text:
|Publication number
|Publication type
|Application number
|Publication date
|Aug 18, 2009
|Filing date
|Dec 8, 2000
|Priority date
|Jun 30, 2000
|Fee status
|Also published as
|Publication number
|David B. Bennett, Thomas K. Brewer, Robert M. Platz, Herman Snyder
|Original Assignee
|Novartis Pharma Ag
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (102), Non-Patent Citations (5), Referenced by (9), Classifications (13), Legal Events (6)
|External Links: USPTO, USPTO Assignment, Espacenet
This application is a continuation-in-part of U.S. patent application Ser. No. 09/607,975, filed Jun. 30, 2000 now abandoned.
The present invention relates generally to systems and methods for manufacturing dry powder formulations. More specifically, the present invention provides systems and methods for the production of spray dried powders suitable for pharmaceutical applications, preferably for dry powders to be administered by inhalation. According to the invention, the drying kinetics of a spray drying process may be controlled, for example, to facilitate surface diffusion of surface active components or to facilitate amorphous-to-crystalline transformations during the manufacture of dry powder formulations.
Over the years, certain drugs have been sold in compositions suitable for pulmonary delivery to treat various conditions in humans. Such pulmonary drug delivery compositions include an aerosolized drug formulation that is inhaled by the patient so that the active agent can reach the alveolar region of the lungs.
Pulmonary drug delivery can be achieved by, for example, delivery of dry powder formulations to the deep lung. These powders have been prepared by spray drying as described in WO 96/32149, WO 99/16419 and U.S. Pat. Nos. 5,976,574, 5,985,248, 6,001,336, and 6,051,256, the disclosures of which are incorporated herein in their entirety. Preparing pharmaceutical compositions as stable dry powders by spray drying, however, poses many challenges. In order to scale up the spray drying process, it is desirable to increase the total solids content of the feed stream. It was found, however, that the emitted dose of powders prepared from higher total solids content feed streams, that is above about 1% (w/v), declined significantly.
In addition, the ability to deliver pharmaceutical compositions as dry powders poses many challenges. For example, particles containing both crystalline and amorphous phases may exhibit physical or chemical instability. Transformations of the materials during storage from amorphous to crystalline may result in such instability as a result of particle fusion and other physical changes. Further, crystallization tends to increase the water content in the remaining amorphous phase and thereby decrease the glass transition temperature (Tg) of the materials. Increased water content of the amorphous region increases molecular mobility and may increase chemical degradation reaction rates (i.e., hydrolysis, aggregation, etc.). Formulations having a higher percentage of crystallinity are less likely to degrade during storage.
It is known to provide spray dryers with drying zones which are maintained at different temperatures in order to provide some control of the drying kinetics. For example, U.S. Pat. No. 4,257,799 discloses a method for producing small hollow glass spheres having an outer diameter from about 100 to 500 microns wherein the method involves introducing aqueous droplets of a glass-forming solution into a long vertical drop oven or furnace having varying temperature regions.
U.S. Pat. Nos. 5,632,100, 5,924,216 and 4,281,024 also disclose spray drying with multiple drying zones, in which larger particles are typically subjected to a secondary drying in order to achieve desired moisture content.
U.S. Pat. No. 6,051,257 discloses structurally modifying particles after they are formed by a spray drying process in order to impart desired physical properties to the particles. The particle modifier is typically a furnace having temperature control independent of the spray dryer furnace and is positioned to receive the formed particles after they exit the spray dryer furnace.
U.S. Pat. No. 5,874,063 to Briggner et al. describes a method for increasing the crystallinity of conventional fine particles by treating the already manufactured fine particles with a solvent in the vapor phase and then removing the excess solvent. The solvent may be an organic solvent or it may be water.
WO 00/64552 discloses a method of spray drying and a plant therefore whereby spray drying is performed at increased pressure. The invention is directed to spray drying where an amorphous product is desired and/or where a high bulk density powder is desired. Spray drying according to this disclosure is conducted in a pressurized environment not below 1.25 bar absolute.
There remains a need to provide control of drying kinetics of spray drying processes in order to produce particles of desired physical properties for pharmaceutical applications such as the preparation of dry powders for inhalation. It is desirable to provide systems and methods which provide for dry powders with acceptable pulmonary delivery characteristics. The present invention overcomes the above shortcomings in the prior art.
The present invention provides exemplary systems and methods for producing dry powder formulations which in one aspect encourage surface diffusion of surface active components during the formation of dry powder medicaments, and therefore have improved emitted doses for pulmonary delivery. In another aspect of this invention, we have found that it is possible to provide improved control of the drying kinetics of spray drying methods in order to encourage amorphous-to-crystalline transformations during drying without exposing the finished fine particles to added water, solvent or thermal processing. We are thus able to reduce or minimize the potential instability of a fine particle formulation throughout its shelf life.
One embodiment of the present invention is directed to spray drying of pharmaceutical formulations containing surface active components. A system is provided for producing dry powders wherein the system includes an atomizer and at least one conditioning zone coupled to the atomizer to suspend an atomized formulation for a residence time where the atomized formulation remains in the liquid state. A dryer is coupled to the conditioning zone to dry the formulation exiting the conditioning zone. Further, a collector collects the dried formulation in powder form. In this manner, by controlling the residence time, temperature and relative humidity in the conditioning zone, the atomized formulation is suspended in a manner which allows the droplets to reach thermodynamic equilibrium, wherein the surface active component diffuses to the surface of the droplets to reach its equilibrium orientation. According to this aspect of the invention, the temperature and relative humidity in the conditioning zone is maintained at levels to minimize droplet drying in the conditioning zone during the period immediately following atomization, preferably at levels which prevent solvent evaporation all together.
The present invention further provides methods for producing a powdered formulation having a high concentration of surface active components on the surface of the particles. In one method of the present invention, an atomized formulation of liquid droplets is introduced into a conditioning zone. The atomized formulation is suspended within the conditioning zone for a residence time, during which the formulation remains in the liquid state to allow the droplets to reach thermodynamic equilibrium and allow diffusion of surface active components to the surface of the droplets. The method includes transferring the conditioned formulation to a dryer, introducing a heated gas into the drier to dry the conditioned formulation and form dry particles, and collecting the dry particles.
In another aspect, the present invention provides exemplary systems and methods for producing dry powder formulations which encourage amorphous-to-crystalline transformations of such formulations during manufacture to result in increased stability during storage. The present invention is based at least in part on the unexpected observation that storage stability of powdered formulations is greatly effected by the manufacturing conditions of the powders. According to this aspect of the invention, a multi-zonal spray dryer system and method of use are provided for producing dry powders. The system includes at least one conditioning zone having an inlet to introduce an atomized formulation into the conditioning zone. Air flow into the conditioning zone is controlled to control temperature and relative humidity.
The atomized formulation remains in the conditioning zone for a residence time at a predetermined temperature and relative humidity to allow equilibration of the water activity in the atomized droplet with the environment of the conditioning zone. This equilibration of water activity, or water content, results in partial drying of the droplet and promotes amorphous-to-crystalline transformations in the atomized formulation. A dryer is coupled to the conditioning zone to dry the atomized formulation into the final dried particles. Further, a collector collects the dried particles. In this manner, by controlling temperature and relative humidity in the conditioning zone and by controlling the residence time, the atomized formulation is conditioned and dried in a manner that promotes amorphous-to-crystalline transformation. According to this aspect of the invention, partially dried particles leave the conditioning zone wherein the particles retain a sufficiently high moisture content so as to require further drying. This excess moisture in the partially dried particles acts as a plasticizer to allow crystallization. The partially dried particles are then exposed to temperatures and relative humidity levels that allow crystallization to occur at a rate to convert amorphous material within a residence time of a few seconds.
According to another aspect of the invention, the pressure is controlled in order to provide elevated pressures of up to 75 atmospheres within the conditioning zones and/or within the dryer.
"Active agent" as described herein includes an agent, drug, compound, composition of matter or mixture thereof which provides some pharmacologic, often beneficial, effect. This includes feeds, feed supplements, nutrients, drugs, vaccines, vitamins, and other beneficial agents. As used herein, the terms further include any physiologically or pharmacologically active substance that produces a localized or systemic effect in a patient. The active agent that can be delivered includes antibiotics, antiviral agents, anepileptics, analgesics, anti-inflammatory agents and bronchodilators, and viruses and may be inorganic and organic compounds, including, without limitation, drugs which act on the peripheral nerves, adrenergic receptors, cholinergic receptors, the skeletal muscles, the cardiovascular system, smooth muscles, the blood circulatory system, synaptic sites, neuroeffector junctional sites, endocrine and hormone systems, the immunological system, the reproductive system, the skeletal system, autacoid systems, the alimentary and excretory systems, the histamine system and the central nervous system. Suitable agents may be selected from, for example, polysaccharides, steroids, hypnotics and sedatives, psychic energizers, tranquilizers, anticonvulsants, muscle relaxants, antiparkinson agents, analgesics, anti-inflammatories, muscle contractants, antimicrobials, antimalarials, hormonal agents including contraceptives, sympathomimetics, polypeptides, and proteins capable of eliciting physiological effects, diuretics, lipid regulating agents, antiandrogenic agents, antiparasitics, neoplastics, antineoplastics, hypoglycemics, nutritional agents and supplements, growth supplements, fats, antienteritis agents, electrolytes, vaccines and diagnostic agents.
