WO2003099290A1

WO2003099290A1 - Pharmaceutical products and methods of manufacture

Info

Publication number: WO2003099290A1
Application number: PCT/US2003/015690
Authority: WO
Inventors: Andrew Bruce Brown; Matthew Skelly FERRITER; Michiel Mary Van Oort
Original assignee: Glaxo Group Limited
Priority date: 2002-05-21
Filing date: 2003-05-20
Publication date: 2003-12-04
Also published as: AU2003251303A1

Abstract

A method of forming pharmaceutical particles comprising a crystalline first subtance, comprising: disposing a first substance proximate at least one sublimable crystallization inducing agent for a period of time sufficient to incude crystallization; and harvesting the resultant crystalline particles.

Description

PHARMACEUTICAL PRODUCTS AND METHODS OF MANUFACTURE

TECHNICAL FIELD OF THE INVENTION

The present invention relates generally to pharmaceutical compositions. More particularly, the present invention relates to pharmaceutical compositions comprising pharmaceutical particles containing crystalline material, such crystalline medicament, for use in the pharmaceutical field, especially in the field of inhalation therapy, and to a process for producing such particles.

BACKGROUND OF THE INVENTION

Pharmaceutical compositions, especially those for the treatment of respiratory conditions such as asthma, are often administered by inhalation. The efficacy of inhalation therapy has, however, been limited by the problems encountered in making appropriate and consistent dosages available to the lungs.

In the field of inhalation therapy, it is generally desirable to employ therapeutic molecules within particles having an aerodynamic particle size in the range of 1 to 10 μm, more preferably, particles between 1 and 5 μm, in order to achieve maximum penetration into the lungs. Particles having geometric diameters less than 10 μm are often highly cohesive and, hence, exhibit poor flow and dispersion characteristics.

Poor flow characteristics create handling difficulties during manufacture of the powder pharmaceutical compositions. Moreover, poor flow properties cause difficulties in metering such materials into containment systems during packaging. Lastly, and importantly, poor flow and aerosolbility of powders adversely impacts the accurate dispersal and aerosolization of the pharmaceutical compositions by an inhalation (or delivery) device. It is desirable that such inhaled powder pharmaceutical particles in inhaled pharmaceutical compositions are generally crystalline, as in many instances, a crystalline particle structure increases the physical and/or chemical stability of the powder composition. The more stable the structure of the individual particle, the less likely it is that the particles in the powder composition will agglomerate or otherwise experience particle growth. The particle will thus maintain a desired particle size that is suitable for inhalation. Crystallinity may also modify the time it takes for the pharmaceutical composition to release its therapeutic agent once delivered.

Prior efforts have been made to increase the flow, meterability and dispersability of powder compositions. For example, particles having hollow, irregular, fissured or porous structures have been indicated to have improved aerosolization properties. Examples of such prior efforts include PCT Pub. Nos. WO 97/36574 to Glaxo Group, Ltd.; WO 97/44013 to MIT; WO 99/66903 to Advanced Inhalation Research; WO 99/16419, WO 99/16421 and WO 99/16422 to Alliance Pharmaceutical Corp., the contents of which are incorporated herein by reference.

Manufactured porous particles are also disclosed in PCT Publication No. WO 00/72827, which describes the production of respirable porous drug matrices by co-precipitating a pore forming agent and a matrix forming agent, and subsequently removing the pore forming agent. The pore forming agent may be a volatile liquid or a volatile solid.

Such approaches have been used previously for other applications. For example, the volatile solid menthol is disclosed in WO 9318757-A1 to facilitate the production of porous tablets that have an amorphous atomic structural configuration.

Crystalline physical structure in respirable particles has been associated with chemical and physical stability, and is therefore also desirable. Prior art processes employed to produce crystalline particles, either directly or through post manufacture conditioning, are disclosed in PCT Pub. Nos. WO 00/10541, WO 00/19982, WO 92/18110 and WO 95/05805, European Pat. No. 437451 and U.S. Pat. Nos. 5,314,506 and

6,221,398, the contents of which are also incorporated herein by reference. Although the above mentioned references provide a variety of alternative manufacturing approaches to produce respirable particles, they do not address all the desired ends of an ideal inhaled pharmaceutical product. Indeed, they may not produce crystalline materials. Further, the particles may have inappropriate size parameters or morphologies for pulmonary delivery. Accordingly, there is a continual search in this art for improved aerosol formulations having a highly crystalline structure, and suitable morphology and size distribution to produce highly aerosolizable pharmaceutical compositions, as indicated by high fine particle fractions out of delivery devices.

It is therefore an object of the present invention to provide substantially crystalline pharmaceutical particles, and methods for preparing same, that substantially reduce or overcome one or more of the aforementioned disadvantages and drawbacks associated with prior art pharmaceutical particles and processes.

It is a further or alternative object of the invention to provide a crystallization promoting agent that facilitates the formation of substantially crystalline pharmaceutical particles.

It is a further alternative object of the invention to provide substantially crystalline, porous pharmaceutical particles for inhalation therapy.

It is a further or alternative object of the invention to provide pharmaceutical compositions having substantially crystalline particles having a rough or porous surface structure.

It is a further or alternative object of the invention to provide pharmaceutical compositions having superior medicament delivery and efficacy properties. It is a further or alternative objective of the invention to provide pharmaceutical compositions comprising a medicament and an excipient matrix, wherein said medicament is substantially crystalline.

It is a further or alternative objective to provide an post production crystalization technique which accelerates the annealing or crystallization process in mediacemnt materials in pharmaceutical particles.

It is a further or alternative objective to provide an integrated production process to incorporate a crystalimny inducing agent into a pharmaceutical composition, which upon - removal renders material in the composition crystalline, thus decreaseing the time required for or elininating altogether, the additional annealing steps generally required to manufacture crystaline medicaments.

These and other objectives and benefits of the present invention will be come clear from the following description.

SUMMARY OF THE INVENTION

In accordance with the above objects and those that will be mentioned and will become apparent below, in one embodiment of the invention, the method of forming substantially crystalline pharmaceutical particles in accordance with the invention comprises: (i) co-dissolving the substance to be crystallized with at least one crystallization inducing agent in a first medium to form a first solution; (ii) spray-drying the first solution at a suitable temperature, for example, greater than 20°C, more preferrably in the range of 35°C to 180°C; (iii) selectively subliming out the crystallization inducing agent; and (iv) harvesting the resulting particles. The substance to be crystallized can be a medicament, excipient or combinations thereof.

In a further embodiment of the invention, the method of forming substantially crystalline pharmaceutical particles comprises: (i) dissolving the substance to be crystallized; (ii) adding at least one crystallization inducing agent in a first medium to form a first solution; (iii) spray-drying the first solution at a suitable temperature, for example, greater than 20°C, more preferrably in the range of 35°C to 180°C; (iv) selectively subliming out the crystallization inducing agent; and (v) harvesting the resulting particles.

In another embodiment of the invention, the method of forming substantially crystalline pharmaceutical particles comprises: (i) placing the substance to be crystallized in a primary medium to form a base substance medium; (ii) adding at least one crystallization inducing agent in a first medium to the base substance medium to form a first solution; (iii) spray-drying the first solution at a suitable temperature, for example in the range of 35°C to 180°C; (iv) selectively subliming out the crystallization inducing agent; and (v) harvesting the resulting particles.

