CN116440084A - Inhalable pharmaceutical powder formulation and method for preparing same - Google Patents

Abstract

The present disclosure relates to an inhalable pharmaceutical powder formulation comprising a pharmaceutically active ingredient and pharmaceutically acceptable excipients, wherein the pharmaceutical powder formulation has a mass median aerodynamic particle size of 0.5 μm-10 μm, wherein the pharmaceutically acceptable excipients comprise any one or more of amino acids, mannitol.

Description

Inhalable pharmaceutical powder formulation and method for preparing same

Technical Field

The present disclosure relates to an inhalable pharmaceutical powder formulation and a method of preparing the same.

Background

Pulmonary administration is receiving attention from the medical community due to the advantages of large absorption area, high drug availability, small toxic and side effects, etc. However, pulmonary administration is susceptible to various factors, and to enhance the therapeutic effect, targeted measures must be taken to increase the pulmonary deposition rate of the drug and enhance the stability of the drug.

Inhalable pharmaceutical powder formulations (also known as dry powder inhalants (dry powder inhalation, DPI)) are special formulations for pulmonary administration, are hot spots for the development of pulmonary administration formulations in recent years, have the advantages of easy use, no propellant and atmospheric pollution, low auxiliary material amount, high drug loading and the like, but how to improve the deposition rate and stability of the lungs is still a problem to be solved.

TFF Pharmaceuticals the main process flow for preparing DPI using film freezing (Thin Film Freezing, TFF) techniques is to strike the rotating cryogenic surface with droplets and freeze them rapidly, then scoop the frozen flakes into a cold collection container with a knife blade, and then transfer the frozen flakes to vacuum freeze drying. TFF technology can form large flaky solids, which brings great trouble to filling, even if the TFF technology is mixed to break the TFF technology, the TFF technology is difficult to achieve 100% filling, and larger flaky solids need to be screened out, so that the yield is reduced; in addition, the deposition rate of the effective part of the TFF technology is lower, and the deposition rate is further greatly reduced in the accelerated placement process, so that the prompt stability is poor. Spraying liquid nitrogen into fog drops at hong Kong university, and vacuum freeze drying to form 20-30 μm spheres. However, due to its large physical diameter, it is difficult to deliver to deeper bronchi or lungs, and the 20-30 μm spheres make the filling dose limited and cannot be industrialized.

The fungal infection is mostly caused by inhalation of fungal spores through the airways, and the lung is a high incidence part of invasive fungal infection, so that the prevention of fungi by ensuring the lung drug concentration is a key point of preventive and antifungal treatment. In recent years, with the increase of immunosuppressed people, the occurrence rate of fungal infection has shown a significant trend. The clinical symptoms of invasive fungal infection have no specificity, lack of effective diagnosis, rapid disease progression and poor prognosis, and become a clinical problem. The current drugs for treating fungal infections in clinical use are: miconazole, fluconazole, voriconazole, itraconazole, etc., wherein voriconazole has become the drug of choice for the clinical treatment of invasive fungal infections.

Voriconazole (Voriconaole) is a triazole drug and has the characteristics of wide antibacterial spectrum and strong antibacterial efficacy. The dosage forms currently on the market are tablets and injections. The dosage of the voriconazole for oral administration and injection is large, the administration period is long, but the voriconazole has high renal toxicity and hepatotoxicity and has great side effects. For example voriconazole should be used carefully in patients allergic to other azole antifungals or in patients with cirrhosis. The voriconazole is prepared into inhalable medicinal powder preparation, so that good treatment effect of fungal infection is expected to be realized, and meanwhile, the administration dosage is reduced, and the toxic and side effects on patients are greatly reduced. However, the voriconazole powder inhalants obtained in the prior art have disadvantages of unsuitable particle size range, low delivery efficiency, poor stability, etc., and it is difficult to achieve desired therapeutic effects, because voriconazole has physical properties of high true density, high viscosity, and difficulty in dispersing between particles.

Disclosure of Invention

The inventors have conducted intensive studies to solve the above-mentioned problems, and have finally found a solution. In particular, the present disclosure provides an inhalable pharmaceutical powder formulation having a particle size of a proper size and uniform distribution, good particle size stability, and simultaneously achieving high delivery efficiency, thereby enabling beneficial therapeutic effects, benefiting patients.

According to one embodiment of the present disclosure, there may be provided an inhalable pharmaceutical powder formulation comprising a pharmaceutically active ingredient and a pharmaceutically acceptable excipient, wherein the pharmaceutical powder formulation has a mass median aerodynamic particle size of 0.5 μm-10 μm, wherein the pharmaceutically acceptable excipient comprises any one or more of amino acids, mannitol.

According to one embodiment of the present disclosure, there may be provided a method of preparing a pharmaceutical powder formulation as disclosed herein, the method comprising the steps of:

(1) Mixing the active ingredients of the medicine, an organic solvent, pharmaceutically acceptable auxiliary materials and purified water to obtain a precursor solution;

(2) And (3) spray freeze drying the precursor liquid obtained in the step (1).

Drawings

Figure 1 shows NGI measurements for the powder formulation of comparative example 1.

Figure 2 shows NGI measurements for the powder formulation of comparative example 2.