Examples of active agents useful in this invention include but are not limited to insulin, calcitonin, erythropoietin (EPO), Factor VIII, Factor IX, ceredase, cerezyme, cyclosporine, granulocyte colony stimulating factor (GCSF), alpha-1 proteinase inhibitor, elcatonin, granulocyte macrophage colony stimulating factor (GMCSF), growth hormone, human growth hormone (HGH), growth hormone releasing hormone (GHRH), heparin, low molecular weight heparin (LMWH), interferon alpha, interferon beta, interferon gamma, interleukin-2, luteinizing hormone releasing hormone (LHRH), somatostatin, somatostatin analogs including octreotide, vasopressin analog, follicle stimulating hormone (FSH), insulin-like growth factor, insulintropin, interleukin-1 receptor antagonist, interleukin-3, interleukin-4, interleukin-6, macrophage colony stimulating factor (M-CSF), nerve growth factor, parathyroid hormone (PTH), thymosin alpha 1, IIb/IIIa inhibitor, alpha-1 antitrypsin, respiratory syncytial virus antibody, cystic fibrosis transmembrane regulator (CFTR) gene, deoxyribonuclease (Dnase), bactericidal/permeability increasing protein (BPI), anti-CMV antibody, interleukin-1 receptor, 13-cis retinoic acid, pentamidine isethionate, natural or synthetic lung surfactant, nicotine, albuterol sulfate, metaproterenol sulfate, beclomethasone dipropionate, triamcinolone acetamide, budesonide acetonide, ipratropium bromide, flunisolide, fluticasone, cromolyn sodium, ergotamine tartrate and the analogues, agonists and antagonists of the above, ciprofloxacin, tobramicin, gentamicin, and azithromicycin. Active agents may further comprise nucleic acids, present as bare nucleic acid molecules, viral vectors, associated viral particles, nucleic acids associated or incorporated within lipids or a lipid-containing material, plasmid DNA or RNA or other nucleic acid construction of a type suitable for transfection or transformation of cells, particularly cells of the alveolar regions of the lungs. The active agents may be in various forms, such as soluble and insoluble charged or uncharged molecules, components of molecular complexes or pharmacologically acceptable salts. The active agents may be naturally occurring molecules or they may be recombinantly produced, or they may be analogs of the naturally occurring or recombinantly produced active agents with one or more amino acids added or deleted. Further, the active agent may comprise live attenuated or killed viruses suitable for use as vaccines.
The active agent of the present invention may optionally be combined with pharmaceutical carriers or excipients which are suitable for respiratory and pulmonary administration. Such carriers or excipients may serve simply as bulking agents when it is desired to reduce the active agent concentration in the powder which is being delivered to a patient, or may be added to the active agent prior to processing to improve the stability and/or dispersability of the powder within a powder dispersion device. In other embodiments, the excipients may be delivered via the pulmonary route without an active agent, for example in clinical trials as a placebo. Such excipients include but are not limited to (a) carbohydrates, e.g., monosaccharides such as fructose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, trehalose, cellobiose, and the like; cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin; and polysaccharides, such as raffinose, maltodextrins, dextrans, and the like; (b) amino acids, such as glycine, arginine, aspartic acid, glutamic acid, cysteine, lysine, and the like; (c) organic salts prepared from organic acids and bases, such as sodium citrate, sodium ascorbate, magnesium gluconate, sodium gluconate, tromethamin hydrochloride, and the like; (d) peptides and proteins such as aspartame, human serum albumin, gelatin, and the like; and (e) alditols, such as mannitol, xylitol, and the like. A preferred group of carriers includes lactose, trehalose, raffinose, maltodextrins, glycine, sodium citrate, human serum albumin and mannitol.
"Dry powder" refers to a composition that consists of finely dispersed solid particles that are free flowing and capable of (i) being readily dispersed in an inhalation device and (ii) inhaled by a subject so that a portion of the particles reach the lungs to permit penetration into the alveoli. Such a powder is considered to by "respirable" or suitable for pulmonary delivery. The term dry, in reference to the powder, means that the composition has a moisture content which allows the particles to be readily dispersed in an inhalation device to form an aerosol. A dry powder will typically contain less than about 10 percent moisture, preferably less than 5% moisture, and more preferably will contain less than about 3 percent moisture.
"Emitted dose" or "ED" refers to an indication of the delivery of dry powder from a suitable a suitable inhaler device after a firing or dispersion event from a powder unit or reservoir. ED is defined as the ratio of the delivered dose to the nominal dose (i.e. the mass of the powder per unit dose placed into a suitable inhaler device prior to firing). The ED is an experimentally-determined amount, and is typically determined using an in-vitro device set up which mimics patient dosing. To determine an ED value, a nominal dose of dry powder (as defined above) is placed into a suitable inhaler device, which is then actuated, dispersing the powder. The resulting aerosol cloud is then drawn by vacuum from the device, where it is captured on a tared filter attached to the device mouthpiece. The amount of powder that reaches the filter constitutes the delivered dose. For example, for a 5 mg, dry powder-containing blister pack placed into an inhalation device, if dispersion of the powder results in the recovery of 4 mg powder on a tared filter as described above, then the ED for the dry powder composition is 4 mg (delivered dose)/5 mg (nominal dose)=80%.
"Mass median diameter" or "MMD" is a measure of median particle size, since the powders of the invention are generally polydisperse (i.e., consist of a range of particle sizes). MMD values as reported herein are determined by centrifugal sedimentation, although any number of commonly employed techniques can be used for measuring median particle size.
"Mass median aerodynamic diameter" or "MMAD" is a measure of the aerodynamic size of a dispersed particle. The aerodynamic diameter is used to describe an aerosolized powder in terms of its settling behavior, and is the diameter of a unit density sphere having the same settling velocity, generally in air, as the particle. The aerodynamic diameter encompasses particle shape, density and physical size of a particle. As used herein, MMAD refers to the midpoint or median of the aerodynamic particle size distribution of an aerosolized powder determined by cascade impaction.
"Powdered formulation" means the active agent as defined above in a formulation that is suitable for pulmonary delivery or the excipient that is suitable for pulmonary delivery or a combination of the active agent and the excipient. The powdered formulation may be delivered in the dry powder form or it may be in a mixture with a suitable low boiling point, highly volatile propellant. It is to be understood that more than one active agent or excipient may be incorporated into the powdered formulation and that the use of the term "agent" or "excipient" in no way excludes the use of two or more such agents or excipients.
"Surface active components" refers to any component of a formulation used with the systems and methods of the present invention which acts to decrease the surface tension of the droplets and may be the active agent including surface active proteins such as insulin, or may be an excipient added to the formulation.
According to a first aspect of the present invention directed to systems and methods for producing dry powders comprising increased surface concentration of surface active components, the active agent, excipient or active agent/excipient combination is dissolved or suspended in feed stock 18 at a concentration from 0.01% (w/v) to 10% (w/v), usually from 0.1% to 5.0% (w/v) and often from 1.0% to 3.0% (w/v). The formulation is atomized and then enters into conditioning zone 12. The atomized formulation remains in the conditioning zone at relative humidity and temperature levels controlled in order to minimize evaporation and allow the droplet to reach thermodynamic equilibrium wherein the surface active component reaches its equilibrium orientation at the droplet surface. According to this aspect of the invention, droplets leaving the conditioning zone maintain a majority of the solvent and thus remain in liquid state as discussed in detail below.
According to this aspect of the present invention, the conditioning zone 12 is operated to minimize slow drying rates in order to facilitate increased diffusion of surface active components, such as proteins including insulin, to the droplet surface prior to formation of a dried particle "skin" as discussed above. Preferably, the temperature in conditioning zone 12 is lowered to minimize droplet drying in the period immediately following atomization. Initial droplet drying is limited by maintaining a high relative humidity environment within conditioning zone 12 at moderate temperatures. Temperatures in conditioning zone 12 are less than 60� C., preferably less than 50� C., and most preferably 25-50� C., and relative humidities of greater than 10%, preferably greater than 20%, and most preferably greater than 25% up to 100%, are maintained in conditioning zone 12. Droplet residence time in conditioning zone 12 according to this aspect of the invention is preferably from about 0.1 second to about 20 seconds, and more preferably is from about 2 seconds to about 5 seconds. However, the specific residence time may vary depending upon the particular formulation of feed stock 18. During the residence time, atomized formulation 18 preferably remains as liquid droplets. The residence time and conditions in the conditioning zone are maintained such that the atomized formulation exiting the conditioning zone 12 remains in liquid form.
