DRY POWDER FORMATION USING A VARIABLY CONSTRAINED, DIVIDED PATHWAY FOR MIXING FLUID STREAMS

Abstract

Methods of making a dry powder, comprise (a) delivering a liquid solution or suspension and a second, immiscible fluid to a flow path, (b) transporting the liquid solution or suspension and the immiscible fluid along the flow path, wherein the flow path includes two or more flow passages of different diameters, at least one flow divider which divides and diverts the flowing mixture into at least two separate passages, wherein the separate passages subsequently intersect to combine their respective flows into a single flowing stream, (c) rapidly reducing the pressure of the single flowing stream, whereby droplets are formed, and (d) passing the droplets through a flow of inert drying gas to form a dry powder. A nebulizing nozzle includes an inlet, a flow path as described, and a restrictor nozzle outlet.

Claims

1. A method of making a dry powder, comprising (a) delivering a liquid solution or suspension and an immiscible supercritical or near critical fluid to a flow path, (b) transporting a mixture of the liquid solution or suspension and the immiscible fluid along the flow path, wherein the flow path along which the mixture is transported includes two flow passages of different diameters, at least one flow divider which divides and diverts the flowing mixture into two separate passages, wherein the separate passages subsequently intersect to combine their respective flows into a single flowing stream, (c) rapidly reducing the pressure of the single flowing stream by passing the stream through a restrictor nozzle, whereby droplets are formed, and (d) passing the droplets through a flow of inert drying gas to form a dry powder.

2. The method of claim 1, wherein the flow path includes a first passage having a first diameter, followed by a second passage having a second diameter larger than the first diameter, followed by a third passage having a third diameter smaller than the second diameter, followed by the flow divider which divides and diverts the flowing mixture into two separate passages, wherein the separate passages subsequently intersect to combine their respective flows into a single flowing stream.

3. The method of claim 2, wherein the first diameter is in a range of from about 0.1 to about 3.0 mm, the second diameter is from about 0.01 to about 8 mm greater than the first diameter, and the third diameter is about 0.01 to about 8 mm less than the second diameter.

4. The method of claim 2, wherein the respective separate passages have diameters equal to the first diameter.

5. The method of claim 2, wherein the respective flows from the separate passages are combined into the single flowing stream in a fourth passage having a fourth diameter less than the diameters of the respective separate passages.

6. The method of claim 2, wherein the first diameter is in a range of from about 0.1 to about 3.0 mm, the second diameter is in a range of from about 1.0 to about 6 mm, the third diameter is in a range of from about 0.1 to about 3.0 mm, the respective separate passages have diameters in a range of from about 1.0 to about 3.0 mm, and the fourth diameter is in a range of from about 0.1 to about 3.0 mm.

7. The method of claim 1, wherein the flow divider divides and diverts the flowing mixture into three or four separate passages which subsequently intersect to combine their respective flows into the single flowing stream.

8. The method of claim 1, wherein the separate passages have respective segments which are parallel to one another.

9. (canceled)

10. The method of claim 1, wherein the restrictor nozzle has a diameter of less than 0.1 mm.

11. The method of claim 1, wherein the supercritical or near critical fluid is carbon dioxide.

12. The method of claim 1, wherein the liquid solution or suspension comprises at least one active ingredient.

13. The method of claim 12, wherein the active ingredient is at least one selected from the group consisting of vaccine, insulin, amino acid, peptide, protein, enzyme, anti-viral, anti-fungal, antibiotic, anti-inflammatory agent, antihistamine, analgesic, anti-cancer agent, antimicrobial agent, immune suppressant, thrombolytic, anticoagulant, central nervous system stimulant, decongestant, diuretic vasodilator, antipsychotic, neurotransmitter, sedative, hormone, anesthetic, and siRNA.

14. The method of claim 1, wherein the dry powder comprises at least 30% of particles of a size of less than 5.8 m as modeled by an Andersen Cascade Impactor according to US Pharmacopeia <601>.