In another embodiment, the method of forming substantially crystalline pharmaceutical particles comprises disposing a crystallization inducing agent proximate the substance to be crystallized for a sufficient period of time to induce crystallization and harvesting the resulting crystals. Preferably, the crystallization inducing agent is also sublimable. The sublimable crystalline inducing agent is preferably present in a vapour phase and is exposed to said substance to be crystalized. Advantageously, this pocess is conducted at above ambient temperatures, preferably above 30° C, more preferably, between 30°C and 60°C, e.g., approxiamately 50°C.

In yet another embodiment, the invention comprises pharmaceutical compositions comprising crystalline medicament particles formed in accordance with the present invention. According to the invention, the noted pharmaceutical compositions can optionally include at least one pharmaceutically acceptance diluent or excipient.

In an additional embodiment, the invention comprises pharmaceutical compositions comprising crystalline excipient particles formed in accordance with the invention, preferably lactose particles and a particulate medicament. According to the invention, the noted composition can similarly include at least one pharmaceutically acceptable additive, such as a diluent or an additional excipient.

In a further embodiment, the invention comprises pharmaceutical compositions comprising particles of respirable size having crystalline medicament incoφorated in an excipient matrix, and optionally, excipients dilluents and/or carrier particles. These diluent of carrier partiucles may comprise excipient particles or respirable and/or non- respirable size. Such embodiments also includes methods for preparing such medicament containing particles, pharmaceutical compositions containing such particles and the therapeutic use of such products. BRIEF DESCRIPTION OF THE DRAWINGS

Further features and advantages will become apparent from the following and more particular description of the preferred embodiments of the invention, as illustrated in the accompanying drawings, and in which like referenced characters generally refer to the same parts or elements throughout the views, and in which:

FIGURE 1 is a graph of differential scanning calorimetry data (i.e., heat flow vs. temp.) of fluticasone propionate particles formed with 0% and 5% menthol in accordance with the invention;

FIGURE 2 is a graphical illustration of the effects of spray-drying temperature and % menthol on crystallization exotherms of fluticasone propionate particles formed in accordance with the invention;

FIGURE 3 is a graph of differential scanning calorimetry ("DSC") data of fluticasone propionate particles formed with 0% and 10% menthol in accordance with the invention;

FIGURES 4 through 6 are bar graphs of average particle size for particles formed from various solutions of menthol and fluticasone propionate in accordance with the invention;

FIGURES 7 through 18 are X-ray diffraction scans (XRD) of particles formed from various solutions of menthol and fluticasone propionate and at various spray-drying temperatures in accordance with the invention; and

FIGURES 19 through 22 are scanning electron micrographs of particles formed from various solutions of menthol and fluticasone propionate and at various spray-drying temperatures in accordance with the invention. FIGURE 23 is a DSC of Fluticasone 17α-2 Furoate exposed to menthol at room temperature for 48 hours.

FIGURE 24 DSC of Fluticasone 17α-2 Furoate exposed to 50°C for 48 hours without menthol.

FIGURE 25 DSC of Fluticasone 17α-2 Furoate exposed to menthol at 50°C for 2 hours

FIGURE 26 DSC of Fluticasone 17α-2 Furoate exposed to menthol at room temp for 26 hours and stripped for 45 minutes in vacuum chamber and allowed to stand overnight in moving air stream.

FIGURE 27 is an XRD of Fluticasone 17α-2 Furoate exposed to menthol at 50°C for 2 hours compared to a FF standard.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Before describing the present invention in detail, it is to be understood that this invention is not limited to particularly exemplified compositions or process parameters as such may, of course, vary. Although a number of methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, the preferred materials and methods are described herein. It is also to be understood that the terminology used herein is for the puφose of describing particular embodiments of the invention only, and is not intended to be limiting.

All publications, patents and patent applications cited herein, whether supra or infra, are hereby incoφorated by reference in their entirety.

It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "a particle" includes a mixture of two or more such particles; reference to "an excipient" includes mixtures of two or more such excipieυts, and the like.

Definitions

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains.

In describing the present invention, the following terms will be employed, and are intended to be defined as indicated below.

By the term "crystallization inducing agent", as used herein, it is meant to mean a substance or solution capable of inducing crystallization of a molecule. As discussed in detail herein, the "crystallization inducing agent" can be in solution or suspension, as well as being in any other form. By the term "sublimable medium", as used herein, it is meant to mean a substance capable of converting directly from a solid to vapor phase.

By the term "medicament", as used herein, is meant to mean and include any substance (i.e., compound or composition of matter) which, when administered to an organism (human or animal) induces a desired pharmacologic and/or physiologic effect by local and/or systemic action. The term therefore encompasses substances traditionally regarded as actives, drugs and/or bioactive agents, as well as biopharmaceuticals (e.g., peptides, hormones, nucleic acids, gene constructs, etc.), including, but not limited to, analgesics, e.g., codeine, dihydromoφhine, ergotamine, fentanyl or moφhine; anginal preparations, e.g., diltiazem; antiallergics, e.g., cromoglycate (e.g., as the sodium salt), ketotifen or nedocromil (e.g., as the sodium salt); antiinfectives, e.g., cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine; antihistamines, e.g., methapyrilene; anti- inflammatori.es, e.g., beclomethasone (e.g., as the dipropionate ester), fluticasone (e.g., as the propionate ester or as 6 , 9α-difluoro-llβ-hydroxy-16α- methyl-3-oxo- 17α-propionyloxy-androsta-l ,4-diene- 17β-carbothioic acid S-(2-oxo- tetr-Λydro-furan-3-yl) ester), flunisolide, budesonide, rofleponide, mometasone (e.g., as the furoate ester), ciclesonide, triamcinolone (e.g., as the acetonide); antitussives, e.g., noscapine; bronchodilators, e.g., albuterol (e.g., as free base or sulphate), salmeterol (e.g., as xinafoate), ephedrine, adrenaline, fenoterol (e.g., as hydrobromide), formoterol (e.g. as fumarate), isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol (e.g., as acetate), reproterol (e.g., as hydrochloride), rimiterol, terbutaline (e.g., as sulphate), isoetharine. tulobuterol or 4-hydroxy-7-[2-[[2-[[3-(2-phenylethoxy) propyljsulfonyl] ethyl]amino]ethyl-2(3H)-benzothiazolone; adenosine 2a agonists, e.g., 2R,3R,4S,5R)-2-[6-Amino-2-(lS-hydroxymethyl-2-phenyl-ethylamino)-ρurin-9-yl]-5-(2- ethyl-2H-te1xazol-5-yl)-tetrahydro-furan-3,4-diol (e.g., as maleate); α₄ integrin inhibitors, e.g., (2S)-3-[4-({[4-(aminocarbonyl)-l-piperidinyl]carbonyl} oxy)phenyl]-2-[((2S)-4- methyl-2-{[2-(2-methylphenoxy) acetyl]amino} pentanoyl)amino] propanoic acid (e.g., as free acid or potassium salt), diuretics, e.g., amiloride; anticholinergics, e.g., ipratropium

(e.g. as bromide), tiotropium, atropine or oxitropium; hormones, e.g., cortisone, hydrocortisone or prednisolone; xanthines, e.g., aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; therapeutic proteins and peptides, e.g., insulin or glucagon. The noted medicaments may also be employed in the form of salts, (e.g., as alkali metal or amine salts or as acid addition salts) or as esters (e.g., lower alkyl esters) or as solvates (e.g., hydrates) to optimize the activity and/or stability of the medicament.