The control of temperature, relative humidity of the air added to the conditioning zone 12 and control of the residence time within conditioning zone 12 facilitates the production of exemplary dry powders by suspending the atomized feed stock 18 in liquid form for a sufficient duration to encourage increased surface enrichment of surface active components. Conditioning of the liquid droplets at minimized drying rates compared to standard spray drying systems, such as those manufactured by Buchi, Niro, APV, Yamato Chemical Company, Okawara Kakoki Company and others, facilitates the droplets reaching thermodynamic equilibrium and diffusion of the surface active components to the droplet surface. In this manner, increased solids content in the atomized feed stock 18 can be processed while enriching the surface of the dry powders produced with surface active components. Accordingly, the dry powders so produced will have a higher emitted dose as compared to those produced in a standard Buchi or Niro spray drier (see
According to another aspect of the present invention directed to promoting amorphous to crystalline transformation of a spray dried formulation, the present invention provides for systems and methods for producing dry powders that are more stable than previously produced spray dried powders. Dry powders are preferably prepared by spray drying under conditions which often result in a mixed amorphous and crystalline powder. Bulk active agent, usually in crystalline form, is dissolved in a physiologically acceptable aqueous buffer, typically a citrate buffer having a pH range from about 2 to 9. Excipients may be added to the solution either in combination with the active agent or, where no active agents to be delivered, by themselves. The active agent is dissolved or suspended in a feed stock at a concentration typically from 0.01% (w/v) to 3% (w/v), usually from 0.2%-2.0% (w/v). It is to be understood that higher concentrations of active agent in the feed stock are within the scope of this invention. According to this aspect of the invention, the atomized formulation passes through at least one conditioning zone where temperature and relative humidity are controlled to provide amorphous to crystalline transformation of the formulation. According to this aspect of the invention, a majority of the liquid phase is evaporated from the atomized formulation prior to the final drying process such that the droplets entering the conditioning zone leave as partially dried particles. The partially dried particles retain sufficient moisture to act as a plasticizer and allow crystallization.
According to this aspect of the present invention, the partially dried particles are exposed to significantly increased relative humidities for prolonged residence times. According to this aspect of the invention, the temperature in conditioning zone 12 is within 35-120� C. the relative humidity in conditioning zone 12 is from 10-99% and the residence times are sufficient to allow amorphous-to-crystalline transformation to the extent where substantially no further crystallization occurs. Residence times are preferably from about one second to about 60 seconds, and more preferably is from about 2 seconds to about 20 seconds. However, the specific residence time may vary depending upon the particular formulation of feed stock 18. According to this aspect of the invention, partially dried particles exit conditioning zone 12 for further conditioning and/or final drying prior to collection. A majority of the liquid has been evaporated from the atomized formulation exiting the conditioning zone (or the last conditioning zone if multiple conditioning zones are used) prior to entering the final drying stage.
Referring back to FIG. 1., atomizer 20 operates as an inlet to conditioning zone 12. More specifically, feed stock formulation 18 is atomized by atomizer 20 and injected into conditioning zone 12, where it remains for a residence time as discussed above. For preparation of dry powders intended for inhalation, atomizer 20 produces droplets of less then 50μm, preferably less then 30μm, and most preferably less than 20μm in diameter. The time that atomized formulation 18 remains in conditioning zone 12 will vary according to the size, type and number of conditioning zone(s) 12. Preferably, conditioning zone 12 is configured to provide prolonged residence times of formulation 18 within conditioning zone 12 as compared to more rapid drying environments as discussed above.
System 10 can be used with a variety of feed stock 18 to form a dry powder 30. For example, feed stock 18 may include the active agents described above alone or in combination with any of the excipients described above or the feed stock 18 may include the excipients in the absence of active agents. One or more active agents and one or more excipients may be included in the feed stock formulation. The feed stock formulation may also include a solvent or cosolvent system. The solvents may be but are not limited to water, ethanol, acetone, isopropanaol, and methanol or combinations thereof.
In one embodiment, conditioning zone 12 comprises a plug flow conditioning zone 12, i.e. a first-in-first-out (FIFO) conditioning zone. Alternatively, conditioning zone 12 may be a back mixing conditioning zone 12, i.e. a recirculation conditioning zone. Further, more than one conditioning zone 12 may be used, including combinations of FIFO and recirculation (continuous stirred tank reactors) configurations. In this manner, the residence time can be controlled by controlling the time feed stock 18 spends in the desired temperature/relative humidity environment within conditioning zone 12. In one embodiment, conditioning zone 12 comprises an elongate insulated tube (such as a glass tube) having a length of about 2 meters to about 6 meters.
For embodiments using relative humidity controller 14, controller 14 allows enough humid air into the conditioning zone 12 to control its relative humidity to be at least 10%, preferably between about 20% and about 99%.
During operation, it is preferable to monitor the temperature within system 10. Estimates of effective temperature in relative humidity environments may be extimated from a differential scanning calorimetry (DSC) thermoactivity monitor (TAM), moisture sorption and x-ray powder diffraction. In one embodiment, temperatures in conditioning zone 12 range from between about 35� C. and about 110� C. depending upon the temperature/relative humidity combination selected for an individual run.
In one embodiment, feed stock formulations of known composition and solids content are pumped through a twin fluid atomizer 20 at liquid rates of between about 2.5 to about 100.0 milliliters per minute (ml/min), often between about 2.5 and 7.0 ml/min for a laboratory scale process and about 10.0 to 100.0 ml/min for a pilot commercial scale process. Atomizer 20 gas pressures and flow rates are between about 30 pounds per square inch (psig) to about 100 psi and about 0.5 to 1.3 scfm, respectively for a laboratory scale process and about 30-130 psig and 5-20 scfm for a pilot commercial scale process.
As depicted in
Dryer 24 can have a variety of configurations within the scope of the present invention. For example, in one embodiment dryer 24 is an insulated glass chamber or tube about 2 meters to about 6 meters in length. In one embodiment, drying zone 24 is an insulated glass chamber or tube about 1 meter to about 3 meters in length. In one particular embodiment for promoting crystallinity, particle residence time in drying zone 24 is about 0.4 seconds.
Total airflow through system 10 will vary depending upon system 10 configuration, collection device, and feed stock 18 being processed. In one example, total airflow is from about 19 scfm to about 23 scfm, taking into account atomizer air, feed stock 18 and air injected into conditioning zone 12 and heated air injected into dryer 24.
The dried formulation comprises dry powder 30 that is collected in a collector 28. Collector 28 may comprise, for example, a cyclone or baghouse collector. It will be appreciated by those skilled in the art that other collectors also may be used within the scope of the present invention. Dry powder 30 preferably has a mass median diameter (MMD) from between about 0.5 microns to about 10.0 microns and a mass median aerodynamic diameter (MMAD) between about 1 and 5 microns.
The present invention further provides exemplary methods of producing powdered formulations using system 10. As shown in
In one aspect, the conditioning zone is configured to suspend the atomized droplets for a residence time in the range from about 0.1 second to about 20 seconds. In another aspect, the conditioning zone includes an elongate insulated tube having a length of at least about 1 meter. By controlling, inter alia, the conditioning zone size and the feed stock formulation flow rate through the conditioning zone, the residence time can be controlled. In one aspect, the conditioning zone includes a tank capable of suspending the feed stock formulation. In one aspect, a humidifier is coupled to the conditioning zone to control the relative humidity therein. Similarly, in another aspect the system includes a temperature controller to control the temperature of the feed stock formulation upon entry into the conditioning zone. Controlling the formulation temperature and conditioning zone relative humidity assists in the diffusion of surface active particles, in part by maintaining the atomized formulation in the liquid state in the conditioning zone.
In one aspect, the formulation is suspended in conditioning zone 12 by passing the formulation through an elongate tube of the conditioning zone. Alternatively, the formulation is suspended by circulating the formulation in a tank of the conditioning zone. Hence, a variety of conditioning zones may be used within the scope of the present invention.
