CN115006372A

CN115006372A - Nimodipine-loaded lung inhalation porous microspheres and preparation method thereof

Info

Publication number: CN115006372A
Application number: CN202210714061.9A
Authority: CN
Inventors: 洪鸣凰; 任国宾; 齐明辉; 朱彬; 杨青青
Original assignee: East China University of Science and Technology
Current assignee: East China University of Science and Technology
Priority date: 2022-06-22
Filing date: 2022-06-22
Publication date: 2022-09-06
Anticipated expiration: 2042-06-22
Also published as: CN115006372B

Abstract

The invention relates to a pulmonary inhalation porous microsphere carrying nimodipine and a preparation method thereof. The invention particularly discloses a lung inhalation porous microsphere with significantly improved drug-loading rate and inhalable drug delivery, and the drug-loading of the microsphere can significantly improve the lung targeting property and curative effect of the loaded drug. The invention also discloses a preparation method of the microsphere.

Description

Nimodipine-loaded lung inhalation porous microspheres and preparation method thereof

Technical Field

The invention relates to the field of medicines, in particular to a nimodipine-loaded lung inhalation porous microsphere and a preparation method thereof.

Background

Nimodipine is a dihydropyridine calcium ion antagonist, and can selectively act on cerebrovascular smooth muscle, dilate cerebral vessels and increase cerebral blood flow; has protective and therapeutic effects on injury caused by ischemia of various brain tissues, such as ischemic cerebral vasospasm, ischemic nervous disorder, hypertension, etc. Nimodipine, upon increasing the dose, may on the one hand lower blood pressure without reducing cerebral blood flow. In addition, nimodipine has direct effect on neurons, can change the function of the neurons, has an improvement effect on dysmnesia caused by hypoxia and electroshock, and also has certain effects on resisting depression, protecting and promoting memory and promoting intelligence recovery.

The first-pass effect of nimodipine in liver is obvious, the oral bioavailability is only 5-10%, the effective blood concentration is 7ng/mL, the peak time of blood concentration is 0.5-2.0h, the half-life period is 1-2h, and the complete elimination time is about 8.5 h. The short half-life period leads to short effective action time of nimodipine in the traditional administration route, needs frequent administration and is not beneficial to improving the medication compliance of patients.

The Chinese hypertension guide recommends that long-acting antihypertensive drugs are preferentially used to effectively control 24-hour blood pressure and more effectively prevent cardiovascular and cerebrovascular complications, so that the antihypertensive effect of nimodipine is limited.

Most of the traditional sustained-release and controlled-release dosage forms are oral preparations which are convenient to take, but the oral administration often generates the first pass effect of the liver and reduces the blood concentration of the medicine in the body. The lung inhalation administration can directly deliver the medicine to the lung, has no liver first-pass effect, has high bioavailability, obviously reduces the medicine dosage and improves the treatment effect. But the requirement of the lung inhalation route on raw materials is high, the aerodynamic diameter needs to be about 5 mu m, and the apparent diameter is more than 10 mu m; the common inhalator on the market has low transportation efficiency; and the inherent clearance pathways (phagocytes, etc.) present in the lung, limit the development of pulmonary formulations. The microsphere drug delivery system breaks through the limitation of the drug delivery route of the common dosage form, and can be individually designed according to the action part of the drug, namely the target of the drug molecule. The porous microsphere has ideal aerodynamic property due to its unique pore channel structure, and is convenient for inhalation administration, and can increase the deposition of medicine in lung and prolong the action time of medicine. The structure of the porous microsphere has larger pore volume and specific surface area, the medicine can be adsorbed on the surface or enter the inside of the pore channel, and the medicine release speed can be regulated and controlled by adjusting the size of the pore channel.

At present, compared with common microsphere production methods, the common microsphere production methods comprise an emulsion solvent volatilization method, a phase separation method, a spray drying method, a microfluidic technology and the like, and most of the methods have higher requirements on equipment. The most common method is an emulsion solvent volatilization method, which is usually a single organic solvent, the porous microspheres are prepared by an oil-in-water and water-in-water method, the pore-forming agent is difficult to completely remove, the size is uncontrollable, the pore diameter is often large, the drug-loading rate is also low and is usually below 10%, and the drug effect of the microspheres prepared into the sustained-release preparation is finally influenced.