Fig. 3 shows ACI measurement results of the powder formulation of comparative example 3.

Fig. 4 shows a scanning electron microscope image of the powder formulation of example 4.

Figure 5 shows NGI measurements for the powder formulation of example 4.

Fig. 6 shows a scanning electron microscope image of the powder formulation of example 5. .

Figure 7 shows NGI measurements for the powder formulation of example 5.

Fig. 8 shows a scanning electron microscope image of the powder formulation of example 6.

Figure 9 shows NGI measurements for the powder formulation of example 6.

Fig. 10 shows a scanning electron microscope image of the powder formulation of example 7. .

Figure 11 shows NGI measurements for the powder formulation of example 7.

Fig. 12 shows a scanning electron microscope image of the powder formulation of example 8.

Figure 13 shows NGI measurements for the powder formulation of example 8.

Fig. 14 shows a scanning electron microscope image of the powder formulation of example 9.

Figure 15 shows NGI measurements for the powder formulation of example 9.

Fig. 16 shows a scanning electron microscope image of the powder formulation of example 10.

Fig. 17 shows a scanning electron microscope image of the powder formulation of example 11.

Figure 18 shows NGI measurements for the powder formulation of example 11.

Fig. 19 shows a scanning electron microscope image of the powder formulation of example 12.

Figure 20 shows NGI measurements for the powder formulation of example 12.

Detailed Description

Unless otherwise indicated, all numbers expressing quantities, concentrations, proportions, weights, particle sizes, percentages, technical effects, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about" or "approximately". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations. Unless otherwise indicated, terms used herein have the ordinary understood meaning to those skilled in the art. It will be appreciated by those skilled in the art that each numerical parameter should be construed in light of the number of significant digits and conventional rounding techniques, or in a manner well understood by those skilled in the art, depending upon the desired properties and effects sought to be obtained by the present disclosure.

Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the disclosure are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Every numerical range given throughout this specification will include every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein.

As used herein, the expression "a and/or B" includes three cases: (1) A; (2) B; and (3) A and B. The expression "A, B and/or C" includes seven cases: (1) A; (2) B; (3) C; (4) A and B; (5) A and C; (6) B and C; and (7) A, B and C. Similar expressions may be used in this sense.

As used herein, the term "aerodynamic particle size (aerodynamic diameter, da)" also known as aerodynamic equivalent diameter (aerodynamic equivalent diameter) is an artifact particle size (particle diameter) that describes particle motion. Sisi (Chinese character)Tobert (W.Stober) defines it as: density per unit (ρ) ₀ ＝1g/cm ³ ) When moving at low reynolds numbers in still air, the spheres reach the same diameter as the actual particles at the final sedimentation velocity (Vs). I.e. the actual particle size is replaced by an equivalent diameter (or equivalent diameter) having the same aerodynamic properties. Since the particle size and density of the actual particles are not usually measured, the aerodynamic particle size can be measured directly by dynamic methods, which allows a uniform measurement of particle sizes with different shapes, densities, optical and electrical properties. The aerodynamic particle size can be calculated with reference to the following method: the particle size (volume particle size) Dv of the powder sample was measured by a laser particle size analyzer according to da= (ρ/ρ) ₁ ) ^1/2 X Dv is calculated to give an aerodynamic particle size Da. Where ρ is the density of the particles, ρ ₁ ＝1g/cm ³ Dv is the average particle diameter of the particles. The value of ρ can be estimated from the tap density, ρ being about 1.26 times the tap density.

As used herein, the term "mass median aerodynamic particle size" or "MMAD (mass median aerodynamic diameter)" refers to: when the total mass of the various sized particles in a particle that is less than a certain aerodynamic particle size is 50% of the total mass of the particle (i.e., the sum of the masses of all the different sized particles), then this particle size is referred to as the mass median aerodynamic particle size.

As used herein, the term "effective fraction deposition rate" or "FPF (fine particle fraction)" refers to the percentage of the recovered dose in particle doses of 5 μm or less calculated as follows:

wherein:

FPD refers to the fine particle dose, namely the particle dose with the mass median aerodynamic particle diameter less than or equal to 5 mu m, calculated according to the drug mass of each level of ACI or NGI and the corresponding cut-off particle diameter of each level under the test flow rate;

the recovery dose refers to the sum of the drug mass of the capsule residue, the device residue, and the drug mass entering each level of ACI or NGI.

The higher the effective site deposition rate, the higher the pulmonary delivery efficiency.

As used herein, the term "hydrophobic amino acid" has the meaning commonly understood in the art, including alanine, valine, leucine, isoleucine, proline, glycine, methionine (methionine), tryptophan, and phenylalanine.

As used herein, the term "phospholipid" has a meaning commonly understood in the art including, but not limited to, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, biphospholipid glycerol.

As used herein, the term "nodules" has a meaning generally understood in the art and refers to a crystal habit or habit that a particular crystal species exhibits on the appearance of the crystal during spontaneous growth under normal external conditions. The stability of the corresponding preparation can be judged by the crystal nodule shape observed by an electron microscope. For example, the nodules being blocky particles indicate that the corresponding formulation has excellent stability.

As used herein, the term "small molecule compound" refers to a compound having a molecular weight of less than 1000Da.