Turning now to
The use of multiple conditioning zones 52, 62-64 further enables the introduction of a variety of constituents into the flow of system 50 at appropriate locations. For example, in certain circumstances it may be desirable to introduce additional material such as solvents and solvent vapors into system 50. The introduction of such materials can occur at appropriate locations within system 50 and, more specifically, within desired conditioning zones 52, 62-64. As shown in
For example, multiple conditioning zones enable the sequential transformation and drying of constituents within formulation 58 by using cosolvents having different vapor pressures. In one embodiment, formulation 58 comprises an active agent and an excipient in a ethanol/water cosolvent. The evaporation of one cosolvent, for example the ethanol, causes solidification of components that were dissolved therein and results in the composition of the drying surface of the droplet to be enriched by those components. Next, evaporation of the remaining solvent, for example the water, results in the solidification of the ethanol soluble components. It will be appreciated by those skilled in the art that the use of water and ethanol is but one example of many cosolvents and multi-solvents that may be processed in system 50. For example, to the active agent ethanol/water cosolvent formulation 58 described above, a first material 70, comprising excess ethanol, and a second material 72, comprising heated dry air may be added. As previously described, the ethanol will evaporate first, and then the water will evaporate. However, since ethanol has been added in excess, the ethanol dissolved component will remain dissolved until after the second material 72 is added. The first solvent to evaporate will determine the surface of the drying particle since the components dissolved in that solvent will solidify first. The remaining solvent(s) evaporate through that drying skin and their dissolved components solidify on the inside of the drying skin.
In one embodiment, second material 72 or Nth material 74 comprise reagents capable of reacting with the surface components of the dispersed particles forming part of formulation 58. Such reagents could provide, for example, a coating of formulation 58. Such reagents may include, but are not limited to phospholipids, saccharin, leucine and cholesterol. Materials 70-74 further may include the heated gas streams containing sublimed materials. When added to the flow of gas and formulation 58 through conditioning zones 52, 62-64 sublimed material may be deposited as a solid coating around the particle.
As shown in
Turning now to
Similarly, as shown in
According to another embodiment of the present invention, any of the conditioning zones or dryers discussed above are operated at elevated pressure up to about 75 atmospheres, preferably up to 15 atmospheres, and most preferably up to about 10 atm. (150 psig). Operation at such elevated pressures provides the ability to de-couple absolute and relative humidity effects to modulate the drying kinetics and augment crystalline growth rate. Operation at elevated pressure also provides the ability to reduce the initial droplet size from the atomizer, reduce secondary atomization caused by internal droplet expansion due to dissolved gasses in the liquid, and increase the drying gas mass flow and hence powder throughput by an order of magnitude. It further provides an expanded range of gas mixing rates by the manipulation of gas jet density ratios.
For example, for a given temperature and absolute humidity, the relative humidity increases in proportion to the absolute pressure. Therefore, the relative humidity increases as the dryer system pressure increases for any given set of flow rates and temperature. The residual moisture in a dried powder is a function of formulation and the relative humidity it is in equilibrium with. This causes a significant increase in the moisture content of a powder in the dryer or collector or conditioning zone at several atmospheres pressure. Thus, decoupling of the absolute and relative humidities can be manipulated to increase the rate of crystallization for some formulations including those containing polyols such as mannitol.
The conditioning zones and/or dryer are pressurized by providing a source of pressurized gas such as air or nitrogen in communication with the conditioning zone and/or dryer. According to the invention, the pressure source is capable of providing a pressure of up to about 75 atmospheres within the conditioning zone and/or dryer, and preferably provides a pressure of up to about 15 and most preferably 10 atmospheres. The dryer may also be pressurized by providing the hot drying gas to the chamber under pressure.
In one particular aspect, the formulation includes at least about 1 percent solids content, and the dry particles have an emitted dose of at least about 60 percent. The present invention further includes dry powdered formulations produced according to the claimed methods.
The amount of active agent in the powdered formulation will be that amount necessary to deliver a therapeutically effective amount of the active agent to achieve the desired result. In practice, this will vary widely depending upon the particular agent, the severity of the condition, and the desired therapeutic effect. However, pulmonary delivery is generally practical for active agents that must be delivered in doses of from 0.001 mg/day to 100 mg/day, preferably 0.01 mg/day to 50 mg/day.
Powdered formulations suitable for use in the present invention include dry powders and particles suspended or dissolved within a propellant. The powdered formulations have a particle size selected to permit penetration into the alveoli of the lungs, that is, preferably less than 10 μm mass median diameter (MMD), preferably less than 7.5 μm, and most preferably less than 5 μm, and usually being in the range of 0.1 μm to 5 μm in diameter. The emitted dose (ED) of these powders is >30%, usually >40%, preferably >50% and often >60% and the aerosol particle size distribution is about 1.0-5.0 μm mass median aerodynamic diameter (MMAD), usually 1.5-4.5 μm MMAD and preferably 1.5-4.0 μm MMAD. These dry powders have a moisture content below about 10% by weight, usually below about 5% by weight, and preferably below about 3% by weight. Such powders are described in WO 95/24183, WO 96/32149, and WO 99/16419 which are incorporated by reference herein.
Dry powders are preferably prepared by spray drying. The active agent, excipient, or combination of active agent and excipient, is dissolved or suspended in a physiologically acceptable aqueous buffer, typically a citrate buffer having a pH range from about 2 to 9.
The dry powders may be delivered using Inhale Therapeutic Systems' dry powder inhaler as described in U.S. Pat. Nos. 5,740,794, 5,785,049, WO 96/09085 and in U.S. patent application Ser. Nos. 60/136,418 and 60/141,793 which are incorporated herein by reference. The dry powders may also be delivered using a metered dose inhaler as described by Laube et al in U.S. Pat. No. 5,320,094, which is incorporated by reference herein.
Other features and advantages of the invention will appear from the following description in which the preferred embodiment has been set forth in detail in conjunction with the accompanying drawings.
A multi-zonal spray dryer (MZD) in accordance with
The 60 percent insulin formulation was prepared by dissolving human zinc insulin, mannitol, sodium citrate, sodium hydroxide and glycine in deoinized water for a total solids concentration as listed in Table 1. The residence time was between 3.6 and 3.8 seconds and was designed to be of sufficient length to encourage surface diffusion of insulin protein molecules. The success of the example was determined by comparing emitted dose (ED) as a function of total solids. Results and operating conditions for four test runs using solutions containing 3% solids are provided in Table 1 below. The values are plotted as triangles on the graph shown in
TABLE 1 MZD operating conditions for spray aging of I-016 powders. Conditioning Formulation solution zone Drying zone Cyclone [soln] pump temp./RH time temp./RH time temp./RH Yield MMD Moisture lot # (%) (ml/min (� C.)/(%) (sec) (� C.)/(%) (sec) (� C.)/(%) (%) (μm) (%, w/w) 97322 3 5 50/45 3.8 63/19 0.4 60/19 85 2.20 2.8 97381 3 7 35/43 3.7 68/6 0.4 66/6 80 1.48 3.4 97382 3 7 41/31 3.6 68/6 0.4 66/6 80 1.67 2.3 97383 3 7 44/27 3.6 67/6 0.4 65/6 90 1.66 2.3
The conditioning zone was an insulated glass tube about 2.1 meters in length and the drying zone was an insulated glass chamber about 0.6 meters in length. The conditioning zone temperature was monitored at a position immediately prior to the hot dry air inlet position. Temperature was nearly constant along the length of the conditioning zone (plus or minus about 2� C.). Monitored temperatures were used to calculate system relative humidity.
As shown above in Table 1, in one run (lot #97322) a 60 percent insulin formulation having about three percent solids was pumped into the conditioning zone at a rate of 5 ml/min. The conditioning zone was operated at about 50 degrees Celsius and about 45 percent relative humidity. The formulation remained in the conditioning zone for about 3.8 seconds before proceeding into the dryer. The now partially dried particles passed through the dryer in about 0.4 seconds, with the dryer operating at about 63 degrees Celsius and about 19 percent relative humidity. Dried particles were collected by a cyclone collector operating at about 60 degrees Celsius and about 19 percent relative humidity. An 85% yield was produced having an MMD of about 2.20 microns. The moisture content in the dry powder on a weight-to-weight percentage was about 2.8 percent.
As shown in
A multi-zonal spray dryer (MZD) in accordance with
Aqueous solutions containing 1.5% PTH (1-34 parathyroid hormone) and mannitol were dried in the MZD according to the following procedure and in the concentrations shown in Table 2. Water was pumped into Buchi 1 at a rate of between about 9 mL/min and about 22.5 mL/min. The inlet temperature of Buchi 1 was set between about 200 and 215� C. The drying airflow rate was about 10 standard cubic feet per min (scfm) to about 14 scfm. Atomizer gas pressure and flow rate were set to 35 psi and 0.7-1.0 scfm. The outlet temperature of the humid air from Buchi 1 ranged from about 52� C. to about 72� C.
The humid air from Buchi 1 was fed into Buchi 2. The active agent formulation feed solution was further atomized into Buchi 2 at a rate of about 2.5-7 mL/min. Atomizer pressure and flow rate were set to 80-100 psi and 1.0-1.3 scfm, respectively. The temperature of the atomized formulation that reached the conditioning zone was controlled by the volume and temperature of humid air added. The conditioning zone temperature was monitored at a position immediately after formulation atomization and the hot dry air inlet position. Temperature was nearly constant along the length of the conditioning zone (plus or minus about 2� C.). Monitored temperatures were used to calculate system relative humidity. Relative humidity calculations were based on the total amount of water entering the system, conditioning zone temperature, and assumed no leaks in the system.