15. The method of claim 1, wherein the inert drying gas is nitrogen or carbon dioxide.

16. The method of claim 1, wherein the method is conducted at a temperature of not more than 40 C.

17.-21. (canceled)

22. The method of claim 2, wherein the supercritical or near critical fluid is carbon dioxide.

23. The method of claim 2, wherein the liquid solution or suspension comprises at least one active ingredient.

24. The method of claim 23, wherein the active ingredient is at least one selected from the group consisting of vaccine, insulin, amino acid, peptide, protein, enzyme, anti-viral, anti-fungal, antibiotic, anti-inflammatory agent, antihistamine, analgesic, anti-cancer agent, antimicrobial agent, immune suppressant, thrombolytic, anticoagulant, central nervous system stimulant, decongestant, diuretic vasodilator, antipsychotic, neurotransmitter, sedative, hormone, anesthetic, and siRNA.

25. The method of claim 2, wherein the dry powder comprises at least 30% of particles of a size of less than 5.8 m as modeled by an Andersen Cascade Impactor according to US Pharmacopeia <601>.

26. The method of claim 2, wherein the inert drying gas is nitrogen or carbon dioxide.

27. The method of claim 2, wherein the method is conducted at a temperature of not more than 40 C.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0022] The detailed description of the invention will be more fully understood in view of the drawings, in which:

[0023] FIG. 1 shows a schematic diagram of the formulation-dependent drying process of a droplet into a particle with folded-shell morphology (Vehring 2007).

[0024] FIG. 2A shows the morphology of folded-shell immunoglobulin particles spray dried without the addition of leucine (Vehring 2007) and FIG. 2B shows the morphology of folded-shell immunoglobulin particles spray dried with the addition of 25% leucine by weight (Vehring 2007).

[0025] FIG. 3 shows the morphology of a solid-foam particle created under the trade name of PulmoSpheres (Vehring 2007).

[0026] FIG. 4 shows a schematic diagram of the currently used CAN-BD nozzle described in U.S. Pat. No. 6,630,121.

[0027] FIG. 5 shows a scanning electron micrograph (SEM) image of a typical CAN-BD-produced powder (produced from an aqueous solution containing 5% w/w sucrose) in the case in which no shell-forming or blowing agents are added to the formulation (Cape 2008).

[0028] FIG. 6 shows a graph of the distribution of aerodynamic particle sizes produced from carbon dioxide (CO.sub.2) nebulization and nitrogen (N.sub.2) nebulization. The instrument employed in the measurement of the aerodynamic diameter (TSI Aerosizer DSP, Model 3225, equipped with an Aero-Disperser, Model 3230) imparts a sufficient dispersing force to the powder that aerodynamic diameter can be considered roughly equivalent to the geometric diameter.

[0029] FIG. 7 shows a schematic diagram of the flow pattern and mixing of two liquids inside the CAN-BD nozzle described in U.S. Pat. No. 6,630,121, as modelled by the computational fluid dynamics (CFD) capability of Solidworks software.

[0030] FIG. 8 shows quantitatively the extent of mixing of two liquids inside the CAN-BD nozzle described in U.S. Pat. No. 6,630,121, as modelled by the CFD capability of Solidworks software and represented by the mass fraction of one of the liquids encountered across a lateral cross section of the opening of the tee.

[0031] FIG. 9 shows a 3D model of an example nozzle of the invention as described in Example 1, rendered by Solidworks software.

[0032] FIG. 10A shows a schematic diagram of a specific embodiment of a nebulizing nozzle according to the invention.

[0033] FIG. 10B shows a schematic diagram of the flow pattern and increased mixing of two liquids inside the nozzle of the invention, as modelled by the CFD capability of Solidworks software and described in Example 1.

[0034] FIG. 11 shows quantitatively the extent of mixing of two liquids inside the nozzle of the invention, as modelled by the CFD capability of Solidworks software and described in Example 1.

[0035] FIG. 12 shows a photograph of the nozzle of the invention as described in Example 2.

[0036] FIG. 13 shows an SEM of the 90% mannitol/10% methionine dry microparticulate powder produced by the CAN-BD nozzle described in U.S. Pat. No. 6,630,121 at 800 magnification.

[0037] FIG. 14 shows an SEM of the 90% mannitol/10% methionine powder produced by the CAN-BD nozzle described in U.S. Pat. No. 6,630,121 at 3700 magnification.