As used herein, the term "medium molecular compound" refers to a compound having a molecular weight greater than or equal to 1000Da and less than 5000Da.

As used herein, the term "macromolecular compound" is synonymous with "macromolecular compound" and refers to a compound having a molecular weight greater than or equal to 5000Da.

The inhalable medicine powder preparation has loose texture, small and uniform particle size, good particle size stability, simple and convenient medicine administration method, high lung delivery efficiency, capability of generating high concentration of medicine in the lung, small dosage, low blood concentration and small adverse reaction, and can remarkably improve the compliance of patient administration.

According to one embodiment of the present disclosure, there may be provided an inhalable pharmaceutical powder formulation comprising a pharmaceutically active ingredient and a pharmaceutically acceptable excipient, wherein the pharmaceutical powder formulation has a mass median aerodynamic particle size of 0.5 μm-10 μm, wherein the pharmaceutically acceptable excipient comprises any one or more of amino acids, mannitol.

In some embodiments of the disclosure, the amino acid may be a hydrophobic amino acid. In some embodiments of the present disclosure, the amino acid may be any one or more of valine, leucine, glycine.

In some embodiments of the present disclosure, the pharmaceutically acceptable excipients may further comprise a phospholipid. In some embodiments of the present disclosure, the phospholipid may comprise any one or more of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine. In some embodiments of the present disclosure, the phospholipid may be phosphatidylcholine. In some embodiments of the present disclosure, the phospholipid may be any one or more of dipalmitoyl phosphatidylcholine (DPPC), hydrogenated soybean lecithin (HSPC), distearoyl phosphatidylcholine (DSPC). In some embodiments of the present disclosure, the phospholipid may be DPPC.

In some embodiments of the present disclosure, the pharmaceutically acceptable adjuvant may be a combination of mannitol and a phospholipid. In some embodiments of the present disclosure, the pharmaceutically acceptable adjuvant may be a combination of an amino acid and a phospholipid. In some embodiments of the present disclosure, the pharmaceutically acceptable excipient may be a combination of an amino acid and DPPC. In some embodiments of the present disclosure, the pharmaceutically acceptable adjuvant may be a combination of leucine and DPPC. In some embodiments of the present disclosure, the pharmaceutically acceptable adjuvant may be a combination of leucine and phospholipid.

In some embodiments of the present disclosure, the weight ratio of the pharmaceutically active ingredient to the pharmaceutically acceptable excipient may be in the range of about 1:1 to about 100:1. In some embodiments of the present disclosure, the weight ratio of the pharmaceutically active ingredient to the pharmaceutically acceptable excipient may be in the range of about 5:1 to about 30:1. In some embodiments of the present disclosure, the weight ratio of the pharmaceutically active ingredient to the pharmaceutically acceptable excipient may be in the range of about 8:1 to about 20:1.

In some embodiments of the present disclosure, the pharmaceutical powder formulation may have a mass median aerodynamic particle size of about 0.5 μm to 5 μm. In some embodiments of the present disclosure, the pharmaceutical powder formulation may have a mass median aerodynamic particle size of about 1 μm to 5 μm. In some embodiments of the present disclosure, the pharmaceutical powder formulation may have a mass median aerodynamic particle size of about 2 μm to 5 μm. In some embodiments of the present disclosure, the pharmaceutical powder formulation may have a mass median aerodynamic particle size of about 3 μm to 5 μm. In some embodiments of the present disclosure, the pharmaceutical powder formulation may have a mass median aerodynamic particle size of about 3.5 μm to 5 μm.

In some embodiments of the present disclosure, the pharmaceutically active ingredient may be a small molecule compound or a medium molecule compound. In some embodiments of the present disclosure, the pharmaceutically active ingredient may be an antifungal small molecule compound or a medium molecule compound. In some embodiments of the present disclosure, the pharmaceutically active ingredient may be any one or more of miconazole, fluconazole, voriconazole, itraconazole. In some embodiments of the present disclosure, the pharmaceutically active ingredient may be voriconazole.

In some embodiments of the present disclosure, the molecular weight of the pharmaceutically active ingredient is less than or equal to 500Da. In some embodiments of the present disclosure, the molecular weight of the pharmaceutically active ingredient is less than or equal to 1000Da. In some embodiments of the present disclosure, the molecular weight of the pharmaceutically active ingredient is less than or equal to 2000Da. In some embodiments of the present disclosure, the molecular weight of the pharmaceutically active ingredient is less than or equal to 3000Da. In some embodiments of the present disclosure, the molecular weight of the pharmaceutically active ingredient is less than or equal to 4000Da. In some embodiments of the present disclosure, the molecular weight of the pharmaceutically active ingredient is less than or equal to 5000Da. In some embodiments of the present disclosure, the molecular weight of the pharmaceutically active ingredient is less than or equal to 10000Da. In some embodiments of the present disclosure, the molecular weight of the pharmaceutically active ingredient is less than or equal to 20000Da. In some embodiments of the present disclosure, the molecular weight of the pharmaceutically active ingredient is less than or equal to 50000Da. In some embodiments of the present disclosure, the molecular weight of the pharmaceutically active ingredient is less than or equal to 100000Da. In some embodiments of the present disclosure, the molecular weight of the pharmaceutically active ingredient is less than or equal to 1000000Da. In some embodiments of the present disclosure, the molecular weight of the pharmaceutically active ingredient is less than or equal to 10000000Da.