From the conditioning zone, the formulations entered the drying zone and remained there from between about 0.4 and 0.5 seconds. The temperature of the drying zone was measured just before the cyclone collector and was between 40 and 80� C. The temperature of the dry air was between 90 and 180� C. A cyclone collector was used for powder collection. Table 1 shows the operating conditions and product characteristics of PTH/mannitol compositions prepared according to the invention. Table 3 shows emitted dose of the formulations.
MZD operating conditions and product characteristics of PTH/mannitol lots.
Formulation solution
Drying zone
lot #
(%, w/w)
n.d. = not determined
Emitted doses for PTH/mannitol lots prepared with the MZD.
% Collected
Lot #
% Left (� SD)
5 (2)
75 (4)
70.9 (4.4)
7 (6)
69 (4)
64.4 (6.2)
5 (2)
68 (4)
64.5 (3.3)
9 (5)
56 (8)
50.5 (7.6)
3 (6)
66 (3)
64.3 (4.0)
7 (4)
67 (4)
62.3 (2.8)
n.d. = not determined
The amount of crystallizable components were estimated by comparison of enthalpies of crystallization (ΔHc) obtained by differential scanning calorimetry (DSC) for particles prepared according to the invention (MZD) and those prepared by conventional spray drying systems.
Compared to a similar formulation processed through a Buchi or Niro system, the multi-zonal dryer of the present invention produced a much lower ΔHc (see Table 4). This indicates that a much higher level of crystallization occurred as a result of processing through the present invention. With increased crystallinity observed as a result of the present invention system and method, the resultant particles had a higher rate of amorphous-to-crystalline transformation during processing and thus will show a much greater storage stability than those processed in conventional manners.
Thermal analysis results for PTH/mannitol powders.
ΔHc 1
Lot #
Spray drier
zone temp.
MZD of Example 5 was used to spray dry a 1.5% solution of 85% mannitol and 15% citrate. Operating conditions and product characteristics are shown in Table 5. Particle sizes (mass median diameter, MMD) were determined by centrifugal sedimentation (Horiba) and moisture contents were determined by Karl Fisher titration.
MZD operating conditions and product characteristics of placebo (X-001) lots.
Formulation solution
Drying zone
lot #
(%, w/w)
1particle fusion observed for these lots; n.d. = not determined
The emitted dose of the first lot stored for 5 months in a dry box showed less than a 10% drop as compared to greater than 25% drop for powders produced by conventional spray drying. This further indicates the stability of powders produced in the multizonal dryer.
The invention has now been described in detail. However, it will be appreciated that certain changes and modifications may be made. Therefore, the scope and content of this invention are not limited by the foregoing description rather the scope and content are to be defined by the following claims.
|Cited Patent
|Filing date
|Publication date
|Apr 26, 1972
|Nov 6, 1973
|Knapsack Ag
|Spray nozzle for a spray dryer
|Jun 5, 1972
|Feb 5, 1974
|Rnb Ass Inc
|Method and apparatus for generating monodisperse aerosol
|Mar 23, 1973
|Jul 23, 1974
|Par Wey Mfg Co
|Liquid spray head
|May 14, 1975
|May 11, 1976
|W. R. Grace & Co.
|Method for drying fructose solutions
|Jun 30, 1975
|Jul 12, 1977
|American Cyanamid Company
|Rapidly dissolving, water-soluble polymers and spray drying method for their production
|Oct 7, 1975
|Oct 4, 1977
|J. M. Huber Corporation
|Spray dryer discharge system
|Dec 7, 1977
|Nov 28, 1978
|Outokumpu Oy
|Process for producing pulverous selenium from raw selenium
|Nov 20, 1978
|Sep 9, 1980
|Nakaya Sangyo Kabushiki Kaisha
|Liquid spraying device
|Oct 26, 1976
|Apr 14, 1981
|The Lion Fat & Oil Co., Ltd.
|Multistage spray drying method for detergent slurry
|May 16, 1983
|Dec 4, 1984
|Basf Wyandotte Corporation
|Spray-dried vitamin powders using hydrophobic silica
|Sep 20, 1982
|Sep 10, 1985
|Freund Industry Company, Limited
|Process for the preparation of activated pharmaceutical compositions
|May 3, 1984
|May 20, 1986
|Fisons Plc
|Inhalation pharmaceuticals
|Sep 3, 1985
|Oct 27, 1987
|Nestec S.A.
|Dryer and drying method
|Aug 4, 1984
|Jan 26, 1988
|Pyare Seth
|Novel pharmaceutical compositions containing hydrophobic practically water-insoluble drugs adsorbed on pharmaceutical excipients as carrier; process for their preparation and the use of said compositions
|Apr 18, 1986
|May 31, 1988
|Nestec S.A.
|Preparing a heat stable aqueous solution of whey proteins
|Oct 21, 1986
|Jul 26, 1988
|American Home Products Corporation (Del.)
|Spray dried acetaminophen
|Apr 6, 1987
|Nov 15, 1988
|Damrow Company, Inc.
|Spray drying method and apparatus for concurrent particle coating
|Nov 27, 1987
|Dec 27, 1988
|Bayer Akteingesellschaft
|Process for the preparation of polymer powders by spray drying
|Apr 29, 1988
|Apr 4, 1989
|Lever Brothers Company
|Spray drying of a detergent containing a porus crystal-growth-modified carbonate
|Jun 15, 1987
|May 30, 1989
|American Home Products Corporation
|Spray dried ibuprofen
|Apr 19, 1988
|Oct 3, 1989
|Corning Incorporated
|Spherical particles having narrow size distribution made by ultrasonic vibration
|Mar 17, 1988
|Aug 28, 1990
|Elan Corporation, P.L.C.
|Controlled release powder and process for its preparation
|May 23, 1990
|Mar 19, 1991
|Basf Corporation
|Process for spray drying riboflavin to produce a granulate product having low binder content
|Mar 22, 1989
|Apr 23, 1991
|Union Carbide Chemicals And Plastics Technology Corporation
|Methods and apparatus for obtaining wider sprays when spraying liquids by airless techniques
|Oct 19, 1988
|May 21, 1991
|Medicis Corporation
|Method of producing antibody-fortified dry whey
|Aug 25, 1988
|Jun 25, 1991
|Nestec S.A.
|Process for the preparation of an antioxydant extract of spices
|Mar 13, 1990
|Nov 12, 1991
|Stork Friesland B.V.
|Spray drying apparatus; method for preparation of a spray-dried product having a desired bulk density
|May 26, 1992
|Jun 22, 1993
|Bayer Aktiengesellschaft
|Process for isolating polycarbonates with co2 under pressure
|Jul 2, 1991
|Nov 9, 1993
|Fisons Plc
|Inhalation pharmaceuticals
|Aug 5, 1991
|Dec 14, 1993
|Northeastern University
|Production of polymer particles in powder form using an atomization technique
|Jul 16, 1991
|Jan 18, 1994
|Imperial Chemical Industries Plc
|Spray drying process with spinning atomizer
|Jun 29, 1993
|Jan 24, 1995
|Innovata Biomed Limited
|Pharmaceutical formulations comprising microcapsules
|Feb 23, 1994
|Jan 9, 1996
|Massachusetts Institute Of Technology
|Controlled released microparticulate delivery system for proteins
|Apr 10, 1992
|May 21, 1996
|Andaris Limited
|Preparation of diagnostic agents
|Jul 15, 1994
|Dec 3, 1996
|Prestrelski; Steven J.
|Formulation of a reconstituted protein, and method and kit for the production thereof
|Jun 7, 1995
|Mar 4, 1997
|Cima Labs, Incorporated
|Taste masking microparticles for oral dosage forms
|May 31, 1995
|Apr 22, 1997
|Takeda Chemical Industries, Ltd.
|Prolonged release microparticle preparation and production of the same
|Apr 21, 1994
|Apr 29, 1997
|Ultrasonic Dryer, Ltd.
|Spray drying system
|Dec 15, 1993
|May 13, 1997
|Imperial Chemical Industries Plc
|Production of particulate materials
|Jun 22, 1994
|Jul 15, 1997
|Schwarz Pharma Ag
|Process for the production of microcapsules
|Feb 13, 1995
|Jul 29, 1997
|Takeda Chemical Industries, Ltd.
|Prolonged release microparticle preparation and production of the same
|Jun 7, 1995
|Sep 16, 1997
|Emisphere Technologies, Inc.
|Spray drying method and apparatus
|Sep 5, 1995
|Nov 18, 1997
|Tsai; Shirley Cheng
|Ultrasound-modulated two-fluid atomization
|Nov 14, 1994
|Feb 10, 1998
|Union Carbide Chemicals & Plastics Technology Corporation
|Method for producing coating powders catalysts and drier water-borne coatings by spraying compositions with compressed fluids
|Mar 7, 1996
|Mar 3, 1998
|Takeda Chemical Industries, Ltd.