The term "medicament" also encompasses formulations containing combinations of active ingredients, including, but not limited to, salbutamol (e.g., as the free base or the sulphate salt) or salmeterol (e.g., as the xinafoate salt) or formoterol (e.g., as the fumarate salt) in combination with an anti-inflammatory steroid such as a beclomethasone ester

(e.g., the dipropionate) or a fluticasone ester (e.g., the propionate or 6α,9α-difluoro-17α- [(2-furanylcarbonyl)oxy]- 11 β-hydroxy- 16α-methyl-3-oxo-androsta- 1 ,4-diene- 17β- carbothioic acid S-fluoromethyl ester) or budesonide.

"Pharmaceutical particles" mean particles which themselves contain at least one medicament. Pharmaceutical particles may also comprise additional components, such as as excipients or additional medicaments.

"Excipient particles", a.k.a. "carrier particles" are particles of comprising one or more excipients, but lacking medicament. Excipient particles may be incoprorated in pharmacuetical compositions containing pharmaceutical particles to permit the pharmeceutical particles to be metered into doses (ie., as diluents), to improve powder flow properties or to increase or modulate aerosolization properties (as carriers or lubricants), or for the puφoses of taste masking or chemical or physical stabilization.

By the term "pharmaceutical composition", as used herein, it is meant to mean a collection of individual particles, comprising at least one medicament containing pharmaceutical particle. The term "pharmaceutical composition" also encompasses formulations comprising a combination of pharmaceutical particles and and one or more added components or elements, such as an "excipient particles" or "carrier particles" As will be appreciated by one having ordinary skill in the art, the terms "excipient" and "carrier" generally refer to substantially inert materials that are non-toxic and do not interact with other components of the composition in a deleterious manner. Examples of normally employed "excipients," include pharmaceutical grades of carbohydrates, including monosaccharides, disaccharides, cyclodextrans, and polysaccharides (e.g., dextrose, sucrose, lactose, raffinose, mannitol, sorbitol, inositol, dextrins and maltodextrins); simple and compound amino acids; starch; cellulose; salts (e.g., sodium or calcium phosphates, calcium sulfate, magnesium sulfate); citric acid; tartaric acid; glycine; high molecular weight polyethylene glyols (PEG); surfactants, including pluronics; and combinations thereof. Examples of suitable "carriers" include water, silicone, gelatin, waxes, and like materials. Excipients may be incoφorated into pharmaceutical particles.

Excipient particles or carrier particles, ie., those particles containing no medicament, may be incoφrated into pharmaceutical compositions, which also contain pharmaceutical particles.

Pharmaceutical compositions may also comprises mixtures or pharmaceutical particles having different medicaments contained therein. For example, a pharmaceutical formulation may comprise pharmaceutical particles of "type A" contaning a first medicament, and pharmaceutical particle of "type B" containing a second mediocament, and optionally, one or more excipient particles.

By the term "porosity", as used herein, it is meant to mean the void spaces (or "defining pores") created by the removal of a "sublimable medium" by sublimation. According to the invention, "porosity" can be expressed as a percentage of void spaces by volume in a particle or the percentage of sublimable medium by weight in a particle prior to sublimation. As the measurement of porosity of a given particle is difficult, porosity measurements may be made by measuring the percentage of sublimable medium by weight of the a composition of pharmaceutical particles.

By the term "pharmaceutical delivery device", as used herein, it is meant to mean a device that is adapted to administer a controlled amount of a pharmaceutical composition to a patient, including, but not limited to, the Diskus® device disclosed in U.S. Pat Nos. Des. 342,994; 5,590,654, 5,860,419; 5,837,630 and 6,032,666; the Diskhaler™ device disclosed in U.S. Pat. Nos. Des 299,066; 4,627,432 and 4,811,731; the Rotadisk™ device disclosed in U.S. Pat No. 4,778,054; the Cyclohaler™ device by Norvartis; the Turbohaler™ device by Astra Zeneca; the Twisthaler™ device by Scheling Plough; the Handihaler™ device by Boelxringer Engelheim and the Airmax™ device by Baker-Norton, which are incoφorated by reference herein. The term "Pharmaceutical delivery device" includes any suitable pulmonary delivery system, including metered dose inhalers, dry powder inhalers, nebulizer systems, and vibrational or electrohydrodynamic delivery systems.

As will be appreciated by one having ordinary skill in the art, the present invention substantially reduces or eliminates one or more disadvantages and drawbacks associated with conventional methods for producing crystalline pharmaceutical particles. In a first embodiment of the invention, the method of forming substantially crystalline pharmaceutical particles that are particularly suitable for inhalation therapy generally comprises: (i) co-dissolving the substance to be crystallized with at least one crystallization inducing agent in a first medium to form a first solution; (ii) spray-drying the first solution at a suitable temperature, e.g., in the range of approximately 35°C to 180°C; (iii) selectively subliming out the crystallization inducing agent; and (iv) harvesting the resultant crystalline particles. According to the invention, the substance to be crystallized can be a medicament, excipient or mixtures thereof.

According to the invention, the co-dissolving step can be performed at a temperature in the range of approximately 10°C to 50°C. More preferably, the co- dissolving step is performed at a temperature in the range of approximately 20°C to 40°C.

In a further embodiment of the invention, the method of forming substantially crystalline pharmaceutical particles comprises: (i) dissolving the substance to be crystallized in a primary medium to form a dissolved substance medium; (ii) adding at least one crystallization inducing agent in a first medium to the dissolved substance medium to form a first solution; (iii) spray-drying the first solution at a temperature in the range of 35°C to 180°C; (iv) selectively subliming out the crystallization inducing agent; and (v) harvesting the resulting particles.

In yet another embodiment of the invention, the method of forming substantially crystalline pharmaceutical particles comprises: (i) placing the substance to be crystallized in a primary medium to form a base substance medium; (ii) adding at least one crystallization inducing agent in a first medium to the base substance medium to form a first solution; (iii) spray-drying the first solution at a temperature in the range of 35°C to 180°C; (iv) selectively subliming out the crystallization inducing agent; and (v) harvesting the resulting particles.

According to the invention, the primary and first mediums can be in the form of an aqueous solution, organic solution (e.g. organic solvent) or mixtures thereof. In a preferred embodiment of the invention, the first medium comprises an organic solution, such as acetone. A major component of the processes of the invention is the "crystallization inducing agent." As indicated above, the "crystallization inducing agent" comprises a substance (in solution or suspension) that is capable of inducing crystallization of a molecule.

According to the invention, the "crystallization inducing agent" is substantially sublimable (i.e., sublimable medium). In a preferred embodiment of the invention, the "crystallization inducing agent" comprises menthol.

In the noted first embodiment of the invention, approximately 0.5% to 10%, more preferably, 5% to 10%, by weight, of the crystallization inducing agent is co-dissolved with the substance to be crystallized. Even more preferably, approximately 10%, by weight, of the crystallization inducing agent is co-dissolved with the substance to be crystallized.

As indicated above, the spray-drying is preferably performed at a temperature in the range of approximately 35°C to 180°C. In a preferred embodiment, the spray-drying is performed at a temperature < 60°C. As will be appreciated by one having ordinary skill in the art, substances subjected to spray-drying, freeze drying or rapid solvent quenching will often exhibit amoφhous and metastable crystalline (i.e., partly amoφhous) forms, in addition to crystalline forms. An additional "conditioning" step, such as that disclosed in U.S. Pat. No. 5,707,884, is thus often required to convert the amoφhous and partly amoφhous forms to a stable crystalline form.

In contrast to the noted prior art teaching, Applicants have found that the mere presence of the menthol during the processes of the invention effectuates the conversion

(or recrystallization) of the amoφhous and partly amoφhous forms of the spray-dried substance (i.e., particles), particularly, fluticasone esters, such as fluticane propionate and fluticasone 17α-2 furoate, to a stable crystalline form. Applicants theorize that the menthol interacts with, or facilitates the rearrangement of, at least the outer layer of the amoφhous or partly amoφhous particles to form the desired crystalline form. It is to be understood that such conversion is encompassed within the scope of the present invention.