Disclosure of Invention

The invention aims to provide lung inhalation porous microspheres with significantly improved drug-loading rate and inhalable drug delivery, and the drug-loading of the microspheres can significantly improve the lung targeting property and curative effect of the loaded drugs.

In a first aspect of the present invention, a method for preparing porous microspheres for pulmonary inhalation is provided, which comprises the following steps:

1) providing an oil phase solution, an aqueous phase solution, a first surfactant solution and a second surfactant solution, wherein,

the oil phase solution comprises a low-boiling-point organic solvent, and a biodegradable high molecular polymer and a hydrophobic drug dissolved in the low-boiling-point organic solvent;

the aqueous phase solution comprises water and an inorganic salt porogen dissolved therein;

the first surfactant solution comprises water and a first surfactant;

the second surfactant solution comprises water and a second surfactant;

2) mixing the oil phase solution and the water phase solution to obtain a first mixed solution;

3) ultrasonically treating the first mixed solution in ice-water bath to obtain a second mixed solution;

4) adding the second mixed solution into the first surfactant solution to obtain a third mixed solution;

5) stirring the third mixed solution, adding the obtained solution into the second surfactant solution, and continuously stirring to obtain a fourth mixed solution;

6) and centrifuging the fourth mixed solution, washing the obtained solid product with water, and freeze-drying to obtain the microspheres.

In another preferred embodiment, the low boiling point organic solvent is selected from the group consisting of: dichloromethane, chloroform, or a mixed solvent thereof.

In another preferred example, the low-boiling organic solvent is a mixed solvent of chloroform and dichloromethane.

In another preferred example, in the low-boiling-point organic solvent, the volume ratio of chloroform to dichloromethane is 1: 3-8, preferably 1: 3-6, more preferably 1: 4-5.

In another preferred embodiment, the biodegradable high molecular polymer is selected from the group consisting of: poly L-lactide PLLA, poly DL-lactide PDLLA, poly lactide-co-glycolide PLGA, poly adipate PBAT, polyesters PBS, PBSA, poly epsilon-caprolactone PCL, poly 3-hydroxyalkanoate PHA, cellulose, chitosan, starch, modified starch, or combinations thereof.

In another preferred embodiment, the mass-to-volume ratio of the biodegradable high molecular polymer to the low boiling point organic solvent in the oil phase solution is 50-120mg/ml, preferably 65-105mg/ml, and more preferably 75-90 mg/ml.

In another preferred embodiment, the hydrophobic drug is nimodipine.

In another preferred embodiment, the mass ratio of the biodegradable high molecular polymer to the hydrophobic drug in the oil phase solution is 4 to 20, preferably 5 to 15, and more preferably 5 to 10.

In another preferred embodiment, the inorganic salt porogen is selected from the group consisting of: ammonium bicarbonate, sodium chloride, calcium chloride, or a combination thereof.

In another preferred embodiment, the concentration of the inorganic salt-forming pore-forming agent in the aqueous phase solution is 7.5-60mg/ml, preferably 15-45mg/ml, and more preferably 20-40 mg/ml.

In another preferred embodiment, the first surfactant and the second surfactant are independently selected from the group consisting of: PVA, Span, Tween, or combinations thereof.

In another preferred embodiment, the volume concentration of the first surfactant solution is 1-5%, preferably 2-4%, and more preferably 3%.

In another preferred embodiment, the volume concentration of the second surfactant solution is 0.1 to 0.8%, preferably 0.2 to 0.5%, more preferably 0.3 to 0.4%.

In another preferred example, in step 2), the mixing volume ratio of the oil phase solution and the water phase solution is 1:6 to 1:20, preferably 1:9 to 1:15, and more preferably 1: 10.

In another preferred example, in step 3), the treatment time of the ultrasonic treatment is 0.5-10min, preferably 1-3 min.

In another preferred example, in the step 4), the mixing volume ratio of the second mixed solution and the first surfactant solution is 1:3-1:10, preferably 1:3-1:8, and more preferably 1:4-1: 6.

In another preferred example, in step 5), the mixing volume ratio of the obtained solution and the second surfactant solution is 1:4 to 1:10, preferably 1:5 to 1:8, and more preferably 1:6 to 1: 7.

In another preferred embodiment, in step 5), the processing rotation speed of the stirring treatment is 1000-; and/or

The treatment time of the stirring treatment is 3-30min, preferably 5-15min, and more preferably 7-10 min.