|Microparticle preparation and production thereof
|Nov 15, 1995
|Apr 21, 1998
|Andaris Limited
|Preparation of hollow microcapsules by spray-drying an aqueous solution of a wall-forming material and a water-miscible solvent
|Jun 7, 1995
|Jul 7, 1998
|The Board Of Regents Of The University Of Oklahoma
|Rapidly dissolving dosage form
|Dec 11, 1996
|Sep 1, 1998
|Industrial Technology Research Institute
|Generator for producing a narrowly size-distributed aerosol
|Feb 3, 1994
|Sep 15, 1998
|The Board Of Regents Of The University Of Oklahoma
|Rapidly dissolving tablet
|Jan 16, 1997
|Jan 5, 1999
|Massachusetts Instite Of Technology
|Particles incorporating surfactants for pulmonary drug delivery
|Oct 29, 1996
|Feb 23, 1999
|Massachusetts Institute Of Technology
|Aerodynamically light particles for pulmonary drug delivery
|Apr 30, 1997
|Jul 20, 1999
|Powdering Japan, K.K.
|Two-stage drying spray dryer
|Jun 5, 1995
|Sep 28, 1999
|Andaris Limited
|Preparation of further diagnostic agents
|Dec 29, 1997
|Nov 2, 1999
|Inhale Therapeutic Systems
|Processes for spray drying hydrophobic drugs in organic solvent suspensions
|Jun 17, 1998
|Nov 9, 1999
|University Technology Corporation
|Solubilization of pharmaceutical substances in an organic solvent and preparation of pharmaceutical powders using the same
|Dec 29, 1997
|Nov 16, 1999
|Inhale Therapeutic Systems
|Processes for spray drying solutions of hydrophobic drugs and compositions thereof
|Nov 17, 1997
|Nov 16, 1999
|Massachusetts Institute Of Technology
|Preparation of particles for inhalation
|Jun 7, 1995
|Nov 30, 1999
|Quadrant Healthcare (Uk) Limited
|Spray-dried microparticles and their use as therapeutic vehicles
|Mar 21, 1997
|Dec 7, 1999
|Inhale Therapeutic Systems
|Methods and compositions for pulmonary delivery of insulin
|Dec 29, 1997
|Dec 14, 1999
|Inhale Therapeutic Systems
|Processes for spray drying aqueous suspensions of hydrophobic drugs and compositions thereof
|Jun 5, 1995
|Jan 18, 2000
|Quadrant Healthcare (Uk) Limited
|Preparation of further diagnostic agents
|Oct 4, 1996
|Jan 25, 2000
|Andaris Limited
|Use of hollow microcapsules
|Aug 22, 1995
|Feb 8, 2000
|Quadrant Healthcare (Uk) Limited
|Preparation of diagnostic agents
|May 8, 1996
|Apr 18, 2000
|Inhale Therapeutic Systems
|Dispersible macromolecule compositions and methods for their preparation and use
|Feb 24, 1998
|Apr 18, 2000
|Superior Micropowders, Llc
|Powder batch of pharmaceutically-active particles and methods for making same
|Dec 29, 1997
|Jun 20, 2000
|Inhale Therapeutic Systems
|Systems and processes for spray drying hydrophobic drugs with hydrophilic excipients
|Sep 28, 1995
|Sep 12, 2000
|Takeda Chemical Industries, Ltd.
|Sustained-release microcapsule of amorphous water-soluble pharmaceutical active agent
|Dec 15, 1998
|Oct 24, 2000
|Massachusetts Institute Of Technology
|Aerodynamically light particles for pulmonary drug delivery
|Apr 10, 1997
|Nov 21, 2000
|Merck Patent Gesellschaft Mit
|Taste of active pharmaceutical ingredients
|Nov 13, 1998
|Jan 16, 2001
|Universidad De Sevilla
|Device and method for creating dry particles
|Nov 13, 1998
|Mar 6, 2001
|Universidad De Sevilla
|Device and method for creating spherical particles of uniform size
|May 3, 1999
|May 1, 2001
|Acusphere, Inc.
|Spray drying apparatus and methods of use
|Oct 17, 1996
|Jul 10, 2001
|Inhale Therapeutic Systems, Inc.
|Stable glassy state powder formulations
|Dec 2, 1994
|Sep 18, 2001
|Quandrant Holdings Cambridge Limited
|Solid dose delivery vehicle and methods of making same
|Jan 9, 2001
|Oct 30, 2001
|Acusphere, Inc.
|Spray drying method
|May 18, 2000
|Nov 13, 2001
|Flak Pharma International, Ltd.
|Rapidly disintegrating solid oral dosage form
|Nov 22, 1999
|Dec 18, 2001
|Accentus Plc
|Formation of monodisperse particles
|Aug 1, 2000
|Dec 18, 2001
|Quadrant Holdings Cambridge Limited
|Solid dose delivery vehicle and methods of making same
|Mar 17, 2000
|Apr 2, 2002
|Inhale Therapeutic Systems, Inc.
|Systems and processes for spray drying hydrophobic drugs with hydrophilic excipients
|Feb 13, 1998
|May 7, 2002
|Invitrogen Corporation
|Dry powder cells and cell culture reagents and methods of production thereof
|Dec 21, 1998
|Jul 9, 2002
|Quadrant Healthcare (Uk) Limited
|Microparticles and their therapeutic or diagnostic use
|Feb 4, 2000
|Jul 23, 2002
|Inhale Therapeutic Systems
|Dispersible macromolecule compositions and methods for their preparation and use
|Jun 29, 1999
|Sep 17, 2002
|Quadrant Healthcare (Uk) Limited
|Spray-drying process for the preparation of microparticles
|May 23, 1997
|Jan 7, 2003
|Massachusetts Institute Of Technology
|Aerodynamically light particles for pulmonary drug delivery
|Oct 26, 2001
|May 13, 2003
|Acusphere, Inc.
|Spray drying apparatus and methods of use
|Dec 22, 1998
|May 20, 2003
|Inhale Therapeutic Systems, Inc.
|Methods of spray drying pharmaceutical compositions
|Feb 8, 2002
|Jun 3, 2003
|Inhale Therapeutic Systems, Inc.
|Systems and processes for spray drying hydrophobic drugs with hydrophilic excipients
|Apr 14, 1995
|Jun 24, 2003
|Inhale Therapeutic Systems, Inc.
|Spray drying of macromolecules to produce inhaleable dry powders
|Nov 9, 2001
|Jul 15, 2003
|Inhale Therapeutic Systems, Inc.
|Dispersible macromolecule compositions and methods for their preparation and use
|Jun 28, 2001
|Dec 2, 2003
|Yamanouchi Pharmaceutical Co., Ltd.
|Quick disintegrating tablet in buccal cavity and manufacturing method thereof
|Jul 31, 2001
|Jun 13, 2002
|Herm Snyder
|Apparatus and process to produce particles having a narrow size distribution and particles made thereby
|Aug 14, 2001
|Jun 27, 2002
|Norton Healthcare Ltd.
|Spray dried powders for pulmonary or nasal administration
|Jun 19, 2002
|Nov 28, 2002
|Carlisle Friesland B. V.
|Devic for atomizing a liquid product, a spray-drying and conditioning device provided therewith, and a method for conditioning a liquid product
|Oct 31, 2002
|Jul 3, 2003
|Inhale Therapeutic System, Inc.
|Spray drying methods and related compositions
|Mar 31, 2003
|Oct 30, 2003
|Gordon Marc S.
|Systems and processes for spray drying hydrophobic drugs with hydrophilic excipients
|Mar 31, 2003
|Nov 20, 2003
|Platz Robert M.
|Dispersible macromolecule compositions and methods for their preparation and use
|Jul 6, 1982
|Feb 16, 1983
|FISONS plc
|Inhalation drugs, methods for their production and pharmaceutical formulations containing them
|Jun 3, 1988
|Dec 6, 1989
|NIRO-Sterner Inc.
|Spray drying method and apparatus for concurrent particle coating
|Jul 21, 1989
|Jan 23, 1991
|Ohkawara Kakohki Co., Ltd.
|Spray drying apparatus
|Jun 14, 1991
|Dec 18, 1991
|Merck & Co., Inc.
|A crystallization method to improve crystal structure and size
|Jul 3, 1991
|Feb 5, 1992
|Zeneca Limited
|Spray drying
|Apr 10, 1992
|Nov 11, 1992
|Andaris Limited
|Preparation of diagnostic agents
|Carpenter, John F. et al., "Modes of Stabilization of a Protein by Organic Solutes During Desiccation," Cryobiology. 1988. vol. 25, pp. 459-470.
|He et al., "Chitosan Microspheres Prepared by Spray Drying," International J. of Pharm. (Amsterdam), vol. 187, No. 1, o. 53-65 1991.