According to the invention, crystallization can also be enhanced or, in some instances, effectuated by sonocrystallization, vortex mixing, single or double emulsion techniques. In certain cases, crystallization can occur by a solid state transition process following formation of an amoφhous material, e.g., amoφhous lactose as a mixture with a suitable solute that is converted to crystalline lactose at elevated temperatures during the extraction process to dissolve out the solute. It is to be understood that such transitions are similarly encompassed within the scope of the present invention.

Sublimation of the crystallization inducing agent, in accordance with the invention, can take place by any suitable conventional process, including known vacuum processes. Harvesting of the crystals can similarly be achieved by standard techniques known in the art. In a further embodiment of the invention, the method of forming substantially crystalline pharmaceutical particles merely comprises disposing a crystallization inducing agent proximate the substance to be crystallized for a sufficient period of time to induce crystallization and harvesting the resultant particles. According to the invention, the crystallization inducing agent, which preferably comprises menthol, can be in a solid or vapor phase.

As discussed in detail herein, the inhalable particles formed in accordance with the invention are substantially crystalline. Preferably, the particles have an aerodynamic diameter < 10 μm and, most preferably, an aerodynamic diameter suitable for targeted delivery in the lung. Preferably, particles intended for treatment of local conditions are in the range of approximately 2 - 5 μm. The particles intended for systemic delivery of therapeutics are preferably in the range of approximately 1 to 2 μm.

Preferably, the particles produced by the present invention have a geometric diameter < 10 μm, more preferably, in the range of approximately 2 - 5 μm. Particles geometrically larger than 10 μm are also able to be formed according to the present invention. Referring to Figs. 19 - 21, the crystalline particles may also exhibit rough, irregular or porous surface structures. As will be appreciated by one having ordinary skill in the art, low density particles (particles with unit densities less than 1 g/cc) will tend to aerosolize from a delivery device more efficiently than particles with unit densities greater than 1 g/cc, with rough, porous or irregular surface structures enhancing the ability of the particles to be dispersed and aerosolize, resulting in higher respirable fractions of inhaled medicaments.

The noted porous/roughened/irregular particles will also exhibit better flow characteristics and have a much higher specific surface area than solid micronized particles. Thus, dissolution of the medicament from such particles is faster than from non- porous particles. Further, formation of small (aerodynamically less than 3 μm) highly porous particles of medicament used in the treatment of respiratory disorders may be particularly suitable for delivery to the terminal bronchioles/alveolar region of the respiratory tract. Conventional non-porous medicament particles are typically too large to reach these sites or so small that they either penetrate into the alveolar region or are exhaled. If the small particles are highly porous, while travelling along the respiratory tract, they can take up water due to the combined effect of an extremely large surface area of the particle and the 100% humidity extant within the airways. The aerodynamic diameter of the particle would thus increase gradually while travelling from the trachea via bronchi to bronchioles due to an increase in particle density. Careful engineering of the diameter and porosity of the particle can therefore produce porous medicament particles that will primarily reach the bronchioles.

As indicated above, the substance to be crystallized, in accordance with the present invention, can comprise any of the aforementioned medicaments, excipients or mixtures thereof. Preferably, the substance to be crystallized is a medicament or a pharmaceutically acceptable excipient that is soluble in an organic solvent. Most preferably, the substance is solely medicament.

Preferred medicaments (for administration using powder compositions comprising an excipient prepared in accordance with the invention, or for crystallization themselves) include anti-allergies, bronchodilators and anti-inflammatory steroids of use in the treatment of respiratory disorders such as asthma by inhalation therapy, for example cromoglycate (e.g., as the sodium salt), salbutamol (e.g., as the free base or as the sulphate salt), salmeterol (e.g., as the xinafoate salt), terbutaline (e.g., as the sulphate salt), reproterol (e.g., as the hydrochloride salt), beclomethasone dipropionate (e.g., as the monohydrate), fluticasone propionate, 6 , 9α-difluoro-llβ-hydroxy-16α-methyl-3-oxo- 17α-propionyloxy-androsta-l,4-diene-17β-carbothioic acid S-(2-oxo-tefrahydro-furan-3- yl) ester (refered to herein as "fulticasone 17α-2 furoate" or "FF") or (-)-4-amino-3,5- dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]amino]methyl] benzenemethanol.

Salmeterol, salbutamol, fluticasone propionate, beclomethasone dipropionate and physiologically acceptable salts and solvates thereof are especially preferred. Most preferred medicaments are fluticasone propionate, salmeterol xinafoate, salbutamol sulphate and ipratropium bromide.

Preferred excipients include monosaccharides, such as mannitol, arabinose, xylitol and dextrose and monohydrates thereof, disaccharides, such as lactose, maltose and sucrose, polysaccharides, such as starches, dextrins or dextrans, and simple and compound amino acids, such as diamino acids, triamino acids and polyamino acids. More preferred excipients comprise particulate crystalline sugars such as glucose, fructo.se, mannitol, sucrose and lactose. In a preferred embodiment of the invention, the excipient comprises mannitol, lactose or lactose monohydrate.

Preferably, the average size (i.e., geometric diameter) of the excipient particles (when distributed by mass) is in the range of approximately 5 - 1000 μm. More preferably, the average excipient particle size is in the range of approximately 50 - 250 μm; even more preferably, the average excipient particle size is in the range of approximately 50 - 100 μm. Most preferably, at least 95% of the excipient particles preferably have a size in the range of approximately 50 - 100 μm.

According to a further aspect, the present invention comprises crystalline, porous pharmaceutical particles formed by the processes as hereinbefore described. In a preferred embodiment, the particles comprise substantially crystalline fluticasone propionate particles.

The particles obtained in accordance with the present invention can be employed to form powder pharmaceutical compositions that are particularly suitable for inhalation therapy. Such compositions would be expected to exhibit superior fine particle mass (FPM) performance, i.e., optimum dispersion of medicament particles.

accordingly, a further aspect of the present invention comprises pharmaceutical compositions, including excipient particles formed in accordance with the present invention, preferably, lactose particles and a particulate medicament. The noted compositions can optionally include at least one pharmaceutically acceptable additive such as a diluent or an additional excipient.

A further aspect of the present invention comprises pharmaceutical compositions, including particulate medicament particles formed in accordance with the present invention (i.e., neat drugs). The noted compositions can similarly optionally include at least one pharmaceutically acceptable diluent or excipient.

It will be appreciated by those skilled in the art that the pharmaceutical compositions formed in accordance with the invention can, if desired, contain a combination of two or more medicaments or components, including combinations of bronchodilatory agents (e.g., ephedrine and theophylline, fenoterol and ipratropium, and isoetharine and phenylephrine formulations). The combined medicaments or components can optionally be produced by a process according to the present invention.

Other pharmaceutical compositions may contain bronchodilators such as salbutamol (e.g. as the free base or as the sulphate salt), salmeterol (e.g. as the xinafoate salt), formoterol or isoprenaline in combination with an anti-inflammatory steroid such as a beclomethasone ester (e.g. the dipropionate) or a fluticasone ester (e.g. the propionate or

6α,9α-difluoro- 17α- [(2-furany lcarbonyl)oxy] - 11 β-hydroxy- 16α-methyl-3 -oxo-androsta- l,4-diene-17β-carbothioic acid S-fluoromethyl ester) or a bronchodilator in combination with an antiallergic such as cromoglycate (e.g. the sodium salt). Combinations of isoprenaline and sodium cromoglycate, salmeterol and fluticasone propionate, or salbutamol and beclomethasone dipropionate are especially preferred.