In some embodiments of the present disclosure, the nodules of the pharmaceutical powder formulation are any one or more of needles, flakes, lumps, and/or spheres. In some embodiments of the present disclosure, the nodules of the pharmaceutical powder formulation are needle-like powder, hollow spheres, platelet particles, or bulk particles. In some embodiments of the present disclosure, the nodules of the pharmaceutical powder formulation are platelet-like powder, long needle-like powder, small needle-like powder, hollow spheres, platelet-like particles, or block-like particles. In some embodiments of the present disclosure, the nodules of the pharmaceutical powder formulation are bulk particles.

In some embodiments of the present disclosure, the pharmaceutical powder formulation may be obtained by a spray freeze drying process.

According to one embodiment of the present disclosure, there may be provided a method of preparing a pharmaceutical powder formulation as described in the present disclosure, the method comprising the steps of:

(1) Mixing the active ingredients of the medicine, an organic solvent, pharmaceutically acceptable auxiliary materials and purified water to obtain a precursor solution;

(2) And (3) spray freeze drying the precursor liquid obtained in the step (1).

In some embodiments of the present disclosure, step (1) may comprise the sub-steps of:

(i) Mixing the pharmaceutically active ingredient with an organic solvent to obtain a mixture (a);

(ii) Mixing pharmaceutically acceptable auxiliary materials with purified water to obtain a mixture (b);

(iii) Mixing the mixture (a) with the mixture (b) to obtain a precursor solution;

wherein the pharmaceutically acceptable auxiliary materials are amino acid and/or mannitol;

wherein the order of (i) and (ii) is not limited, and (i) may be performed before (ii), after (ii), or simultaneously with (ii) separately.

In some embodiments of the present disclosure, step (1) may comprise the sub-steps of:

(i) Mixing the pharmaceutically active ingredient and the phospholipid with an organic solvent to obtain a mixture (a);

(ii) Mixing pharmaceutically acceptable auxiliary materials with purified water to obtain a mixture (b);

(iii) Mixing the mixture (a) with the mixture (b) to obtain a precursor solution;

wherein the pharmaceutically acceptable auxiliary materials are amino acid and/or mannitol;

wherein the order of (i) and (ii) is not limited, and (i) may be performed before (ii), after (ii), or simultaneously with (ii) separately.

In some embodiments of the present disclosure, the precursor liquid obtained in step (1) may be sprayed into a spray cooling tower. Because the precursor liquid is sprayed into the spray cooling tower without directly contacting liquid nitrogen, the defects of low yield, high heavy metal content in the product, difficulty in removal, uneven particle size and the like of preparing the powder preparation by directly spraying the precursor liquid into the liquid nitrogen are overcome. By using the preparation method disclosed by the invention, the inhalable medicine powder preparation can be obtained in high yield, the powder preparation does not contain heavy metals, has loose texture and smaller and more uniform particle size, and can be directly delivered to the lung in an inhalation mode, the medicine delivery method is simple and convenient, the lung delivery efficiency is high, the medicine can be generated in the lung, the dosage is small, the blood concentration is low, the adverse reaction is small, and the medicine compliance of a patient can be obviously improved.

In some embodiments of the present disclosure, the organic solvent may include any one or more of an alcohol compound, acetonitrile, methylene chloride, dimethyl sulfoxide, N-dimethylformamide. In some embodiments of the present disclosure, the organic solvent may include any one or more of methanol, ethanol, propylene glycol, t-butanol, acetonitrile. In some embodiments of the present disclosure, the organic solvent may include any one or more of ethanol, t-butanol, acetonitrile. In some embodiments of the present disclosure, the organic solvent may include any one or more of ethanol, tert-butanol. In some embodiments of the present disclosure, the organic solvent may be ethanol or t-butanol.

In some embodiments of the present disclosure, the weight ratio of the organic solvent to the purified water may be in the range of about 1:9 to about 9:1. In some embodiments of the present disclosure, the weight ratio of the organic solvent to the purified water may be in the range of about 0.5:1 to about 5:1. In some embodiments of the present disclosure, the weight ratio of the organic solvent to the purified water may be in the range of about 0.9:1 to about 3:1. In some embodiments of the present disclosure, the weight ratio of the organic solvent to the purified water may be in the range of about 0.9:1 to about 2.5:1.

In some embodiments of the present disclosure, the sum of the weight of the pharmaceutically active ingredient and pharmaceutically acceptable excipients may be from about 1% to about 30% of the total weight of the precursor solution. In some embodiments of the present disclosure, the sum of the weight of the pharmaceutically active ingredient and pharmaceutically acceptable excipients may be from about 1% to about 10% of the total weight of the precursor solution. In some embodiments of the present disclosure, the sum of the weight of the pharmaceutically active ingredient and pharmaceutically acceptable excipients may be from about 1% to about 5% of the total weight of the precursor solution.

The various embodiments and preferences described above for the pharmaceutical powder formulations of the present disclosure may be combined with one another (as long as they are not inherently contradictory to one another) and are equally applicable to the methods of preparing the pharmaceutical powder formulations of the present disclosure, and the various embodiments resulting from such combination are considered to be part of the disclosure of the present application.