[0038] FIG. 15 shows an SEM of the 90% mannitol/10% methionine powder produced by the nozzle of the invention as described in Example 2, at 800 magnification.

[0039] FIG. 16 shows an SEM of the 90% mannitol/10% methionine powder produced by the nozzle of the invention as described in Example 2, at 3000 magnification.

[0040] The drawings show certain features related to the invention but are not to be construed as limiting of the invention in any manner.

DETAILED DESCRIPTION

[0041] The present invention provides a method for the creation of relatively low-density particles irrespective of the chemical composition of the particles and, in certain embodiments, provides a method for the creation of low-density particles of aerodynamic properties suitable for inhalation, irrespective of the chemical composition of the particles.

[0042] In order to obviate the need for shell-forming excipients or blowing agents in the creation of low-density particles, voids must be created within the particle physically during the spray-drying process. Immiscible supercritical or near critical fluids such as supercritical carbon dioxide or near critical carbon dioxide are improved nebulizing mediums for the creation of gas-filled bubbles. After leaving the nozzle, the bubbles may be dried quickly under a stream of warm, dry gas to produce hollow particles.

[0043] In contrast to the mechanism of traditional spray dryer nozzles, in which the forceful aerosolization of droplets is accomplished only by the proximity of the feed solution to a stream of a pressurized gas, the formation of gas-filled bubbles necessitates that the nebulizing gas and liquid solution become intimately mixed prior to exiting the nozzle. Carbon dioxide is preferred over many other fluids in this respect as it is easily compressed at room temperature into a liquid at reasonable pressures (above 900 psig). In its fluid state, carbon dioxide assumes the physical properties associated with liquids, and can be intimately mixed into an emulsion with another liquid. The cellular structure of the emulsion forms the basis for a fine plume of droplets to be created once the emulsion is rapidly decompressed to atmospheric pressure. Small particles are created by the greater expansion ratio, and thus greater expansion energy, of the liquid carbon dioxide than that of gaseous nitrogen. The volume expansion ratio of liquid carbon dioxide is roughly 1:533 (liquid:gas), while the expansion of gaseous nitrogen will simply follow the linear relationship defined by the ideal gas law. Rapid release of pressurized liquid carbon dioxide to atmospheric pressure produces greater energy release and greater atomization of the droplets in the spray plume, ultimately resulting in dried particles of smaller average geometric diameters than the same nozzle conditions with compressed nitrogen as the nebulizing gas.

[0044] Additionally, carbon dioxide has a much higher solubility in water (about 80-fold) at room temperature than does nitrogen. The higher solubility of carbon dioxide and the solvent properties, controlled by pressure, of its liquid phase allow for the dissolution of some of the carbon dioxide in the liquids with which it is mixed. According to Henry's law, the solubility of gases in liquids increases proportionately with increasing pressure, allowing a substantial amount of carbon dioxide to be dissolved in the opposing liquid upon mixing. The dissolved carbon dioxide serves as a placeholder within a droplet after leaving the nozzle, and upon return to atmospheric pressure, much of the dissolved carbon dioxide leaves the droplet as a gas, creating hollow regions within the particle. The timescale of the oversaturation, followed by vaporization and removal from the droplet, of the dissolved carbon dioxide is slower than the vaporization of the liquid carbon dioxide contained in the emulsion. Through the combination of these processes, small droplet diameters are created, and hollow regions within the droplets are formed, resulting in the creation of small, low-density particles. To accomplish this, the emulsion and dissolution of carbon dioxide within the mixing space must be as thorough and consistent as possible, and the liquids must be allowed to mix completely.

[0045] Accordingly, incomplete mixing of the fluid carbon dioxide and liquid solution is likely to result in only a portion of the resultant particles possessing a hollow morphology. The mixing of equal proportions of two liquids inside the current CAN-BD nozzle described by U.S. Pat. No. 6,630,121, as modelled by Solidworks using computational fluid dynamics (CFD), is schematically depicted in FIG. 7. In this configuration, partial mixing of the two liquids occurs at the boundary between them (indicated in light grey), but a substantial portion of each liquid remains in an unmixed form. The extent of mixing of the two liquids is shown quantitatively in FIG. 8, which shows the mass fraction of one of the liquids across a lateral cross-section of the outlet in the tee. Absolute mixing would be represented by a flat line at 0.5 mass fraction across the entire lateral cross section.