The pharmaceutical compositions of the invention preferably comprise 0.1 - 99.9% w/w, preferably, 0.5 - 75% w/w, more preferably, 1 - 50% w/w of medicament relative to the weight of the excipient. The noted particulate composition(s) can optionally contain one or more conventional pharmaceutically acceptable components (i.e., ingredients), such as diluents and flavouring agents. The particle size of any such component will preferably be such as to substantially prevent their inhalation into the bronchial system upon administration of the powder composition.

In a preferred embodiment, the pharmaceutical compositions of the invention preferably comprise 0.1 - 99% w/w medicament and 99.9- 0.1% w/w excipient. More preferably, the pharmaceutical composition comprises 1 - 50% w/w medicament, the remainder being excipient.

The pharmaceutical compositions of the invention can conveniently be filled into a bulk storage container, such as a multi-dose reservoir, or into unit dose containers such as capsules, cartridges or blister packs, being piercable or equipped with a yeelable covering, which may be used with an appropriate pharmaceutical delivery device, for example, as described in GB 2041763, WO 91/13646, GB 1561835, GB 2064336, GB 2129691 and GB 2246299, which are incoφorated by reference herein. The noted devices and aforementioned pharmaceutical delivery devices, which contain a pharmaceutical composition in accordance with the invention are deemed novel and, hence, form a further aspect of the invention.

Administration of the pharmaceutical compositions of the present invention may be appropriate for the treatment of mild, moderate or severe acute or chronic symptoms or for prophylactic treatment. It will be appreciated that the precise dose administered will depend on the age and condition of the patient, the particular medicament used and the frequency of administration and will ultimately be at the discretion of the attendant physician. When combinations of medicaments are employed the dose of each component of the combination will in general be that employed for each component when used alone.

Typically, administration may be one or more times, for example from 1 to 8 times per day, giving for example 1, 2, 3 or 4 unit doses each time.

Thus, for example, each actuation may deliver 25 micrograms salmeterol, 100 micrograms salbutamol, 25, 50, 125 or 250 micrograms fluticasone propionate or 50, 100,

200 or 250 micrograms beclomethasone dipropionate. According to the invention, the excipients obtained by the present invention are not limited to use in pharmaceutical delivery devices. The excipients can also be compressed to produce other medicament forms (e.g., tablets).

The present invention, thus, further comprises the use of lactose monohydrate particles, as hereinbefore defined, in the preparation of a pharmaceutical composition, where the composition is preferably in the form of a tablet or capsule.

EXAMPLES

The examples that are set forth herein are for illustrative puφoses only and are not meant to limit the scope of the invention(s) in any way.

Example 1

In the following example, a series of designed experiments (DOE) \\ ere performed to determine the effects of menthol on fluticasone propionate (FP) particles; in particular, the effects of the concentration of the menthol in the feed solution, the concentration of FP in the feed solution and the spray drying temperature. The first set of experiments was run at high levels of menthol, ranging from 10% to 50%, and temperatures of 100°C and 180°C. The second set of experiments was run at low levels of menthol, ranging from 0.5 to 5%, the third set of experiments was similarly run at high menthol concentrations, but at lower temperature levels of 35°C (the mimmum attainable of the Buchi B-191 Spray Dryer) and 60°C.

FACTORS

Referring to Table I, there is shown the factors that were evaluated for their effect on the physical properties of the resulting particles and, hence, powders.

Table I

Referring now to Tables II-IV, there are shown the actual test parameters employed for DOE's 1-3, respectively.

Table II

Table III

Table IV

PROCEDURE

Feedstock Preparation

The fluticasone propionate (FP) was weighed into glass bottles. If employed, menthol was added (see test parameters). The proper amount of acetone was then added to yield either a 1% or a 5% FP solution. In the case of the 5% solutions, gentle heating was employed to dissolve the FP.

Spray Drying

A Buchi B-191 Spray Dryer was set up to run under an inert atmosphere of nitrogen. The inlet temperature was set to the desired level and the spray dryer was allowed to equilibrate to the temperature. The spray drying commenced when the outlet temperature had stabilized. The flow rate and gas pressure employed in the spray drying process are set forth in Table N below.

Table V

After completion of the spray drying process, the spray dryer was allowed to cool to 60°C - 70°C. The powder was then recovered from both the cyclone and the collection vessel into a glass jar.

Removal of Menthol

The glass jar was then covered and placed in a vacuum desiccator to begin the process of vacuum stripping of the menthol. The same process was followed for the samples containing no menthol to verify that the vacuum stripping process had no effect on the resulting particles.

Upon completion of a full set of experiments, the glass jars were sealed and subjected to a complete stripping process in a vacuum oven at room temperature. PHYSICAL CHARACTERIZATION

Differential Scanning Calorimetry

A TA Instruments DSC 2010 Differential Scanning Calorimeter was employed to quantify the amount of amoφhous material present in each sample. The DSC information was also employed to determine if the stripping process was successfully removed the menthol from each sample.

DOE 1 The DSC results reflected the production of crystalline (Form I) FP in each sample containing menthol (10%, 25% and 50% menthol). Referring to Table VI, only the samples produced with 0% menthol displayed an exotherm event due to the conversion from amoφhous to crystalline.

Table VI

due to recrystallization

DOE 2

Referring to Table Nil, two of the samples that were spray dried with menthol exhibited a crystallization exotherm on the initial DSC run, but on subsequent runs the crystallization exotherm was not exhibited. In the runs that did contain an exotherm, the temperature of the crystallization event was shifted to a lower temperature. Also evident is a long, shallow endotherm, which is due to the sublimation of the menthol still present in the sample.

Table VII

The presence of the exotherm in the first DSC, and its absence in subsequent runs indicates that the FP had not completely crystallized at the time the first DSC was run and that menthol was still present in the sample. The position of the exotherm at 66 ° C rather than 110°C, which is normally observed, demonstrates the plasticizing effect of the menthol on FP, allowing it to crystallize at a lower temperature.

The noted phenomena are illustrated in Fig. 1, wherein curve A reflects the DSC for one of non-menthol containing samples; curve B reflects the initial DSC collected for the sample (which was spray dried containing 5% menthol); and curves C and D reflect DSC analyses collected on subsequent days.

Referring now to Fig. 2, there is shown the effects of temperature and menthol concentration. Fig. 2 indicates that, in general, the higher the temperature condition at which the spray dryer is run (i.e., 180°C, the more crystalline the material is (as evidenced by a lower exotherm of crystallization). In DOE 1, it was seen that none of the samples produced with menthol (10% being the lowest concentration) had crystallization exotherms, regardless of temperature.

DOE 3

Referring now to Fig. 3, there is shown a graphical illustration of DSC results for samples with and without menthol. As was the case in the DOE1, only the samples prepared with 0% menthol (curve #1) exhibited an exotherm associated with the conversion from amoφhous to crystalline FP. None of the menthol containing samples

(curve #2) exhibited this exotherm, but did show a slow gradual drop in the baseline, which is likely due to the sublimation of residual menthol.

Porosity/Surface Area

The Micromeritics Tristar 3000 (Micrometrics, Inc., Norcross, GA) was employed to perform both surface and porosity measurements on samples produced in DOE 1 and DOE 3 (high menthol concentrations). Since the Tristar 3000 has an upper limit for pore size detection of approximately 300 nm, particle pore sizes >300 nm were generally undetected. However, referring to Figs. 20 and 22, pores were readily discernible in the samples that were stripped of menthol (10% and 25% menthol, respectively).