The technical aspects of the present disclosure will be more clearly and clearly illustrated below by way of example in conjunction with examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present disclosure in any way. The scope of the present disclosure is limited only by the claims.

Examples

Materials and methods

Voriconazole used in the examples was purchased from Sichuan ren Andrugstrom Co., ltd., mannitol was purchased from ROQUETTE Co., france, glycine was purchased from Country chemical reagent Co., ltd., leucine was purchased from Ara Ding Shiji (Shanghai) Co., ltd., t-butanol was purchased from Ara Ding Shiji (Shanghai) Co., ltd., tween 80 was purchased from Shanghai Lingfeng chemical reagent Co., ltd., and ethanol was purchased from Country chemical reagent Co., ltd. DPPC was purchased from japan refinement. The inhaler being of North America

The mass median aerodynamic particle size and the effective part deposition rate were measured using an anderson eight-stage impactor (ACI cascade sampler) or a new generation eight-stage impactor (NGI cascade sampler), and the specific operation procedure is as follows: filling the powder into capsule No. 3 for useAn inhaler device and device adaptor connected to the artificial throat air inlet end of the impactor; the pumping flow rate of the pump was adjusted to 60L/min, and the pumping time was set to 4 seconds. Puncturing the capsule to start inhaling, and enabling the powder to enter different levels of the impactor along with the airflow; and (3) cleaning the powder of different levels of the impacter into a volumetric flask by using methanol water (the volume ratio of methanol to water is 7:3), fixing the volume, and detecting the content of the powder of each level of the impacter by using a high performance liquid chromatography.

The parameters of the spray freeze drying process carried out in the spray cooling tower are as follows:

a spray freezing parameters:

atomizing nozzle	BUCHI B-290 type spray head
		Spray cooling tower temperature	-60℃
Atomizing air flow rate	17L/min
		Feed liquid sample injection speed	5mL/min

b lyophilization curve parameters:

the stability measurement method is as follows:

the obtained powder was filled into No. 3 capsules, two aluminum bags were sealed, and the resultant was placed at 40℃and 75% humidity for 6 months. And taking out the materials in 1, 2, 3 and 6 months respectively, and detecting the aerodynamic particle size of the related substances and the mass median and the deposition rate of the effective parts.

Comparative example 1: preparation of powder formulations by micronizing voriconazole drug substance

Prescription a

Voriconazole as a raw material.

b process

Micronizing voriconazole raw material medicine by DEC MC ONE, and detecting the obtained micronized voriconazole by adopting a new generation eight-level impactor.

Results c

NGI measurements are shown in figure 1. As can be seen from fig. 1, most of the drug resides in the device, throat, level 1 and level 2. The effective part deposition rate of the obtained powder preparation is only 14.91 percent through calculation, and the mass median aerodynamic particle size is 6.602 mu m. The agglomeration tendency of the drug powder is obvious.

Comparative example 2: preparation of powder formulations by high pressure homogeneous vacuum drying

Prescription a

Component (A)	Voriconazole	Tween 80	Purified water
				Quality (g)	4	0.6	400

b process

1) Dispersing: weighing Tween 80 with prescription amount, dissolving in purified water, adding voriconazole with prescription amount, and homogenizing

Wetting at 7000 rpm;

2) Homogenizing under high pressure: adding the uniformly dispersed suspension into a high-pressure homogenizer, wherein the primary pressure is 1900rpm, and the secondary pressure is 150rpm for 6 times;

3) Vacuum drying: the suspension after high-pressure homogenization is filtered and collected, and is dried in vacuum for 24 hours at 25 ℃.

Results c

NGI measurements are shown in figure 2. As can be seen from fig. 2, most of the drug resides in the device, throat, level 1 and level 2. The effective part deposition rate of the obtained powder preparation is 24.68 percent through calculation, and the mass median aerodynamic particle size is 4.571 mu m. The agglomeration tendency of the drug powder is obvious.

Comparative example 3: preparation of powder formulations by spray drying

Prescription a

Component (A)	Voriconazole	Ethanol
			Quality (g)	3	300

b process

The spray drying was carried out using a BUCHI spray dryer, adjusting the atomizing gas pressure to 60mm Hg, pump speed 5%, inlet temperature 60 ℃.

Results c

The ACI measurement results are shown in fig. 3. As can be seen from fig. 3, most of the drug resides in the throat, level 0. The effective part deposition rate of the obtained powder preparation is only 16.81 percent through calculation, and the mass median aerodynamic particle size is 6.006 mu m. The agglomeration tendency of the drug powder is obvious.

Example 4: preparation of powder formulations by spray freeze drying voriconazole

Prescription a

Component (A)	Voriconazole	Tert-butanol	Purified water
				Quality (g)	3.0325	21.6359	51.4777

b process

1) Preparing liquid: weighing the prescription amount of voriconazole, adding the voriconazole into tertiary butanol, uniformly stirring, adding the prescription amount of purified water, and stirring by ultrasonic to dissolve.

2) Preparation: using BUCHI B-290 type double-fluid spray head, adjusting the flow rate of atomized gas to 17L/min and the feeding speed of liquid medicine to 5mL/min, spraying the solution into a spray cooling tower at-60 ℃, and transferring into a freeze dryer for freeze drying.