[0046] Mixing is improved immensely according to the invention when a variably constrained (variable diameter), divided pathway is introduced into the nozzle in place of the simple meeting of two liquid streams which is described in U.S. Pat. No. 6,630,121. One embodiment of a nozzle for use in the present invention is shown schematically in FIG. 9. By variably constraining and dividing the flow pathway, turbulence, eddies and other flow perturbations are introduced that encourage mixing of the two liquids. Initially, the nozzle invention comprises a similar geometry to the low-volume tee described in U.S. Pat. No. 6,630,121. The two liquid streams meet in the center of the tee, in which partial mixing takes place.

[0047] The flow then progresses through an area of variable constraint, such that the diameter of the flow path is variable, i.e., increased and decreased along the flow path. In a specific embodiment, the flow path is initially increased and then decreased. In an alternate specific embodiment, the flow path is initially decreased and then increased. The variation in constraint may encompass any suitable effective pathway diameter for a desired amount of liquid mixing. Within the present disclosure, reference to a flow path passage diameter refers to the inside diameter of a conduit constituting the flow path passage. In a specific embodiment, the diameter along the flow path is constrained, i.e., may vary, from about 0.01 mm to about 8 mm. In a more specific embodiment, the diameter is constrained from about 2 mm to about 7 mm. In yet a more specific embodiment, the diameter is constrained from about 1.5 mm to about 6 mm. Additionally, the diameter may be constrained in a manner as to produce particles suitable for inhalation. Suitable diameters along the flow path include from about 0.01 mm to about 8 mm, more specifically from about 2 mm to about 7 mm, and even more specifically from about 1.5 mm to about 6 mm. These dimensions are exemplary only and various components of the nozzle may occur in any order, in any number of repetition, and at any distance between the meeting of the supercritical fluid and feed solution or suspension and the restrictor nozzle outlet.

[0048] The flow through the improved nozzle also progresses to an area of flow pathway division, such that the flow stream is divided into two or more branches or separate passages. The number of divisions may encompass any suitable effective number for a desired amount of liquid mixing. In a specific embodiment, the number of branches comprises from about 2 to about 4. In a more specific embodiment, the number of branches comprises from 2 or 3. In yet a more specific embodiment, the number of branches is 2. Additionally, the number of branches may be comprised in a manner as to produce particles suitable for inhalation. In specific embodiments, the separate passages have respective segments that are parallel to one another.

[0049] In a specific embodiment as shown in FIG. 10A, the invention is directed to a nebulizing nozzle 100 comprising at least one inlet, shown in FIG. 10A as inlets 102 and 104, a restrictor nozzle outlet 106, and a flow path 108 in communication with the inlet and the restrictor nozzle outlet. In the specific embodiment of FIG. 10A, the flow path includes a mixing T 110, followed by a first passage 112 in communication with the inlets and having a first diameter, followed by a second passage 114 having a second diameter larger than the first diameter, followed by a third passage 116 having a third diameter smaller than the second diameter, followed by a flow divider 118 which divides and diverts flow into at least two separate passages. In a specific embodiment, the separate passages have segments 120 and 122, respectively, which are parallel with one another. The separate passages subsequently intersect at 124 to combine and form a fourth passage 126 in communication with the restrictor nozzle outlet 106. This configuration is exemplary only and various components of the nozzle may occur in any order, in any number of repetition, and at any distance between the meeting of the supercritical fluid and feed solution or suspension and the restrictor nozzle outlet.