Particle Size

The particle size of the FP particles was determined using the Sympatec Laser

Diffraction Particle Sizer equipped with a RODOS dry powder disperser (Sympatec, Inc., Princeton, NJ). The samples were analyzed at both 1.0 bar and 3.0 bar pressure in order to determine if the higher pressure results in any de-agglomeration or fracture of the particles.

DOE 1 Referring now to Fig. 4, it can be seen that there was a general trend in the particle size data for larger particles to be formed when using the higher solids concentration (5% versus P/o). For example, the average particle size resulting from the 5% solutions of drug was 2.952 μm, while the 1% solutions yielded an average particle size of 2.032 μm (at 3 bar pressure on the Sympatec).

DOE 2

Referring to Fig. 5, it can be seen that the 1% FP solutions resulted in smaller particle sizes than the 5% solutions (an average of 2.71 μm versus 3.14 μm, respectively).

DOE 3

Referring to Fig. 6, it can be seen that the trend toward smaller particles at lower feedstock concentration is evident in this set of experiments as well (an average of 2.26mm for the 1% FP solutions and 2.71mm for the 5% FP solutions).

X-ray Diffraction

X-ray powder diffraction ("XRD" or "XRPD") was performed on each of the samples using the Scintag PAD-N diffractometer. The X-ray source was a copper anode tube with a DGM-105 scintillation detector. Samples were scanned from 2 - 50° theta at l°theta per minute. Slit widths used were 1 mm, 2 mm, 0.5 mm and 0.3 mm for divergent incident, scatter incident, scatter diffracted and receiving, respectively.

DOE 1 The X-ray diffraction results were consistent with the results obtained by DSC. The spray-dried particles without menthol contained noncrystalline material as evidenced by a large amoφhous halo in the baseline (see Fig. 7). Referring now to Figs 8 (10% menthol), 9 (25% menthol) and 10 (50% menthol), it can be seen that of the samples spray-dried with menthol exhibited peaks in the x-ray characteristic of racemic mixture of crystalline Form I and Form II FP. DOE 2

As reflected in DOE 1, the samples spray dried without menthol showed a large amoφhous halo in the X-ray pattern, indicating little long-range order in the powder (see Fig. 11). Referring now to Fig. 12 (.5% menthol/1% FP @ 180°C), Fig. 13 (1% menthol/1% FP @ 180°C) and Fig 14 (5% menthol/1%) FP @ 180°C), the samples spray- dried with higher concentrations of menthol tended to have shaφer peaks and less of the amoφhous "hump" in the baseline, indicating higher levels of crystallinity. The particles spray dried with lower concentrations of menthol (especially in the 0.5% menthol samples) had less discrete peaks and the distinct amoφhous feature in the baseline.

In this set of experiments, the temperature effect is noticeable, since the temperature is not being overshadowed by the high menthol levels, as in DOE 1. In general, higher spray drying temperatures and menthol concentrations resulted in more crystalline samples.

DOE 3

Referring now to Figs. 15-18, there are shown X-ray diffraction scans of samples run at 60°C and including the following formulations: 0% menthol/ 1%FP (Fig. 15); 10% menthol/1% FP (Fig. 16); 25% menthol/1% FP (Fig. 17); and 50% menthol/1% FP (Fig. 18). The noted data similarly indicates that samples produced with high levels of menthol are generally more crystalline.

Scanning Electron Microscopy

A Zeiss-Leo DSM 960 Scanning Electron Microscope ("SEM") was employed to produce images of the FP particles. The samples were prepared by placing ~50 mg onto carbon tape adhered to an alumim^'um stage. The samples were then sputter coated with gold at 20 milliamps for ~4 minutes and analyzed in the SEM.

Referring to Fig. 19, there is shown a SEM image of particles produced without menthol. Figs. 20, 21 and 22 are SEM images of particles produced with and following subsequent removal of 10%>, 25% and 50% menthol, respectively. As illustrated in Fig. 19, the particles produced without menthol are very smooth. These particles also show a crystallization exotherm in the DSC. The samples produced with 10%), 25% and 50% menthol have roughened surfaces, indicating a high degree of crystallinity, which is also supported by the DSC results.

Example 2 Preparation of Mannitol Particles

Feedstock Preparation

Weigh 5.0 grams of mannitol and 0.5 g of menthol into a glass bottle. To this add 75 ml of a 50:50 wateπmethanol solvent mixture. Gentle heating may be applied to hasten dissolution.

Spray Drying

Set up the Buchi B- 191 or other commercially available Spray Dryer to run under an inert atmosphere of nitrogen. Set the spray dryer parameters to the values set forth in the Table NΪII below. Commence spray drying when the outlet temperature reaches a stable value.

Table VIII

Allow the spray dryer is allowed to cool to 60°C - 70°C, after completion of the spray drying process. Recover the powder from both the cyclone and the collection vessel into a glass jar. Removal of Menthol

Immediately place the glass jar in a vacuum desiccator to begin the process of vacuum stripping of menthol from the powder.

Example 3

Preparation of Fluticasone Propionate/Mamiitol Particles

Feedstock Preparation

Weigh 5.0 grams of mannitol, 0.5 g of menthol and 0.25 g of fluticasone propionate into a glass bottle. To this add 100 ml of a 50:50 water:acetone solvent mixture. Gentle heating may be applied to hasten dissolution.

Spray Drying

Set up the Buchi B-191 Spray Dryer to run under an inert atmosphere of nitrogen. Set the spray dryer parameters to the values set forth in Table IX below. Commence spray drying when the outlet temperature reaches a stable value.

Table IX

Allow the spray dryer is allowed to cool to 60°C - 70°C, after completion of the spray drying process. Recover the powder from both the cyclone and the collection vessel into a glass jar.

Removal of Menthol Immediately place the glass jar in a vacuum desiccator to begin the process of vacuum stripping of menthol from the powder.

SUMMARY The noted results thus indicate that the tendency to produce crystalline particles increased with the increasing levels of menthol. Greater than 10% menthol consistently produced fully crystalline particles.

The results further reflect the mere contact of amoφhous fluticasone propionate with menthol "vapor" induces the amoφhous material to crystallize. Thus, a low concentration of menthol in a feedstock solution is likely to induce the crystallization of an amoφhous spray-dried material or medicament, particularly fluticasone propionate, given sufficient residence time in contact with the material.

The results additionally indicate that the combination of a high level of menthol (e.g., > 25%) and a low spray-drying temperature (e.g., < 60°C) produces porous, crystalline fluticasone propionate.

Inducing Conversion from Amorphous to Crystalline Form through Exposure to Menthol Vapors.

The present invention, in an alternative embodiment, may be employed for producing materials having a thermally stable amoφhous phase which is observed state in certain manufacturing processes. Our experiences have indicated that, in a spray-drying environment, molecules with relatively slow induction times for crystallization produce amoφhous particles immediately upon drying. This is followed by a thermally induced amoφhous to crystalline transition occurring while particles travel through the remainder of the spray drying system to produce crystalline particles in a single process. However, where the time spent in the spray dryer at elevated temperatures is not sufficient to allow crystallization, only amoφhous product is produced. Certain compounds, such as 6a, 9α- difluoro- 11 β-hydroxy- 16 -methyl-3-oxo- 17α-propionyloxy-androsta- 1 ,4-diene- 17β- carbothioic acid S-(2-oxo-tetrahydro-furan-3-yl) ester (herein referred to as "fluticasone

17β-2 furoate or FF") are examples of these types of molecules. In such instances, the process of manufacturing crystalline product directly from spray dryer presents difficulties, which may be resolved by employing the process of the present invention. The use of menthol in the proximity of a particles to aid crystallization as described in this patent application is beneficial as an after production process step yielding crystalline material. According to this aspect of the invention, amoφhous to crystalline conversion of compound may be initiated and/or accelerated by placing an amoφhous material in proximity to an crystalinity inducing agent, such as a sublimable crystalinity- inducing agent, such as menthol, as indicated in the following experiment. Heat may also be employed to accelerate this crystallization process.