Results c

1) Scanning electron microscope results:

and (4) using a high-resolution field emission scanning electron microscope to perform scanning after the metal spraying treatment of the obtained powder preparation, wherein the obtained scanning electron microscope is shown in fig. 4. As can be seen from fig. 4, the powder preparation obtained by spray-freezing and drying voriconazole in a spray-cooling tower is in the form of tablet needles, and the grain size is large.

2) NGI measurement results:

the NGI measurement results are shown in fig. 5. The effective part deposition rate of the obtained powder preparation is calculated to be 20.07 percent, and the mass median aerodynamic particle diameter is 5.249 mu m.

Example 5: by passing throughSpray freeze drying voriconazole to prepare a powder formulation

Prescription a

Component (A)	Voriconazole	Tert-butanol	Purified water
				Quality (g)	3.0149	50.3279	21.5414

b process

1) Preparing liquid: weighing prescription amount of voriconazole, adding into tertiary butanol, stirring uniformly, adding prescription amount of purified water, stirring ultrasonically for dissolution,

2) Preparation: using BUCHI B-290 type double-fluid spray head, adjusting the flow rate of atomized gas to 17L/min and the feeding speed of liquid medicine to 5mL/min, spraying the solution into a spray cooling tower at-60 ℃, and transferring into a freeze dryer for freeze drying.

Results c

1) Scanning electron microscope results:

and (3) using a high-resolution field emission scanning electron microscope to perform scanning after the metal spraying treatment of the obtained powder preparation, wherein the obtained scanning electron microscope is shown in fig. 6. As can be seen from fig. 6, the powder preparation obtained by spray-freezing and drying voriconazole in a spray cooling tower is long needle-shaped aggregated powder, and the grain size is small.

2) The NGI measurement results are shown in fig. 7. The effective part deposition rate of the obtained powder preparation is 27.05 percent, and the mass median aerodynamic particle size is 4.585 mu m.

Example 6: preparation of powder formulations by spray freeze drying voriconazole with mannitol

Prescription a

Component (A)	Voriconazole	Mannitol (mannitol)	Tert-butanol	Purified water
					Quality (g)	2.7065	0.3186	52.2965	23.2644

b process

1) Preparing liquid: weighing prescription dose of voriconazole, adding the prescription dose of voriconazole into tertiary butanol, stirring uniformly, weighing prescription dose of mannitol, adding the mannitol into purified water, stirring and dissolving, and adding mannitol solution into voriconazole Kangshu butanol suspension, stirring and dissolving by ultrasound.

2) Preparation: using BUCHI B-290 type double-fluid spray head, adjusting the flow rate of atomized gas to 17L/min and the feeding speed of liquid medicine to 5mL/min, spraying the solution into a spray cooling tower at-60 ℃, and transferring into a freeze dryer for freeze drying.

Results c

1) Scanning electron microscope results:

and (3) using a high-resolution field emission scanning electron microscope to perform scanning after the metal spraying treatment of the obtained powder preparation, wherein the obtained scanning electron microscope is shown in fig. 8. As can be seen from fig. 8, the powder preparation obtained by spray-freezing and drying voriconazole in a spray cooling tower is long needle-shaped aggregated powder, and the grain size is large.

2) The NGI measurement results are shown in fig. 9. The powder preparation obtained by calculation has an effective part deposition rate of 31.69% and a mass median aerodynamic particle size of 4.664 μm.

Example 7: preparation of powder formulations by spray freeze drying voriconazole with leucine

Prescription a

Component (A)	Voriconazole	Leucine (leucine)	Tert-butanol	Purified water
					Quality (g)	1.9146	0.1037	33.7808	14.5577

b process

1) Preparing liquid: weighing prescription dose of voriconazole, adding the prescription dose of voriconazole into tertiary butanol, stirring uniformly, weighing prescription dose of leucine, adding the prescription dose of leucine into purified water, stirring and dissolving, and adding leucine solution into voriconazole Kangshu butanol suspension, stirring and dissolving by ultrasound.

2) Preparation: using BUCHI B-290 type double-fluid spray head, adjusting the flow rate of atomized gas to 17L/min and the feeding speed of liquid medicine to 5mL/min, spraying the solution into a spray cooling tower at-60 ℃, and transferring into a freeze dryer for freeze drying.

Results c

1) Scanning electron microscope results:

and (3) using a high-resolution field emission scanning electron microscope to perform scanning after the metal spraying treatment of the obtained powder preparation, wherein the obtained scanning electron microscope is shown in fig. 10. As can be seen from fig. 10, the powder preparation obtained by spray-freezing leucine and voriconazole in a spray-cooling tower and drying is a small needle-like powder.

2) NGI measurement results:

the NGI measurement results are shown in fig. 11. The powder preparation obtained by calculation has an effective part deposition rate of 41.27% and a mass median aerodynamic particle size of 4.231 μm.

3) Geometric results:

D10(μm)	D50(μm)	D90(μm)
			1.00	4.65	10.04

the geometry was measured using a neopatak laser particle sizer, wherein an R1 lens was selected, the dispersion pressure was 1bar, the feed rate was 60%, and the measured powder physical geometry D50 was 4.65 μm.