[0050] In more specific embodiments of the nebulizing nozzle shown in FIG. 10A, the first diameter is in a range of from about 0.1 to about 3.0 mm, the second diameter is from about 0.01 to about 8 mm greater than the first diameter, and the third diameter is about 0.01 to about 8 mm less than the second diameter. In further embodiments, the respective separate passages have diameters greater than the third diameter. In another embodiment, the fourth passage has a fourth diameter less than the diameters of the respective separate passages. In further embodiments, the first diameter is in a range of from about 0.1 to about 3.0 mm, the second diameter is in a range of from about 1.0 to about 6 mm, the third diameter is in a range of from about 0.1 to about 3.0 mm, the respective separate passages have diameters in a range of from about 1.0 to about 3.0 mm, the fourth diameter is in a range of from about 0.1 to about 3.0 mm, and the restrictor nozzle has a diameter of less than about 0.1 mm.

[0051] The length of the flow path over which each diameter is changed from one passage to the next is sufficiently short to achieve good mixing. In one embodiment, there is an abrupt change from one diameter to the next, with no transition area, as shown in FIG. 10A. In another embodiment, the length of the flow path over which each diameter is changed from one passage to the next ranges up to about the larger diameter of the two passages, up to about 0.5 times the larger diameter of the two passages, or up to about 0.25 times the larger diameter of the two passages.

[0052] The length of each passage of a constant diameter may be varied as desired. In a specific embodiment, the length of each passage of a constant diameter, i.e., each of the first through fourth passages, is of a length of at least the respective diameter of the passage.

[0053] The mass fraction of one liquid component in the mixture, upon complete mixing, will be substantially consistent throughout the entire lateral cross section of the opening of the nozzle and will be numerically defined by Equation 2:

[00002]$\begin{array}{cc}{w}_i=\frac{Q_l}{Q_T}.& \mathrm{Equation}.Math..Math.2\end{array}$

where w.sub.i is the mass fraction of the liquid, Q.sub.l is the volumetric flow rate of the liquid, and Q.sub.T is the total volumetric flow rate. In a specific embodiment, the mass fraction of the liquid does not vary by more than about 25%, more than about 20%, more than about 15%, or more than about 10% throughout the entire lateral cross section of the opening of the nozzle. In a specific embodiment, the mass fraction of the liquid solution or suspension comprises from about 5 to about 95% of the mixture. In a more specific embodiment, the mass fraction of the liquid solution or suspension comprises from about 30 to about 80% of the mixture. In yet a more specific embodiment, the mass fraction of the liquid solution or suspension comprises from about 40 to about 70% of the mixture. The mass fraction of solute or suspended component in the liquid may vary widely. In a specific embodiment, the mass fraction of solutes and suspended components in the liquid is in a range of about 0.0001 to about 20%, to about 10%, to about 1% or to about 0.5%. Additionally, the composition of the mixture may be comprised as to produce particles suitable for inhalation. Suitable mass fractions of supercritical or near critical fluid, for example, liquid carbon dioxide, include from about 5% to about 95% of the mixture, more specifically from about 20% to about 70% of the mixture, and even more specifically from about 30% to about 60% of the mixture.

[0054] The liquid solution or suspension may have any desired composition based on the dry powder to be formed by the inventive methods and nozzle. In specific embodiments, the liquid comprises water, an organic solventwater mixture, or one or more organic solvents. A liquid is easily selected depending on the composition of the component which is desired to be provided in dry powder form. In a specific embodiment, the liquid comprises water, an alcohol, more specifically, methanol, ethanol, isopropanol, propanol, a butyl alcohol, etc., or a mixture thereof. The solute or suspended material may comprise an active agent, examples of which include, but are not limited to, vaccines, insulin, amino acids, peptides, proteins, enzymes, anti-virals, anti-fungals, antibiotics, anti-inflammatory agents, antihistamines, analgesics, anti-cancer agents, antimicrobial agents, immune suppressants, thrombolytics, anticoagulants, central nervous system stimulants, decongestants, diuretic vasodilators, antipsychotics, neurotransmitters, sedatives, hormones, anesthetics, and siRNA. The liquid solution or suspension may further include one or more excipients selected from stabilizers, bulking agents, surfactants, antioxidants, and the like.