|Hino et al., "Development of a new type nozzle and spray-drier for industrial production of fine powders", European J. of Pharmaceutics and Biopharmaceutics (2000), vol. 49, pp. 79-85.
|Masters, "The Process Stages if Spray Drying: Atomization", Spray Drying Handbook, pp. 230-247, 1979.
|Mumenthaler et al., "Feasibility Study on Spray-Drying Protein Pharmaceuticals: Recombinant Human Growth Hormaoine and Tissue-Type Plasminogen Activator." Pharm Res. (1994), 11(1):. p. 12-20.
|Citing Patent
|Filing date
|Publication date
|Sep 15, 2004
|Apr 19, 2011
|Vectura Limited
|Mucoactive agents for treating a pulmonary disease
|May 22, 2014
|Mar 31, 2015
|Pulmatrix, Inc.
|Respirably dry powder comprising calcium lactate, sodium chloride and leucine
|Aug 26, 2011
|Jun 23, 2015
|Pulmatrix, Inc.
|Dry powder formulations and methods for treating pulmonary diseases
|Mar 25, 2015
|Sep 1, 2015
|Pulmatrix Operating Company, Inc.
|Dry powder formulations and methods for treating pulmonary diseases
|May 20, 2015
|Jan 12, 2016
|Pulmatrix, Inc.
|Dry powder formulations and methods for treating pulmonary diseases
|Jul 21, 2015
|Jan 19, 2016
|Pulmatrix Operating Company, Inc.
|Dry powder formulations and methods for treating pulmonary diseases
|Sep 29, 2011
|Sep 6, 2016
|Pulmatrix, Inc.
|Cationic dry powders
|Sep 29, 2011
|May 9, 2017
|Pulmatrix, Inc.
|Monovalent metal cation dry powders for inhalation
|Sep 15, 2004
|Mar 22, 2007
|Vectura Ltd.
|Mucoactive agents for treating a pulmonary disease
|U.S. Classification
|International Classification
|Cooperative Classification
|European Classification
|Oct 7, 2002
Owner name: INHALE THERAPEUTIC SYSTEMS, INC., CALIFORNIA
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text:
Nowadays, Smart Phones can meet our daily needs. But sometimes we will have higher requirement of photos or videos, so you may decide to buy a new digital camera. If you are an avid photographer, you must want full creative control over your images. Of course, you often got what you paid for, which means the digital SLR camera is generally expensive. Good news is that I find three best cameras under 500— Nikon D3200, Canon EOS Rebel T5 and Samsung NX300. You don't worry about the endless flow of technical jargon or huge range of models on offer. Fear not! Whether you're an experienced shooter or a beginner, this page will help you choose the best rated camera under 500 dollars in 2017.
Simple Comparison-Best Rated Camera Under 500 Dollars In 2017
|From Amazon
|Nikon D3300 DSLR Camera
|Canon EOS Rebel T5 Camera
|Canon EOS Rebel T3i Digital SLR Camera
|Nikon D3200 24.2 MP Camera
|Nikon D5100 DSLR Camera
|18-55mm f/3.5-5.6 IS ,75-300mm f/4.0-5.6 III
|Sensor Size
|APS-C (23.5 x 15.6 mm)
|APS-C (22.3 x 14.9 mm)
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|APS-C (23.6 x 15.7 mm)
|Max Resolution
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|18 megapixels
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|Iso Range
|Auto, 100, 200, 400, 800, 1600, 3200, 6400, 12800, 25600 (with boost)
|Auto, 100, 200, 400, 800, 1600, 3200, 6400
|ISO 100-6400 expandable to 12800
|Auto, 100, 200, 400, 800, 1600, 3200, 6400 (12800 with boost)
|Auto, 100- 6400 (plus 12800, 25600 with boost)
|Display Size
|3 inches
|3 inches
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|Continuous Shooting Speed
|Wireless Communication Technology
|Item Weight
|1.06 pounds
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|1.26 pounds
|1.11 pounds
|1.23 pounds
|4.9 x 3 x 3.9 inches
|5.1 x 3.1 x 3.9 inches
|3.94 x 3.15 x 5.24 inches
|3.78 x 3.03 x 4.92 inches
|5 x 3.1 x 3.8 inches
|Check Price
Top 3 DSLR Camera Under 500 Dollars
Nikon D3200 for under 500 dollars
Product Description
Nikon D3200 is armed with a Nikon D3200 Digital SLR Camera Body and a Nikon 18-55mm f/3.5-5.6G ED II AF-S DX lens. The camera body includes a powerful 24.2 MP DX-format CMOS sensor, Full HD (1080p) movie recording and EXPEED 3 image-processing for great performance. The lens is a lightweight and compact zoom lens that provides a 3x focal zoom range. It is suitable for everything from vivid images to nature, wildlife photography and sports.
Key Features
Master the camera simply by using it
The D3200 has an EXPEED 3 image processing and the most greatly CMOS sensor Nikon never powers a HD-SLR at this price level. It can capture beautiful and lifelike colors images with the highest resolution. But thanks to the D3200's Guide Mode, it is easy to capture high quality photos and videos.
Capture the best of every scene
Generally, the seasoned photographers optimize their camera settings for the specific scene when they're shooting. But don't worry about it. It's never that easy to optimize your camera settings. The D3200 provides six common Scene Modes like Close up, Landscape, Portrait, Night Portrait, and more. If you don't know which mode to set, you can use Scene Auto Selector.
Customer Reviews
- Absolutely love this camera! I have used this well-made camera for a long time, but it does not have any problem. And it is easy to use for the first time.
Canon EOS Rebel T5 under $500
Product Description
The Canon EOS Rebel T5 SLR camera is armed with a DIGIC 4 image processor and the EF-S 18-55mm IS II standard zoom lens which make it easy to capture amazing photos and movies. It features a helpful Feature Guide and Creative Auto for easy capturing high-quality photos and HD video. So, it is suitable for first-time SLR users, families and building photo enthusiasts.
Key Features
High Resolution Photos and Videos
The EOS Rebel T5 features an 18.0 Megapixel CMOS and a DIGIC 4 Image Processor. The 18.0 Megapixel CMOS provides enough resolution for crops and big enlargements, which means you don't need to worry about the quality when you want to print and frame your photos. The DIGIC 4 Image Processor will provide you with an amazing performance and an intuitive shooting experience you never imagine.
Basic+ and Creative Auto
As I said before, the EOS Rebel T5 is suitable for first-time SLR users because it is always ready to capture high-quality photos automatically. The EOS Rebel T5 provides enough advanced settings to help you to the next level. You can change scene type or ambience on the camera's Quick Control Screen. Basic+ provides a simple way. With Creative Auto mode, I believe you can still capture stunning photographs.
Samsung NX300 for under 500
Product Description
The Samsung NX300 is equipped with a 20.3-megapixel CMOS sensor and 3.3″ AMOLED Touch Screen. It is a portable tablet that weighs only 0.62 pound. With 20.3-megapixel sensor, you can capture incredible color detail to a new level. The Samsung NX300 features 3D technology for shots and videos. What's more, it equips Wi-Fi which makes it easy for you to share with your friends.
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20.3-Megapixel Sensor
The Samsung NX300 camera with the 20.3-megapixel APS-C CMOS sensor is perfect for shooting portraits, wildlife and sports. It can range the ISO from 100 to 25,600, so you can capture amazing photos in different handheld. The Samsung NX300 provides hybrid autofocus system which combines contrast AF and phase detection AF for fast auto focusing. The camera also features a capture rate of 8.6 frames per second, so you can take clear action shots.
Wi-Fi Connectivity for Easy Sharing
The Samsung NX300 includes a Wi-Fi with an app so you can transfer and share your images with your friends. With Wi-Fi, you can connect to Wi-Fi networks quickly. If you are connected, you can upload your videos and photos directly to cloud or computer. After capturing a beautiful photo, you can also upload it straight to YouTube or Facebook.
Basic features contrast
In these TOP three cameras UNDER 500 DOLLARS, Nikon D3200 has the highest CMOS sensor. It equips a 24.2 MP DX-format CMOS sensor. It can provide powerful support to capture beautiful photos or videos. The Samsung NX300 can connect the network to share photos with friends. It is very convenient. The Canon EOS Rebel T5 has a DIGIC 4 image processor, so it can capture photos fast. I think there is always a will for you.
Resources-Find best cameras under 600 dollars
When you get more items listed, the choice become simple. Sometimes, spending more $100 might give you more awesome shooting entertainment, If you have more $100 budget, then you can check out these good value camera under 600 dollars on the market.

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At today's trial of 18 members of the Sasna Dzrer group who seized a Yerevan police building last July, the judge sustained a motion by defense lawyers ...
There is no reason or explanation for the cancelation. I later learnt through social media that the festival had to withdraw two films with LGBT themes ...