In another preferred embodiment, in step 5), the processing rotation speed for continuing stirring is 150-; and/or

The treatment time for continuing stirring is 1-24h, preferably 3-15h, more preferably 5-10 h.

In another preferred embodiment, the processing speed of the centrifugal treatment is 2000-.

In a second aspect of the invention, there is provided a pulmonary inhalation porous microsphere, the microsphere having an apparent diameter of 10-15 um;

the aerodynamic diameter of the microspheres is 4-6 um;

the microspheres have a porous structure;

the porous structure of the microsphere takes biodegradable high molecular polymer as a carrier, and the surface and/or the interior of the microsphere is loaded with hydrophobic drugs.

In another preferred embodiment, the microspheres have an apparent diameter of 10-12 um.

In another preferred embodiment, the microspheres have an aerodynamic diameter of 4.5-5.5 um.

In another preferred embodiment, the microspheres have a porosity of 88% to 98%, preferably 94% to 96%.

In another preferred embodiment, the microspheres have uniform particle size with a deviation of particle size within 10%, preferably within 5%.

In another preferred example, the surface of the microsphere is provided with a skin membrane.

In another preferred embodiment, the microspheres have an average pore size of 0.5-2.5um, preferably 0.5-1.5um, more preferably 0.5-1.0 um.

In another preferred embodiment, the microspheres have uniform pore sizes with a deviation of pore sizes within 10%, preferably within 5%.

In another preferred embodiment, the microspheres are prepared by the method of the first aspect of the invention.

In another preferred embodiment, the pores within the microspheres are intercommunicating.

In another preferred embodiment, the biodegradable high molecular polymer is selected from the group consisting of: poly L-lactide PLLA, poly DL-lactide PDLLA, poly lactide-co-glycolide PLGA, poly adipate PBAT, polyesters PBS, PBSA, poly epsilon-caprolactone PCL, poly 3-hydroxyalkanoate PHA, cellulose, chitosan, starch, modified starch, or combinations thereof; and/or

The hydrophobic drug is nimodipine.

In another preferred embodiment, the drug loading of the microspheres is 10-25%, preferably 12-20%, more preferably 15-20%.

In another preferred embodiment, the encapsulation efficiency of the microspheres is 90-99.5%, preferably 95-99.5%, more preferably 98-99.5%.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Drawings

FIG. 1 shows SEM results of microspheres obtained in example 3.

FIG. 2 is a PXRD pattern of microspheres obtained in example 3.

FIG. 3 is a graph of the cumulative release of the microspheres obtained in examples 1-3.

Detailed Description

Through long-term and deep research, the inventor obtains the lung inhalation porous microsphere with obviously improved drug loading rate and inhalable drug delivery through an optimization process, and the lung targeting property and the curative effect of the loaded drug can be obviously improved by carrying the drug with the microsphere. On the basis of this, the inventors have completed the present invention.

Microspheres and method for preparing same

The invention provides a pulmonary inhalation porous microsphere carrying nimodipine and a preparation method thereof. The preparation method has simple process, and the obtained porous microspheres have good dispersibility and no aggregation and agglomeration phenomenon. The invention takes a antihypertensive drug nimodipine as a model drug, polylactic-co-glycolic acid (PLGA) as a carrier, ammonium bicarbonate as a pore-forming agent, and an improved multiple emulsion solvent volatilization method to prepare PLGA porous microspheres. The key point of the invention is that higher drug-loading rate is obtained by selecting the proportion of different oil phase solvents. The PLGA microspheres obtained by optimizing the conditions have the apparent diameter of about 10-15 mu m, the aerodynamic diameter of about 4-6 mu m, the highest drug loading rate of 16 percent and the encapsulation rate of 98 percent. The low-density porous PLGA microspheres prepared by the invention have higher drug loading rate, can be inhaled for administration, are expected to improve the lung targeting property of nimodipine, improve the antihypertensive curative effect and reduce the toxic and side effects.

The preparation scheme of the nimodipine-loaded porous microsphere is implemented by the following steps:

1) dissolving biodegradable high molecular polymer and hydrophobic drug in low boiling point organic solvent to obtain oil phase solution; dissolving inorganic salt pore-forming agent in water, adding into the oil phase solution under ice water bath condition, and performing ultrasonic treatment to obtain primary emulsion.