Example 4

In this experiment, Fluticasone 17α-2 furoate ("FF") is placed in the presence of menthol vapor and crystalline conversion occurs at greatly accelerated pace as compared to control. Amoφhous FF was prepared by spray drying a solution of FF in methylethylketone ("MEK"). The FF solution was spray dried at an inlet temperature 220°C in a Buchi Model 19 IB Spray Drier. The resulting particles were collected and were determined to be amoφhous by Differential Scanning Calorimetry "DSC". (DSC conditions: 10C per min, 30-160C) and X-Ray Powder Diffraction (XRPD). The particles were stored at ambient conditions for approximately 3 weeks and showed no changes in the energy required for the amoφhous to crystalline transition, indicating no crystallization had occurred. This amoφhous material was used as the starting material for samples 2 — 4.

From these spray-dried particles, three samples were prepared. Each of the three samples was prepared by adding approximately 20mg drug substance to a 2mL high- pressure liquid chromatography (HPLC) vial. The filled HPLC vials were placed into individual 40mL scintillation vials. Approximately 300mg of menthol crystals were added to 2 of the 3 scintillation vials, such that the menthol crystals were not in physical contact with the FF particles, although the contents of the HPLC vials would be exposed to menthol vapor. Samples were placed either on a bench and remained at ambient temperature, or placed in an oven at 50° C, as indicated in the below Table.

Table X

Samples were pulled at 1, 2, 4, 18, 26 and 48 hours and analyzed by DDSC. (DSC conditions: IOC per min, 30-160C). Results are indicated in Figs. 23, 24 and 25. Fig. 23 depicts a DSC plot for FF exposed to menthol at room temperature for 48 hours. Fig. 24 depicts a DSC plot for FF exposed to 50°C for 48 hours without menthol. Fig. 25 depicts a DSC plot for FF exposed to menthol at 50°C for 2 hours.

As can be seen, the results show that menthol affects the conversion of amoφhous to crystalline material. The sample at ambient temperature with menthol exposure

(Sample No. 3) underwent complete crystallization within 48 hours, while the exposure to menthol at 50°C (Sample No. 4) caused complete crystallization in <1 hour. The control sample stored at 50°C with no menthol (Sample No. 2) was not completely crystallized at 48 hours. Thus, menthol appears to accelerate the crystallization process, and temperature appears to also play a factor in the crystallization process.

Effect of Menthol Levels on the Temperature of Amoφhous to Crystalline Transition

In order to look at the effect that menthol in the sample has on the temperature at which the conversion of amoφhous to crystalline occurs, a fraction of the sample stored with menthol under ambient temperature conditions for 26 hours (at which point still contained amoφhous material) was placed in a vacuum oven at ambient temperature and exposed to a vacuum for 45 minutes. A sample was taken and analyzed by DSC. The remaining portion of the sample was placed in the face of a fume hood and allowed to sit in the air flow path, without its cap overnight (~18 hours) before being analyzed by DSC.

Note: Due to limited sample supply, quantitation of the residual menthol levels, by a method such as TGA/mass spec or GC, could not be performed. The removal of menthol is expected at sub-ambient pressures or in an open environment because of the tendency of menthol to sublime.

As seen in Figure 26, the removal of menthol from the sample which had been stored at ambient temperature in the presence of menthol for 26 hours and was subsequently stripped of menthol under vacuum resulted in a shift of peak temperature of nearly 30°C. The implications of the experiment are that having residual menthol in the amoφhous particle as they travel through a spray dryer, as described elsewhere in this application, may allow the crystallization of the particle in the time and at the temperatures achievable in the spray-drying system. Advantageously, menthol can be removed from the sample and is approved for inhalation use by regulatory authorities.

Since the tendency with FF has been to form solvates and different polymoφhs, XRD has been run on the sample exposed menthol at 50°C (Sample 4). As can be seen in

Fig. 27, the sample has undergone complete conversion to "Form I" FF, the thermodynamically most stable form, without new polymoφh or solvate formation.

Throughout the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers but not to the exclusion of any other integer or step or group of integers or steps.

Without departing from the spirit and scope of this invention, one of ordinary skill can make various changes and modifications to the invention to adapt it to various usages and conditions. As such, these changes and modifications are properly, equitably, and intended to be, within the full range of equivalence of the following claims.

Claims

CLAIMSWhat is Claimed is:

1. A method of forming pharmaceutical particles comprising a crystalline first substance, comprising: disposing a first substance proximate at least one sublimable crystallization inducing agent for a period of time sufficient to induce crystallization; and harvesting the resultant crystalline particles.

2. The method of Claim 1 , wherein said crystallization inducing agent comprises menthol.

3. The method of Claim 1 , wherein said first substance con? prises a medicament selected from the group consisting of an analgesic, anginal preparation, antiallergic, antibiotic, antiinfective, antihistamine, anti-inflammatory, antitussive, bronchodilator, α₄ integrin inhibitor, diuretic, anticholinergic, adenosine 2a agonists, hormones, xanthine, vaccine, therapeutic protein, peptide, and combinations thereof.

4. The method of Claim 3, wherein said first substance comprises a medicament selected from the group consisting of codeine, dihydromoφhine, ergotamine, fentanyl, moφhine, diltiazem, cromoglycate, ketotifen, nedocromil; cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines pentamidine; methapyrilene, beclomethasone, fluticasone, flunisolide, budesonide, rofleponide, mometasone, ciclesonide, triamcinolone, noscapine, albuterol, salmeterol, ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, terbutaline, isoetharine, tulobuterol or 4-hydroxy-7-[2-[[2- [[3-(2-phenylethoxy) propyl]sulfonyl]ethyl]amino]ethyl-2(3H)-benzothiazolone, 2R,3R,4S,5R)-2-[6-Amino-2-(lS-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2- ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol, (2S)-3-[4-({[44-(aminocarbonyl)-l- piperidinyljcarbonyl} oxy)phenyl]-2-[((2S)-4-methyl-2- {[2-(2-methylρhenoxy) acetyl] amino}pentanoyl)amino] propanoic acid, arniloride; ipratropium, tiotropium, atropine, oxitropium, cortisone, hydrocortisone, prednisolone, aminophylline, choline theophyllinate, lysine theophyllinate, theophylhne, insulin or glucagon, and salts, esters, and derivatives and combinations thereof.

5. The method of Claim 4, wherein said first substance comprises a medicament selected from the group consisting of fluticasone, fluticasone propionate, 6α, 9α-difluoro- 11 β -hydroxy- 16α-methyl-3 -oxo- 17α-propionyloxy-androsta- 1 ,4-diene- 17 β - carbothioic acid S-(2-oxo-tetrahydro-furan-3-yl) ester, salmeterol, salmeterol xinafoate, albuterol base and sulfate, and combinations thereof.