The Ararat Valley aquifer spans some 1,300 square kilometers. However, many local communities lack potable and irrigation water due to poor resource ...
Koghbavan and Bagaran are border villages in Armenia's Armavir province.
Lousineh says her 5,000 AMD in daily wages is sufficient for the family to get by.
Readers of Hetq might have noticed a recent series of articles describing the sad fate of some 90-100,000 "repatriates" who relocated to the Armenian ...
The collection of paintings includes works by Hakob Hovnatanyan, Vardges Surenyants, Martiros Saryan, Ivan Aivazovsky, Ilya Repin, Tintoretto, Rubens ...
Yerevan's 5th annual Watermelon Festival took place today near Swan Lake, led by workers from the Hovhannes Tumanyan Puppet Theatre.
The Gevorgyan family has been growing broccoli, in hothouses and the open, in the Armavir village of Arshaluys for four years.
Viewed 16776 times Armenia: Gevorgyan Family Gears Up for Another Broccoli Crop
Viewed 11693 times Armenia's Border Villages: Scorching Sun and Drying Apricots
Viewed 11298 times Arshavir from Koghes: Growing Potatoes Today, but Dreaming of Becoming an Armenian Teacher One Day
Viewed 11026 times An Annual Summer 'Game': Demanding a Bit of Air in Nubarashen Penitentiary
Viewed 10650 times Yerevan: 5th Annual Watermelon Festival
Viewed 10414 times No Easy Work: Yerevan Native Lousineh Adapts to Village Life


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Style: Marc Turkel, Morgan Hare, and Shawn Watts design buildings that are, in their words, "intelligent, responsible, inquisitive, and enduring." In the Works: Hester Street Collaborative, the studio's sister nonprofit, is leading New York City's first comprehensive cultural plan. The Next Big Thing: "A return to design basics—understated, thoughtfully crafted architecture. Our responsibilities to the environment. Conceiving and executing sustainable buildings must emerge as a dominant focus in the profession." Key Influences: Roberto Burle Marx, Le Corbusier, Oscar Niemeyer, Isamu Noguchi. ► New York; leroystreetstudio.com
Architecture + Design
2017 AD100: Leroy Street Studio
Discover the work of Leroy Street Studio—from a Woods Hole, Massachusetts, home to an East Hampton, New York, getaway
related stories, expandedrelated stories, collapsedRelated Stories


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Many plant seeds are considered to remain dormant for a period of time depending on various circumstances. Â Dormancy in seeds is often needed by some plants in order to preserve the life of some seeds before actual germination. Â In many cases, not all seeds of a plant will germinate at a specific period. Â Some will remain dormant and will only germinate on a staggered basis. Â Dormancy is important for many seeds because it may serve as form of protection from possible harsh weather conditions and elimination from herbivorous animals. Â With temporary dormancy, the seeds also require to remain viable and healthy for eventual germination. Â This is the very reason that dormant seeds continue to breathe or respire while being somewhat restricted in terms of germination. Â The seeds need to respire just enough air to keep them alive and make them last a period of natural dormancy.
In order for seeds to respire and continue to be alive and healthy, they also need to have enough moisture from water. Â Hydration is said to be very essential for seeds to survive a long dormancy period. Some seeds will remain dormant for several months, while there are also seeds that continue to be dormant for many years. Â There are also cases wherein the length of dormancy is dependent on various circumstances. Â There are seeds for example that have very hard outer shells and only extreme temperatures may be able to break them and allow for germination to occur. Other seeds also need to be pre-treated in order to proceed with the germination process. Â With coats that are literally impermeable, some plant seeds need pre-treatment in order to break the coats and allow the seed to grow and develop. With the possible long dormancy period, seeds must somehow continue to respire and breathe to prepare themselves in their succeeding growth stages.


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Situated in the North part of the Island, The Topaz Hotel is located in the heart of the very popular seaside resort of Bugibba.The Topaz Hotel provides a wide range of facilities which includes large out door pool with kids'section and whirlpool. Large sun terrace and indoor pool (closed June-October), a Games room, TV room and more. The buffet restaurant, snack bar together with the Royal Oak Pub and Peacock lounge bar (closed in summer) and La Perla Pizzeria (open weekend evenings only and closed at certain periods of the year)will ensure your stay at Topaz is enjoyable.Note:Christmas Eve(24.12.11), Christmas Day(25.12.11) and New Years Eve(31.12.11) gala dinners are included when booking HB & AI.The twin-bedded rooms have en suite facilities, euro satellite TV (limited channels), heating (Nov-Apr), air conditioning (May-Oct), direct dial telephone, hairdryer; safe (charge) and most rooms have a balcony.
Located in a popular resort location in the North of the Island, situated on the outer part of Bugibba. The Hotel is less than a ten minute walk from the Bugibba sea front promenade, with the many shops, restaurants and bars. A regular bus service runs to Valletta, Sliema and the northern part of the island.
Large out door pool with kids section.Heated Indoor swimming pool (open in Winter season only)Games Room, TV room, Internet/Wifi corner (at a local charge)Small libraryVolleyball courtMassageSouvenier shopHairdressing salonRegular entertainment programme (in Summer)Snack bar, Royal Oak pub, Peacock lounge bar (closed in summer) La Perla Pizzeria (open weekend evenings only and closed during certain periods of the year)
* Aerobics
* Children's club
* Customer Lifts
* Daytime Entertainment
* Indoor pool
* Lounge
* Outdoor pool
* Reception - 24 hrs


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Businesses For Sale in Jim Wells County TX
Searched the DealStream database for Businesses For Sale in Jim Wells County TX and found the following matches.
Hotel - South Texas- Eagle Ford Drilling Boom Area #347239 posted Jan 2, 2014
- Alice, Texas, United States
- $2,600,000
Full service, 2 story hotel with 102 rooms sitting on 4+ acres. Room For Parking Or Expansion! 25 miles west of Corpus Christi, the New Boom area for the Eagle Ford Shale Port in Corpus Christi. Franchise name may be changed if desired. Texas is Booming!
Did you know that social networking is a great way to buy a business? Sign up now and we'll show you how.


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Incidents of police brutality, especially against black Americans, are becoming more frequent- often ending in death.
Michael Brown, Tamir Rice, Walter L. Scott, Freddie Gray and Trayvon Martin are names we all recognize now for the worst reason: They're all black boys and men mercilessly gunned down by either police or other security personnel in recent past.
Cases of police officers shooting unarmed people are becoming increasingly common. It's all the more disturbing, protesters say, because most of the assaults are the result of racial and ethnic profiling.
Check Out: Crime After Crime, But No Cop Doing Time: Why Police Brutality Endures


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Parenting/Children Books
Youth Indicators 2005: Trends in the Well-Being of American Youth
Rating: Rated: 0 times
Format: PDF
Presents a selection of indicators that provide a broad perspective on youth; it uses trend data that cut across disciplines and agency lines; and it provides information on both positive and negative aspects of the youth experience.
A Parent's Guide to Playing It Safe with Kids and Cars
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Format: PDF
Booklet designed to help you better understand today\'s vehicle safety features, car seats and how to keep kids safe in and around vehicles using vehicle safety features and car seats.
Helping Your Child Succeed in School
15 fun activities to do with your children (ages 5-11) to help expand their imagination, obey, organize, help others, and much more.
When Your Child Is Missing: A Family Survival Guide
Rating: Rated: 0 times
Format: PDF
This guide provides parents with the most current information on, and helpful insights into, what families should do when a child is missing.
Helping Your Child Through Early Adolescence
This guide provides parents with the latest research and practical information that can help you support your children both at home and in school.
Helping Your Child Become a Reader
Help children gain the skills they need to become good readers. Here are ways to turn everyday activities into learning experiences for infants to 6-year old children.
Helping Your Preschool Child
Rating: Rated: 0 times
Format: PDF
This booklet contains activities designed to be fun for both you and your child as well as to help your child gain the skills needed to get ready for school.
Making Single Parenting a Breeze
Rating: Rated: 0 times
Format: PDF, ePub, Kindle, TXT
Discover the best ways to raising your children with my step by step tips and advice about single parenting. We all know that being a single parent isn't easy; Not only is parenthood one of the single greatest blessings in life, it can also feel like a curse – especially when dealing with the...
Smart Parenting
Rating: Rated: 2 times
Format: PDF, ePub, Kindle, TXT
Who Else Wants to Become the World's Greatest Mom or Dad Without Putting Yourself to Wit's End in Raising Highly Successful Children? There is not a perfect parent in the world, but you can surely be the best parent your children can ever have. How will you do that? You must: - Comprehend...
My Pumpkin is a Zombie
Rating: Rated: 3 times
Format: PDF, ePub, Kindle
Have you ever met a zombie pumpkin? Well, I would like you to meet mine and help him with a problem. His light has gone out! Only by reading this book can he shine bright for Halloween Night.