfoxide and 0.5mLN, N- dimethyl methyl
In amide, good solvent phase is obtained.300mg zein is dissolved in 100mL deionized water, is adjusted using 0.5M NaOH solution
PH=9 is completely dissolved to zein, obtains water phase.When temperature is 25 DEG C, good solvent is mutually injected in water phase, is stirred 30 minutes
After filter, collect filter cake, washed with 90 times of deionized water of Gefitinib quality, filter cake be placed in drying box 80 DEG C after suction filtration
Drying for 24 hours, obtains Gefitinib composite particles.
Before collecting Gefitinib composite particles, good solvent is mutually injected to the suspension after stirring 30 minutes in water phase, is adopted
With 2000 particle size analyzer determination partial size of Malvern, D90 is 7.420 μm, carries out X-ray diffraction survey to the fine-particle powder after drying
Examination, result are 7 crystal forms.
Embodiment 5
At room temperature, 100mg Gefitinib bulk pharmaceutical chemicals are dissolved in 1mL dimethyl sulfoxide, obtain good solvent phase.By 50mg
Zein is dissolved in 100mL deionized water, is adjusted pH=9 using 0.5M NaOH solution and is completely dissolved to zein, obtains
Water phase.When temperature is 25 DEG C, good solvent is mutually injected in water phase, stirring filters after 30 minutes, filter cake is collected, with Gefitinib matter
The deionized water of 90 times of amount is washed, and filter cake is placed in 70 DEG C of dryings in drying box after suction filtration and for 24 hours, it is compound micro- to obtain Gefitinib
Grain.
Before collecting Gefitinib composite particles, good solvent is mutually injected to the suspension after stirring 30 minutes in water phase, is adopted
With 2000 particle size analyzer determination partial size of Malvern, D90 is 9.571 μm, carries out X-ray diffraction survey to the fine-particle powder after drying
Examination, result are 7 crystal forms.
Embodiment 6
At room temperature, 100mg Gefitinib bulk pharmaceutical chemicals are dissolved in 1mL dimethyl sulfoxide, obtain good solvent phase.It will
1000mg zein is dissolved in 100mL deionized water, and it is completely molten to zein to adjust pH=9 using 0.5M NaOH solution
Solution, obtains water phase.When temperature is 25 DEG C, good solvent is mutually injected in water phase, stirring filters after 30 minutes, filter cake is collected, with Ji
It is non-to be washed for 90 times of Buddhist nun's mass of deionized water, filter cake is placed in a vacuum drying oven 80 DEG C of dry 6h after suction filtration, obtains Ji Fei
For Buddhist nun's composite particles.
Before collecting Gefitinib composite particles, good solvent is mutually injected to the suspension after stirring 30 minutes in water phase, is adopted
With 2000 particle size analyzer determination partial size of Malvern, D90 is 9.379 μm, carries out X-ray diffraction survey to the fine-particle powder after drying
Examination, result are 7 crystal forms.
Embodiment 7
At room temperature, 100mg Gefitinib bulk pharmaceutical chemicals are dissolved in 1mL dimethyl sulfoxide, obtain good solvent phase.It will
100mg zein is dissolved in 100mL deionized water, and it is completely molten to zein to adjust pH=9 using 0.5M NaOH solution
Solution, obtains water phase.When temperature is 25 DEG C, good solvent is mutually injected in water phase, stirring filters after 30 minutes, filter cake is collected, with Ji
It is non-to be washed for 90 times of Buddhist nun's mass of deionized water, filter cake is placed in 60 DEG C of dryings in drying box after suction filtration and for 24 hours, obtains Gefitinib
Composite particles.
Before collecting Gefitinib composite particles, good solvent is mutually injected to the suspension after stirring 30 minutes in water phase, is adopted
With 2000 particle size analyzer determination partial size of Malvern, D90 is 8.086 μm, carries out X-ray diffraction survey to the fine-particle powder after drying
Examination, result are 7 crystal forms.
Embodiment 8
At room temperature, 100mg Gefitinib bulk pharmaceutical chemicals are dissolved in 1mL dimethyl sulfoxide, obtain good solvent phase.It will
200mg zein is dissolved in 100mL deionized water, and it is completely molten to zein to adjust pH=9 using 0.5M NaOH solution
Solution, obtains water phase.When temperature is 25 DEG C, good solvent is mutually injected in water phase, stirring filters after 30 minutes, filter cake is collected, with Ji
It is non-to be washed for 90 times of Buddhist nun's mass of deionized water, filter cake is placed in a vacuum drying oven 80 DEG C of dry 8h after suction filtration, obtains Ji Fei
For Buddhist nun's composite particles.
Before collecting Gefitinib composite particles, good solvent is mutually injected to the suspension after stirring 30 minutes in water phase, is adopted
With 2000 particle size analyzer determination partial size of Malvern, D90 is 7.551 μm, carries out X-ray diffraction survey to the fine-particle powder after drying
Examination, result are 7 crystal forms.