Example 8: preparation of powder formulations by spray freeze drying voriconazole with glycine

Prescription a

Component (A)	Voriconazole	Glycine (Gly)	Tert-butanol	Purified water
					Quality (g)	1.9220	0.0981	33.8729	14.5268

b process

1) Preparing liquid: weighing prescription amount of voriconazole, adding into tertiary butanol, stirring uniformly, weighing prescription amount of glycine, adding into purified water, stirring for dissolution, adding glycine solution into voriconazole Kangshu butanol suspension, stirring for dissolution by ultrasound.

2) Preparation: using BUCHI B-290 type double-fluid spray head, adjusting the flow rate of atomized gas to 17L/min and the feeding speed of liquid medicine to 5mL/min, spraying the solution into a spray cooling tower at-60 ℃, and transferring into a freeze dryer for freeze drying.

Results c

1) Scanning electron microscope results:

and (3) using a high-resolution field emission scanning electron microscope to perform scanning after the metal spraying treatment of the obtained powder preparation, wherein the obtained scanning electron microscope is shown in fig. 12. As can be seen from fig. 12, the powder preparation obtained by spray-freezing leucine and voriconazole in a spray-cooling tower and drying is a small needle-like powder.

2) NGI measurement results:

the NGI measurement results are shown in fig. 13. The powder preparation obtained by calculation has an effective fraction deposition rate of 43.45% and a mass median aerodynamic particle diameter of 4.124 μm.

3) Geometric results:

the geometry was measured using a neopatak laser particle sizer, wherein an R1 lens was selected, the dispersion pressure was 1bar, the feed rate was 60%, and the measured powder physical geometry D50 was 4.61 μm.

Example 9: preparation of powder formulations by spray freeze drying voriconazole with valine

Prescription a

Component (A)	Voriconazole	Valine (valine)	T-butylAlcohols	Purified water
					Quality (g)	1.9977	0.1052	33.3837	14.5894

b process

1) Preparing liquid: weighing prescription dose of voriconazole, adding the prescription dose of voriconazole into tertiary butanol, stirring uniformly, weighing prescription dose of valine, adding the prescription dose of valine into purified water, stirring and dissolving, and adding valine solution into voriconazole Kangshu butanol suspension, stirring and dissolving by ultrasound.

2) Preparation: using BUCHI B-290 type double-fluid spray head, adjusting the flow rate of atomized gas to 17L/min and the feeding speed of liquid medicine to 5mL/min, spraying the solution into a spray cooling tower at-60 ℃, and transferring into a freeze dryer for freeze drying.

Results c

2) Scanning electron microscope results:

and (4) using a high-resolution field emission scanning electron microscope to perform scanning after the metal spraying treatment of the obtained powder preparation, wherein the obtained scanning electron microscope is shown in fig. 14. As can be seen from fig. 14, the powder preparation obtained by spray-freezing leucine and voriconazole in a spray-cooling tower and drying was a small needle-like powder.

2) NGI measurement results:

the NGI measurement results are shown in fig. 15. The powder preparation obtained by calculation has an effective part deposition rate of 39.00% and a mass median aerodynamic particle size of 4.253 μm.

3) Geometric results:

D10(μm)	D50(μm)	D90(μm)
			0.95	4.60	10.20

the geometry was measured using a neopatak laser particle sizer, wherein an R1 lens was selected, the dispersion pressure was 1bar, the feed rate was 60%, and the measured powder physical geometry D50 was 4.60 μm.

Example 10: preparation of powder formulations by spray freeze drying voriconazole with leucine

Prescription a

Component (A)	Voriconazole	Leucine (leucine)	Ethanol	Purified water
					Quality (g)	0.5111	0.0548	25.1333	26.0054

b process

1) Preparing liquid: weighing prescription dose of voriconazole, adding the prescription dose of voriconazole into ethanol, stirring and dissolving, weighing prescription dose of leucine, adding the prescription dose of leucine into purified water, stirring and dissolving, and adding the leucine solution into the voriconazole ethanol solution, and stirring uniformly.

2) Preparation: using BUCHI B-290 type double-fluid spray head, adjusting the flow rate of atomized gas to 17L/min and the feeding speed of liquid medicine to 5mL/min, spraying the solution into a spray cooling tower at-60 ℃, and transferring into a freeze dryer for freeze drying.

Results c

1) Scanning electron microscope results:

and (3) using a high-resolution field emission scanning electron microscope to perform scanning after the metal spraying treatment of the obtained powder preparation, wherein the obtained scanning electron microscope is shown in fig. 16. As can be seen from fig. 16, the powder preparation obtained by spray-freezing leucine and voriconazole in a spray cooling tower and drying is hollow spheres, and the powder is loose.

Example 11: preparation of powder formulations by spray freeze drying voriconazole with DPPC

Prescription a

Component (A)	Voriconazole	DPPC	Tert-butanol	Purified water
					Quality (g)	3.80	0.20	67.21	28.82

b process

1) Preparing liquid: weighing the prescription amount of voriconazole and DPPC, adding into tertiary butanol, stirring for dissolving, adding into purified water, stirring and stirring uniformly.