[0055] In a specific embodiment, the liquid solution or suspension includes a cannabinoid, a polymer binding agent, a dispersing agent, and a bulking agent, and, optionally, an antioxidant, as described in the Sievers et al U.S. application Ser. No. 15/466,719, filed Mar. 22, 2017, the disclosure of which is incorporated herein by reference in its entirety. Suitable polymer binding agents include polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), poly(lactic-co-glycolic) acid (PLGA), polyvinyl alcohol (PVA), polyacrylic acid (PAA), N-(2-hydroxypropyl) methacrylamide (HPMA), polyoxazoline, polyphosphazenes, xanthan gum, gum arabic, pectins, chitosan derivatives, dextrans, carrageenan, guar gum, cellulose ethers, hyaluronic acid, albumin, and starch. Suitable dispersing agents comprise amino acids which act as surfactants, including methionine, alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, dipalmitoylphosphatidycholine (DPPC), phosphatidic acid (PA), phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphatidylserine (PS), phosphatidylglycerol (PG), Tween 20, and Tween 80. Suitable bulking agents comprise a non-hygroscopic polyol such as mannitol, gum Arabic, monosaccharides such as glucose, galactose, fructose, mannose, allose, altrose, fucose, gulose, sorbose, tagatose, arabinose, lyxose, rhamnose, ribose, xylose, erythrose, and threose, disaccharides such as lactose, maltose, sucrose, trehalose, lactulose, cellobiose, chitobiose, allolactose, sucralose, and mannobiose, and polyols such as maltitol, sorbitol, xylitol, erythritol, isomalt, arabitol, ribitol, galactitol, fucitol, iditol, myo-inositol, volemitol, lactitol, maltotriitol, maltotetraitol, maltodextrin, and polyglycitol. Suitable antioxidants include, but are not limited to, include vitamin A, vitamin C, vitamin E, alpha-carotene, astaxanthin, beta-carotene, canthaxanthin, lutein, lycopene, zeaxanthin, flavonoids (such as apigenin, myricetin, eriodictyol, theaflavin, genistein, resveratrol, malvidin), cinnamic acid, chicoric acid, chlorogenic acid, rosmarinic acid, curcumin, xanthones, eugenol, citric acid, oxalic acid, and lipoic acid. In a specific embodiment, the dispersing agent comprises methionine and an additional antioxidant is not employed.

[0056] In specific embodiments of the dry powder produced by the nozzle of the invention, at least 30% of particles have an aerodynamic diameter of less than 5.8 m as modeled by an Andersen Cascade Impactor according to US Pharmacopeia <601>, and are thus suitable for respiration. Such powders will be effectively aerosolized by any dry powder inhaler and deposited in the airways. Low-density, easily-aerosolized powders may possess tap densities of 0.01 g/ml to 1 g/ml.

[0057] The particle distribution of the dry powder according to the invention comprises mixture of solid spheres and, importantly, hollow spheres. Specifically, the dry powder contains significantly more hollow spheres as compared to the typical CAN-BD nozzle-prepared powder which does not employ the variable flow path of the invention. In specific embodiments, the dry powder produced according to the invention comprises at least about 20%, at least about 25%, or at least about 30%, hollow spheres.

[0058] Various aspects of the dry powders and methods of the invention are illustrated in the following Examples.

EXAMPLE 1

[0059] Mixing of equal volumes of two liquids according to the invention as described herein was modelled by CFD using the Solidworks software.

[0060] The simulated liquid was methanol and the simulated immiscible fluid was supercritical or near critical carbon dioxide. The parameters were as follows: a first inlet was simulated to flow 1.510.sup.5 m.sup.3/s of methanol at a uniform flow rate. A second inlet was simulated to flow 1.510.sup.5 m.sup.3/s of liquid carbon dioxide at a uniform flow rate. The outlet was set to conditions of 101325 Pa and 293.2 K.

[0061] The results of the simulation are depicted schematically in FIG. 10B. The two streams (dark grey) were mixed nearly completely (mid-scale grey) by the time the flow stream reached the opening of the nozzle. The quantitative results of the simulation are shown in FIG. 11. The mass fraction of methanol approaches a value of 0.5 throughout the entire expanse of the lateral cross section of the nozzle opening, demonstrating thorough mixing of the two liquids.

EXAMPLE 2

[0062] Dry inhalable powder according to the invention was prepared as described herein.