2) Adding the colostrum into the water solution containing the surfactant under stirring, reducing the stirring speed, and continuously pouring the low-concentration surfactant water solution.

3) And (3) continuously stirring the solution obtained in the step (2), after the organic solvent is volatilized, carrying out centrifugal water washing treatment, then removing supernatant, and carrying out freeze drying to obtain the medicine-carrying porous microspheres.

Wherein the biodegradable polymer material can be selected from at least one of poly-L-lactide (PLLA), poly-DL-lactide (PDLLA), and poly-lactide-co-glycolide (PLGA). The porous polymer material can be ammonium bicarbonate and/or sodium bicarbonate. The low boiling point organic solvent may be dichloromethane, trichloromethane or a mixed solvent thereof.

Preferably, the mass ratio of the biodegradable polymer material to the bulk drug in the step 1) is 20:1-5: 1.

Preferably, the concentration of the pore-forming agent is 7.5-60 mg/ml; the ultrasonic treatment time is 0.5-4 min.

In the step 2), the stirring conditions are preferably: the temperature is 15-20 ℃, the stirring speed is 200-500rpm, and the stirring is carried out for 5-24 h; further, the conditions of the centrifugation treatment are as follows: centrifuging at 2000-.

Compared with the prior art, the invention has the following main advantages:

(1) the microspheres have obviously improved drug loading capacity, and can obviously improve the lung targeting property and the curative effect of the loaded drug;

(2) the preparation method has simple process;

(3) the microsphere has good dispersibility and no aggregation and agglomeration phenomenon;

(4) the microsphere has good slow release effect, can be maintained for 2-3 days, and is expected to reduce the toxic and side effects of the loaded drug.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.

EXAMPLE 1 preparation of nimodipine-loaded general microspheres

1) Firstly, 240mg of PLGA solid is dissolved in 3ml of dichloromethane solution, then 24mg of nimodipine is dissolved in the dichloromethane solution, after mixing, the mixture is treated by ice-water bath ultrasound for 1min, and then is poured into 15ml of 3% PVA solution.

2) The mixed solution was treated with mechanical stirring (1500rpm) at 20 ℃ for 7min, and 100ml of 0.3% PVA solution was poured in, and stirring (300rpm) was continued for more than 5 hours.

3) And (3) centrifuging the mixed solution at the rotating speed of 3000rpm, washing with water for 3 times, and freeze-drying the precipitate to obtain the nimodipine-loaded porous microspheres.

Example 2 preparation of porous nimodipine-loaded microspheres with dichloromethane as oil phase solvent

1) Firstly, 240mg PLGA solid is dissolved in 3ml dichloromethane solution, then 24mg nimodipine is dissolved in the solution, 30mg ammonium bicarbonate is weighed and dissolved in 1ml deionized water, 300 mul ammonium bicarbonate solution is mixed with dichloromethane solution, then ice water bath ultrasound is carried out for 1min, and then 15ml 3% PVA solution is poured.

Example 3 preparation of porous nimodipine-loaded microspheres with chloroform as the oil phase solvent

1) Firstly, 240mg of PLGA solid is dissolved in 3ml of chloroform solution, then 24mg of nimodipine is dissolved in the chloroform solution, 30mg of ammonium bicarbonate is weighed and dissolved in 1ml of deionized water, 300 mul of ammonium bicarbonate solution is mixed with the chloroform solution, then the mixture is treated with ice water bath ultrasound for 1min, and then the mixture is poured into 15ml of 3% PVA solution.

EXAMPLE 448 mg administration of Single solvent porous nimodipine-loaded microspheres preparation

1) Firstly, 240mg PLGA solid is dissolved in 3ml dichloromethane or chloroform solution, then 48mg nimodipine is dissolved in the solution, 30mg ammonium bicarbonate is weighed and dissolved in 1ml deionized water, 300 mul ammonium bicarbonate solution is mixed with dichloromethane or chloroform solution, then ice water bath ultrasound is carried out for 1min, and then 15ml 3% PVA solution is poured.

3) During the stirring process, drug crystals are separated out and attached to the surfaces of the microspheres.