2) Preparation: using BUCHI B-290 type double-fluid spray head, adjusting the flow rate of atomized gas to 13L/min and the feeding speed of liquid medicine to 5mL/min, spraying the solution into a spray cooling tower at-60 ℃, and transferring into a freeze dryer for freeze drying.

Results c

1) Scanning electron microscope results:

and (3) using a high-resolution field emission scanning electron microscope to perform scanning after the metal spraying treatment of the obtained powder preparation, wherein the obtained scanning electron microscope is shown in fig. 17. As can be seen from FIG. 17, the powder preparation obtained by spray-freezing DPPC and voriconazole in a spray cooling tower and drying the same is a sheet-like particle with a regular orientation of about 200 to 4000 nm.

2) NGI measurement results:

the NGI measurement results are shown in fig. 18. The effective part deposition rate of the obtained powder preparation is 31.14% and the mass median aerodynamic particle diameter is 4.756 μm through calculation.

Example 12: preparation of powder formulations by spray freeze drying voriconazole with DPPC and leucine

Prescription a

Component (A)	Voriconazole	DPPC	Leucine (leucine)	Tert-butanol	Purified water
						Quality (g)	3.60	0.20	0.21	67.28	28.84

b process

1) Preparing liquid: weighing prescription dosage of voriconazole and DPPC, adding into tertiary butanol, stirring for dissolving, adding leucine into purified water, stirring for dissolving, adding leucine solution into voriconazole DPPC tertiary butanol suspension, and stirring uniformly by ultrasound.

2) Preparation: using BUCHI B-290 type double-fluid spray head, adjusting the flow rate of atomized gas to 13L/min and the feeding speed of liquid medicine to 5mL/min, spraying the solution into a spray cooling tower at-60 ℃, and transferring into a freeze dryer for freeze drying.

Results c

1) Scanning electron microscope results:

the powder preparation obtained was subjected to a metal spraying treatment using a high resolution field emission scanning electron microscope and then scanned, and the scanning electron microscope image obtained was as shown in fig. 19. As can be seen from fig. 19, the powder preparation obtained by spray-freezing and drying DPPC and voriconazole in a spray-cooling tower is a block-shaped particle of about 200 to 4000nm having a regular orientation, and smaller particles are attached to the block-shaped particle.

2) NGI measurement results:

the NGI measurement results are shown in fig. 20. The powder preparation obtained by calculation had an effective fraction deposition rate of 47.5% and a mass median aerodynamic particle diameter of 3.561 μm.

Claims (16)

1. An inhalable pharmaceutical powder formulation comprising a pharmaceutically active ingredient and pharmaceutically acceptable excipients, wherein the pharmaceutical powder formulation has a mass median aerodynamic particle size of 0.5 μm-10 μm, wherein the pharmaceutically acceptable excipients comprise any one or more of amino acids, mannitol.

2. The pharmaceutical powder formulation of claim 1, wherein the amino acid comprises a hydrophobic amino acid.

3. The pharmaceutical powder formulation of any one of the preceding claims, wherein the pharmaceutically acceptable adjuvant further comprises a phospholipid.

4. The pharmaceutical powder formulation of any one of the preceding claims, wherein the phospholipid comprises any one or more of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine.

5. The pharmaceutical powder formulation of any one of the preceding claims, wherein the weight ratio of the pharmaceutically active ingredient to the pharmaceutically acceptable adjuvant is in the range of 1:1 to 100:1.

6. The pharmaceutical powder formulation of any one of the preceding claims, wherein the pharmaceutical powder formulation has a mass median aerodynamic particle size of 0.5 μιη -5 μιη.

7. A pharmaceutical powder formulation according to any one of the preceding claims, wherein the pharmaceutically active ingredient is a small molecule compound or a medium molecule compound.

8. A pharmaceutical powder formulation according to any one of the preceding claims, wherein the pharmaceutically active ingredient is an antifungal small or medium molecule compound.

9. The pharmaceutical powder formulation of any one of the preceding claims, wherein the pharmaceutically active ingredient is voriconazole.

10. The pharmaceutical powder formulation of any one of the preceding claims, wherein the nodules of the pharmaceutical powder formulation are needle-like powder, hollow spheres, platelet particles, or bulk particles.

11. The pharmaceutical powder formulation of any one of the preceding claims, wherein the pharmaceutical powder formulation is obtained by a spray freeze drying process.

12. A method of preparing a pharmaceutical powder formulation according to any one of claims 1-11, the method comprising the steps of:

(1) Mixing the active ingredients of the medicine, an organic solvent, pharmaceutically acceptable auxiliary materials and purified water to obtain a precursor solution;

(2) And (3) spray freeze drying the precursor liquid obtained in the step (1).

13. The method of claim 12, wherein the precursor liquid obtained in step (1) is sprayed into a spray cooling tower.

14. The method of claim 12 or 13, wherein the organic solvent comprises any one or more of an alcohol compound, acetonitrile, methylene chloride, dimethyl sulfoxide, N-dimethylformamide.

15. The method of any one of claims 12-14, wherein the weight ratio of the organic solvent to the purified water is in the range of 1:9 to 9:1.

16. The method of any one of claims 12-15, wherein the sum of the weight of the pharmaceutically active ingredient and the pharmaceutically acceptable adjuvant is 1% to 30% of the total weight of the precursor solution.