[0063] A methanol/water solution (7:3 methanol:water) comprising 16% w/w total dissolved solids was made. The dissolved solids were composed of 90% w/w mannitol and 10% methionine. The solution was divided in half and dried using the previously described CAN-BD process with the following parameters: 2.0 ml/min. carbon dioxide flow rate, 1.0 ml/min. solution flow rate, 40 C. nitrogen drying gas temperature, 40 L/min. nitrogen drying gas flow rate, 75 m internal diameter fused silica restrictor, 5 cm long fused silica restrictor, and 0.45 m Nylon powder-collection filter. One half of the solution was dried with the typical CAN-BD low-volume tee nozzle schematically depicted in FIG. 4, and the other half of the solution was dried with an improved nozzle design according to the invention, as shown in FIG. 12.

[0064] The dimensions of the improved nozzle in this example were as follows. The 0.35 mm original flowpath diameter expanded to 1.5 mm flowpath diameter, and then narrowed again to 0.35 mm flowpath diameter. The flowpath then bifurcated into two pathways of 1.5 mm diameter, then was again constrained to a final 0.35 mm diameter flowpath before exiting the nozzle.

[0065] The resulting powder particles dried from the typical CAN-BD low-volume tee nozzle are shown in scanning electron micrographs (SEMs) in FIG. 13 and FIG. 14. The particles are predominantly solid spheres with occasional evidence of hollow particles scattered throughout the powder, as expected. The resulting powder particles dried from the improved nozzle according to the invention are shown in SEMs in FIG. 15 and FIG. 16. The powder particle distribution, although comprised of some solid spheres, contains significantly more (about 30%) hollow spheres as compared to the typical CAN-BD nozzle-prepared powder.

[0066] The specific embodiments and examples described in the present disclosure are illustrative only in nature and are not limiting of the invention defined by the following claims. Further aspects, embodiments and advantages of the methods of the present invention will be apparent in view of the present disclosure and are encompassed within the following claims.