EXAMPLE 548 mg of Mixed solvent loaded porous nimodipine microsphere preparation

1) Firstly, 240mg of PLGA solid is dissolved in 3ml of dichloromethane and chloroform mixed solution (the volume ratio is 90:10, 70:30, 60:40, 50:50, 30:70, 40:60 and 10:90), then 48mg of nimodipine is dissolved in the solution, 30mg of ammonium bicarbonate is weighed and dissolved in 1ml of deionized water, 300 mul of ammonium bicarbonate solution is mixed with the oil phase solution, then the mixture is treated with ice water bath ultrasound for 1min, and then the mixture is poured into 15ml of 3% PVA solution.

EXAMPLE 648 mg preparation of porous nimodipine-loaded microspheres with fixed ratio of mixed solvent as oil phase solvent for administration

1) Firstly, 240mg PLGA solid is dissolved in 3ml dichloromethane and chloroform mixed solution (the volume ratio is 80:20), then 48mg nimodipine is dissolved in the solution, 30mg ammonium bicarbonate is weighed and dissolved in 1ml deionized water, 300 mul ammonium bicarbonate solution is mixed with oil phase solution, then ice water bath ultrasound is carried out for 1min, and then the mixture is poured into 15ml 3% PVA solution.

Scanning Electron Microscope (SEM) analysis was performed on the porous nimodipine-loaded microspheres of example 6, with surface and cross-sectional scanning, and the operation and analysis steps were as follows:

adhering the microspheres on double-sided adhesive, adhering the microspheres on a copper plate sample loading table, spraying gold by using a HITACHIE 1020 gold spraying device, and observing the surface morphology of the microspheres by using an S-3400N type scanning electron microscope. The SEM image of the porous nimodipine-loaded microsphere is shown in the attached figure 1. The medicine-carrying porous microsphere has uniform particle size distribution, a skin membrane attached to the surface, and porous and communicated inner parts.

The porous nimodipine-loaded microspheres of example 6 were subjected to particle size analysis, which was carried out by the following steps:

the particle size of the PLGA suspension was measured using Malvern MS2000 and the aerodynamic diameter Da was calculated in combination with tap density. Filling a sample into a liquid phase sample injection glass vial (2mL), dropping from a certain height (about 14mm) according to specified times (20 times), tightly packing the powder, continuously adding the powder until the powder is filled, leveling, accurately measuring the powder mass and the volume of the glass vial, and dividing the powder mass and the volume of the glass vial to obtain the density rho of the powder. The results are shown in Table 1.

Where ρ is the actual particle density, ρ _a Is the unit particle density (p) _a ＝1g/cm3)，d _g Is the geometric mean particle diameter of the actual particles.

Table 1 table of particle size distribution of example 6

Name(s)

D(0.1)

D(0.5)

D(0.9)

span

ρ

Da

Example 6

6.10μm

11.69μm

19.49μm

1.15

0.176g/cm3

4.88μm

Wherein D (0.1) is the diameter corresponding to 10% of the cumulative distribution of particle sizes (0 to 100%);

d (0.5) refers to the diameter corresponding to 50% of the cumulative distribution of particle sizes (0 to 100%);

d (0.9) refers to the diameter corresponding to 90% of the cumulative distribution of particle sizes (0 to 100%);

SPAN refers to SPAN ═ D (0.9) -D (0.5) ]/D (0.1).

The porous nimodipine-loaded microspheres of example 6 were analyzed by powder X-ray diffraction (PXRD) according to the following procedures:

using a japanese physical X-ray diffractometer, CuK α graphite monochromator, scan rate: 20 DEG min ^-1 The scanning range is as follows: 2 theta is 5-45 degrees, step length: 0.02 degree. The sample was subjected to a grinding treatment.

The PXRD pattern of the porous nimodipine-loaded microspheres is shown in figure 2. Nimodipine is encapsulated in microspheres in amorphous form.

Nuclear magnetic resonance hydrogen (1H NMR) analysis was performed on the porous nimodipine-loaded microspheres of example 6, and the operation and analysis were as follows:

bruker solution NMR (400MHz) was used, deuterated dimethyl sulfoxide was used as the solvent, and tetramethylsilane was used as the internal standard.