Embodiment 9
At room temperature, 100mg Gefitinib bulk pharmaceutical chemicals are dissolved in 1mL dimethyl sulfoxide, obtain good solvent phase.It will
400mg zein is dissolved in 100mL deionized water, and it is completely molten to zein to adjust pH=9 using 0.5M NaOH solution
Solution, obtains water phase.When temperature is 25 DEG C, good solvent is mutually injected in water phase, stirring filters after 30 minutes, filter cake is collected, with Ji
It is non-to be washed for 90 times of Buddhist nun's mass of deionized water, filter cake is placed in a vacuum drying oven 80 DEG C of dry 8h after suction filtration, obtains Ji Fei
For Buddhist nun's composite particles.
Before collecting Gefitinib composite particles, good solvent is mutually injected to the suspension after stirring 30 minutes in water phase, is adopted
With 2000 particle size analyzer determination partial size of Malvern, D90 is 8.542 μm, carries out X-ray diffraction survey to the fine-particle powder after drying
Examination, result are 7 crystal forms.
Embodiment 10
At room temperature, 100mg Gefitinib bulk pharmaceutical chemicals are dissolved in 1mLN, in dinethylformamide, obtain good solvent phase.
400mg zein is dissolved in 120mL deionized water, it is complete to zein to adjust pH=10 using 0.5M NaOH solution
Dissolution, obtains water phase.When temperature is 25 DEG C, good solvent is mutually injected in water phase, stirring filters after 30 minutes, collects filter cake, uses
The deionized water that 90 times of Gefitinib quality is washed, and filter cake is placed in a vacuum drying oven 80 DEG C of dry 8h after suction filtration, obtains Ji
It is non-to replace Buddhist nun's composite particles.
Before collecting Gefitinib composite particles, good solvent is mutually injected to the suspension after stirring 30 minutes in water phase, is adopted
With 2000 particle size analyzer determination partial size of Malvern, D90 is 8.989 μm, carries out X-ray diffraction survey to the fine-particle powder after drying
Examination, result are 7 crystal forms.
Embodiment 11
At room temperature, 100mg Gefitinib bulk pharmaceutical chemicals are dissolved in 1mLN, in dinethylformamide, obtain good solvent phase.
250mg zein is dissolved in 80mL deionized water, it is completely molten to zein to adjust pH=9 using 0.5M NaOH solution
Solution, obtains water phase.When temperature is 25 DEG C, good solvent is mutually injected in water phase, stirring filters after 30 minutes, filter cake is collected, with Ji
It is non-to be washed for 90 times of Buddhist nun's mass of deionized water, filter cake is placed in a vacuum drying oven 80 DEG C of dry 8h after suction filtration, obtains Ji Fei
For Buddhist nun's composite particles.
Before collecting Gefitinib composite particles, good solvent is mutually injected to the suspension after stirring 30 minutes in water phase, is adopted
With 2000 particle size analyzer determination partial size of Malvern, D90 is 9.081 μm, carries out X-ray diffraction survey to the fine-particle powder after drying
Examination, result are 7 crystal forms.
The above is only presently preferred embodiments of the present invention, is not intended to limit the present invention in any form, though
So the present invention has been disclosed as a preferred embodiment, and however, it is not intended to limit the invention, any technology people for being familiar with this patent
Member without departing from the scope of the present invention, when the technology contents using above-mentioned prompt make it is a little change or be modified to
The equivalent embodiment of equivalent variations, but anything that does not depart from the technical scheme of the invention content, it is right according to the technical essence of the invention
Any simple modification, equivalent change and modification made by above embodiments, in the range of still falling within the present invention program.
Claims (10)
1. a kind of preparation method of Gefitinib composite particles, which comprises the following steps:
Gefitinib dissolution is obtained good solvent phase by the first step in organic solvent；
Second step in deionized water by zein dissolution adjusts pH to being completely dissolved, obtains water phase；
Third step mixes the water phase of the good solvent phase of first step preparation and second step preparation, and separation obtains institute after precipitating is precipitated
State Gefitinib composite particles.
2. the preparation method of Gefitinib composite particles according to claim 1, which is characterized in that the organic solvent choosing
From at least one of dimethyl sulfoxide, N,N-dimethylformamide.
3. the preparation method of Gefitinib composite particles according to claim 1, which is characterized in that dissolve Gefitinib
During in organic solvent, temperature is 5-70 DEG C.
4. the preparation method of Gefitinib composite particles according to claim 1, which is characterized in that the Gefitinib with
The mass ratio of zein is 1:(0.5-10).
5. the preparation method of Gefitinib composite particles according to claim 1, which is characterized in that the adjusting pH is 9-
10。
6. the preparation method of Gefitinib composite particles according to claim 1, which is characterized in that in the third step,
The volume ratio of the water phase of the good solvent phase and second step preparation of first step preparation is 1:(40-200).
7. the preparation method of Gefitinib composite particles according to claim 1, which is characterized in that in third step, temperature
It is 15-35 DEG C.
8. the preparation method of Gefitinib composite particles according to claim 1, which is characterized in that described to be separated into pumping
Filter washing, filters, is dry.
9. a kind of Gefitinib composite particles of the described in any item method preparations of claim 1 to 8.
10. Gefitinib composite particles according to claim 9, which is characterized in that the Gefitinib composite particles
Partial size is 1-10 μm.
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