REFERENCES

[0067] Ameri, M.; Maa, Y.-F. Spray drying of biopharmaceuticals: stability and process considerations. Dry. Technol. 2006, 24, 763-768. [0068] Baras, B.; Benoit, M.-A.; Gillard, J. Parameters influencing the antigen release from spray-dried poly(DL-lactide) micro-particles. Int. J. Pharm. 2000, 200,133-145. [0069] Begat, P.; Price, R.; Harris, H.; Morton, D. A. V.; Staniforth, J. N. The influence of force control agents on the cohesive-adhesive balance in dry powder inhaler formulations. KONA. 2005, 23, 109-121. [0070] Bernstein, H.; Straub, J. A.; Brush, H. T.; Wing, R. E. Microencapsulated Fluorinated Gases for Use as Imaging Agents, Acusphere, Inc. U.S. Pat. No. 5,611,344, 1997. [0071] Bittner, B.; Kissel, T. Ultrasonic atomization for spray drying: a versatile technique for the preparation of protein loaded biodegradable microspheres. J. Microencapsul. 1999, 16, 325-341. [0072] Cape, S. P.; Villa, J. A.; Huang, E. T. S.; Yang, T.-H.; Carpenter, J. F.; Sievers, R. E. Preparation of active proteins, vaccines and pharmaceuticals as fine powders using supercritical or near-critical fluids. Pharm. Res. 2008, 25, 1967-1900. [0073] Chew, N. Y. K.; Chan, H.-K. Use of solid corrugated particles to enhance powder performance. Pharm. Res. 2001, 18, 1570-1577. [0074] Freitas, S.; Merkle, H. P.; Gander, B. Ultrasonic atomization into reduced pressure atmosphere: envisaging aseptic spray-drying for microencapsulation. J. Control. Release. 2004, 95, 185-195. [0075] Fu, Y.-J.; Mi, F.-L.; Wong, T.-B.; Shyu, S.-S. Characteristic and controlled release of anticancer drug loaded poly (D,L-lactide) microparticles prepared by spray drying technique. J. Microencapsul. 2001, 18, 733-747. [0076] Geller, D. E.; Weers, J.; Heuerding, S. Development of an inhaled dry-powder formulation of tobramycin using PulmoSphere technology. J. Aerosol Med. 2011, 24, 175-182. [0077] Li, H.-Y.; Birchall, J. Chitosan-modified dry powder formulations for pulmonary gene delivery. Pharm. Res. 2006, 23, 941-950. [0078] Maa, Y.-F.; Costantino, H. R.; Nguyen, P.-A.; Hsu, C. C. The effect of operating and formulation variables on the morphology of spray-dried particles. Pharm. Dev. Technol. 1997, 2, 213-223. [0079] Maa, Y.-F.; Nguyen, P.-A. T.; Hsu, S. W. Spray-drying of air-liquid interface sensitive recombinant human growth hormone. J. Pharm. Sci. 1998, 87, 152-159. [0080] Masters, K. Spray-drying: An Introduction to Principles, Operational Practice and Applications. Leonard Hill, London, 1972. [0081] Maury, M.; Murphy, K.; Kumar, S.; Maurer, A.; Lee, G. Spray-drying of proteins: effects of sorbitol and trehalose on aggregation and FT-IR amide I spectrum of an immunoglobulin G. Eur. J. Pharm. Biopharm. 2005, 59, 251-261. [0082] Mu, L.; Feng, S. S. Fabrication, characterization and in vitro release of paclitaxel (taxol) loaded poly (lactic-co-glycolic acid) microspheres prepared by spray drying technique with lipid/cholesterol emulsifiers. J. Control. Release. 2001, 76, 239-254. [0083] Narayan, P.; Marchant, D.; Wheatley, M. A. Optimization of spray drying by factorial design for production of hollow microspheres for ultrasound imaging. J. Biomed. Mater. Res. 2001, 56, 333-341. [0084] Sacchetti, M.; Van Oort, M. M. Spray-drying and supercritical fluid particle generation techniques. In Hickey, A. J. (ed.) Inhalation Aerosols, Physical and Biological Basis for Therapy, Vol. 94, Lung Biology in Health and Disease. Marcel Dekker, New York, 1996. 337-384. [0085] Samborska, K.; Witrowa-Rajchert, D.; Goncalves, A. Spray-drying of alpha-amylasethe effect of process variables on the enzyme inactivation. Dry. Technol. 2005, 23, 941-953. [0086] Sellers, S. P.; Clark, G. S.; Sievers, R. E.; Carpenter, J. F. Dry powders of stable protein formulations from aqueous solutions prepared using supercritical CO.sub.2-assisted aerosolization. J. Pharm. Sci. 2001, 90, 785-797. [0087] Stahl, K.; Claesson, M.; Lilliehorn, P.; Linden, H.; Backstrom, K. The effect of process variables on the degradation and physical properties of spray dried insulin intended for inhalation. Int. J. Pharm. 2002, 233, 227-237. [0088] Straub, J.; Bernstein, H.; Chickering, D. E.; Randall, G. Porous Celecoxib Matrices and Methods of Manufacture Thereof, Acusphere, Inc. U.S. Pat. No. 6,589,557, 2003. [0089] Ting, T.-Y.; Gonda, I.; Gipps, E. M. Microparticles of polyvinyl alcohol for nasal delivery. I. Generation by spray-drying and spray-desolvation. Pharm. Res. 1992, 9, 1330-1335. [0090] Vehring, R. Pharmaceutical particle engineering via spray drying. Pharm. Res. 2008, 25, 999-1022. [0091] Vehring, R.; Foss, W. R.; Lechuga-Ballesteros, D. Particle formation in spray drying. J. Aerosol Sci. Tech. 2007, 38, 728-746. [0092] Wang, F.-J.; Wang, C.-H. Sustained release of etanidazole from spray dried microspheres prepared by non-halogenated solvents. J. Control. Release. 2002, 81, 263-280. [0093] Zijlstra, G. S.; Hinrichs, W. L. J.; de Boer, A. H.; Frijlink, H. W. The role of particle engineering in relation to formulation and de-agglomeration principle in the development of a dry powder formulation for inhalation of cetrorelix. Eur. J. Pharm. Sci. 2004, 23, 139-149.