Nuclear magnetic resonance hydrogen spectrum of nimodipine:

¹ H NMR(400MHz,Chloroform-d)δ8.13(s,1H),8.00(dd,J＝8.3,2.3Hz,1H),7.66(d,J＝7.6Hz,1H),7.37(t,J＝7.9Hz,1H),5.74(s,1H),5.10(s,1H),4.94(m,J＝6.3Hz,1H),4.18(m,2H),3.54(m,2H),3.35(s,3H),2.36(s,6H),1.26(d,J＝6.2Hz,3H),1.09(d,J＝6.2Hz,3H).

nuclear magnetic resonance hydrogen spectrum of PLGA:

¹ H NMR(400MHz,Chloroform-d)δ5.36–5.06(m,1H),4.95–4.52(m,2H),1.89–1.42(m,3H),1.25(d,J＝6.2Hz,0H).

nuclear magnetic resonance hydrogen spectrum of the nimodipine-loaded porous microspheres:

¹ H NMR(400MHz,Chloroform-d)δ8.13(s,1H),8.00(dd,J＝8.2Hz,1H),7.66(d,J＝7.6Hz,1H),7.37(t,J＝7.9Hz,1H),5.65(s,1H),5.21(dd,J＝15.7,8.8Hz,20H),4.98–4.58(m,32H),4.17(m,2H),3.54(m,2H),3.35(s,3H),2.37(s,6H),1.56(d,J＝6.9Hz,75H),1.25(d,J＝6.0Hz,7H),1.09(d,J＝6.3Hz,3H).

the positions of the nuclear magnetic peaks of the porous drug-loaded microspheres and the nimodipine bulk drug are consistent, and the drug and the carrier material are physically combined.

Example 7 comparison of drug loading of different microspheres

Weighing 10mg of microspheres, dissolving in a fixed amount of dimethyl sulfoxide, precipitating PLGA with ethanol, taking the supernatant, and detecting the concentration by using high performance liquid chromatography, wherein the test results are shown in Table 2.

TABLE 2 drug loading and encapsulation efficiency for different microspheres

Name (R)	Drug loading	Encapsulation efficiency
			Example 1	7.63％	83.93％
Example 2	8.04％	88.44％
			Example 4	7.65％	84.15％
Example 6	16.49％	98.92％

Example 8 comparison of dissolution experiments with different drug loaded microspheres

Microspheres loaded with the same mass of drug were weighed, suspended in phosphate buffer at pH 7.4, tested at 37 ℃, by paddle method at 100rpm, sampled at regular intervals, and tested for concentration using hplc, with the test results shown in fig. 3.

The porous microspheres with different drug loading rates are completely released for about 3 days, and fit to accord with a Higuchi slow release equation.

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims

1. A preparation method of porous microspheres for pulmonary inhalation is characterized by comprising the following steps:

the first surfactant solution comprises water and a first surfactant;

the second surfactant solution comprises water and a second surfactant;

2. The method of claim 1, wherein the low boiling organic solvent is selected from the group consisting of: dichloromethane, chloroform, or a mixed solvent thereof.

3. The method of claim 1, wherein the biodegradable high molecular weight polymer is selected from the group consisting of: poly L-lactide PLLA, poly DL-lactide PDLLA, poly lactide-co-glycolide PLGA, poly adipate PBAT, polyesters PBS, PBSA, poly epsilon-caprolactone PCL, poly 3-hydroxyalkanoate PHA, cellulose, chitosan, starch, modified starch, or combinations thereof.

4. The method of claim 1, wherein the hydrophobic drug is nimodipine.

5. The method of claim 1, wherein the inorganic salt porogen is selected from the group consisting of: ammonium bicarbonate, sodium chloride, calcium chloride, or a combination thereof.

6. The method of claim 1, wherein the first surfactant and the second surfactant are independently selected from the group consisting of: PVA, Span, Tween, or combinations thereof.

7. Porous microspheres for pulmonary inhalation, wherein the microspheres have an apparent diameter of 10-15 um;

the aerodynamic diameter of the microspheres is 4-6 um;

the microspheres have a porous structure;

8. The microsphere of claim 7, wherein the microsphere is prepared by the method of claim 1.

9. The microsphere of claim 7, wherein the pores within the microsphere are intercommunicated.

10. The microsphere of claim 7, wherein the biodegradable high molecular weight polymer is selected from the group consisting of: poly L-lactide PLLA, poly DL-lactide PDLLA, poly lactide-co-glycolide PLGA, poly adipate PBAT, polyesters PBS, PBSA, poly epsilon-caprolactone PCL, poly 3-hydroxyalkanoate PHA, cellulose, chitosan, starch, modified starch, or combinations thereof; and/or

The hydrophobic drug is nimodipine.