6. The method of Claim 5, wherein said first substance comprises fluticasone propionate.

7. The method of claim 1, further including the step of exposing said said first substance to greater than ambient temperaures while in the presence of a vapor phase of said at least one sublimable crystallization inducing agent.

8. The method of claim 7, wherein said greater than ambient temperature is from 35°C o l80°C.

9. The method of claim 7, wherein said greater than ambient temperature is approximately 50°C.

10. The method of claim 7, wherein the step of exposing said said first substance to greater than ambient temperaures while in the presence of a vapor phase of said at least one sublimable crystallization inducing agent occurs for a period of 48 hours or less.

11. The method of claim 9, the step of exposing said said first substance to greater than ambient temperaures while in the presence of a vapor phase of said at least one sublimable crystallization inducing agent occurs for a period of 2 hours or less.

12. The method of Claim 4, wherein said medicament comprises 6α, 9 - difluoro- 11 β-hydroxy- 16α-methyl-3 -oxo- 17α-propionyloxy-androsta- 1 ,4-diene- 17β- carbothioic acid S-(2-oxo-tefrahydro-furan-3-yl) ester.

13. The method of claim 1 , wherein said pharmaceutical particles further comprise at least one excipient.

14. The method of claim 13 , wherein said crystalinity inducing agent is menthol.

15. The method of claim 1 , wherein said crystalinity inducing agent is integrated into said pharmaceutical particle and is subsequently removed, thereby causing said first substance to crystallize.

16. A method of forming pharmaceutical particles comprising crystalline first substance, comprising: co-dissolving a first substance with at least one crystallization inducing agent in a first medium to form a first solution; spray drying said first solution at a temperature in the range of approximately 35°C to 180°C; selectively subliming out said crystallization inducing agent; and harvesting the resultant parmaceutical particles comprising crystalline first substance.

17. The method of Claim 16, wherein said spray drying temperature is less than approximately 60°C.

18. The method of Claim 16, wherein said pharmaceutical particles have a porous structure.

19. The method of Claim 16, wherein said pharmaceutical particles have a geometric diameter in the range of approximately 2 to 5 μm.

20. The method of Claim 16, wherein said crystallization inducing agent comprises menthol.

21. The method of Claim 16, wherein said co-dissolving step is performed at a temperature in the range of 10°C to 50°C.

22. The method of Claim 21, wherein said co-dissolving step is performed at a temperature in the range of 20°C to 40°C.

23. The method of Claim 16, wherein said first substance comprises a medicament selected from the group consisting of an analgesic, anginal preparation, antiallergic, antibiotic, antiinfective, antihistamine, anti- inflammatory, antitussive, bronchodilator, α₄ integrin inhibitor, diuretic, anticholinergic, adenosine 2a agonists, hormones, xanthine, vaccine, therapeutic protein, peptide, and combinations thereof.

24. The method of Claim 23, wherein said first substance comprises a medicament selected from the group consisting of codeine, dihydromoφhine, ergotamine, fentanyl, moφhine, diltiazem, cromoglycate, ketotifen, nedocromil; cephalosporins, pemcillins, streptomycin, sulphonamides, tetracyclines pentamidine; methapyrilene, beclomethasone, fluticasone, flunisolide, budesonide, rofleponide, mometasone, ciclesonide, triamcinolone, noscapine, albuterol, salmeterol, ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, terbutaline, isoetharine, tulobuterol or 4-hydroxy-7-[2-[[2- [[3 -(2-phenylethoxy) propyl] sulfonyl] ethyl] amino] ethyl-2(3H)-benzothiazolone, 2R,3R,4S,5R)-2-[6-Amino-2-(lS-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2- ethyl-2H-tefrazol-5-yl)-tefrahydro-furaιι-3,4-diol, (2S)-3-[4-({[4-(aminocarbonyl)-l- piperidinyl]carbonyl} oxy) phenyl]-2-[((2S)-4-methyl-2- {[2-(2-methylphenoxy) acetyl]amino}pentanoyl)amino] propanoic acid, amiloride; ipratropium, tiotropium, atropine, oxitropium; cortisone, hydrocortisone, prednisolone, aminophylline, choline theophyllinate, lysine theophyllinate, theophylhne, insulin or glucagon, and salts, esters, and derivatives and combinations thereof.

25. The method of Claim 24, wherein said first substance comprises a medicament selected from the group consisting of fluticasone, fluticasone propionate, 6α, 9α-difluoro- 11 β-hydroxy- 16 -methyl-3 -oxo- 17α-propionyloxy-androsta- 1 ,4-diene- 17 β - carbothioic acid S-(2-oxo-tefrahydro-furan-3-yl) ester, salmeterol, salmeterol xinafoate, albuterol base and sulfate, and combinations thereof.

26. The method of Claim 25, wherein said first substance comprises fluticasone propionate.

27. The method of Claim 16, wherein said first substance comprises an excipient selected from the group consisting of monosaccharides, disaccarides, polysaccharides, and combinations thereof.

28. The method of Claim 16, wherein said first substance comprises an excipient selected from the group consisting of simple amino acids, compound amino acids, and combinations thereof.

29. The method of Claim 27, wherein said first substance comprises an excipient selected from the group consisting of lactose, maltose, sucrose, starches, dextrins, dextrans, glucose, fructose and mannitol.

30. The method of Claim 29, wherein said first substance comprises mannitol.

31. The method of Claim 27, wherein said excipient comprises particles having an average geometric diameter in the range of approximately 50 to 200 μm.

32. The method of Claim 16, wherein said first substance comprises at least one medicament, and further comprising the step of adding at least one excipient to said first solution prior to spray drying.

33. The method of Claim 32, wherein at least 95% of the said excipient particles have a geometric diameter in the range of approximately 50 to 100 μm.

34. The method of Claim 16, wherein approximately 0.5%> to 10% w/w of said crystallization inducing agent is co-dissolved with said first substance.

35. The method of Claim 34, wherein approximately 5% to 10% w/w of said crystallization inducing agent is co-dissolved with said first substance.

36. The method of Claim 35 , wherein approximately 10% w/w of said crystallization inducing agent is co-dissolved with said first substance.

37. The method of Claim 16, wherein said first medium comprises an aqueous solution.

38. The method of Claim 16, wherein said first medium comprises an organic solution.

39. The method of Claim 38, wherein said organic solution comprises acetone.

40. The method of Claim 16, wherein said first medium comprises an aqueous- organic solvent mixture.

41. The method of Claim 16, wherein said subliming step comprises continuous extraction under vacuum.

42. A method of forming crystalline pharmaceutical particles, comprising: dissolving a first substance with a primary medium to form a dissolved substance medium; adding at least one crystallization inducing agent in a first medium to said dissolved substance medium to form a first solution; spray drying said first solution at a temperature in the range of approximately 35°C to 180°C; selectively subliming out said crystallization inducing agent; and harvesting the resultant pharmaceutical particles comprising said first substance in crystalline form.

43. The method of Claim 42, wherein said spray drying temperature is less than approximately 60°C.

44. The method of Claim 42, wherein said crystalline particles have a porous structure.

45. The method of Claim 42, wherein said crystalline particles have a geometric diameter in the range of approximately 2 to 5 μm.

46. The method of Claim 42, wherein said crystallization inducing agent comprises menthol.

47. The method of Claim 42, wherein said primary medium comprises acetone.

48. The method of Claim 42, wherein said primary medium comprises an aqueous-organic solvent mixture.

49. The method of Claim 48, wherein said aqueous-organic solvent mixture comprises a water-acetone solution.

50. The method of Claim 48, wherein said aqueous-organic solvent mixture comprises a water-methanol solution.

51. The method of Claim 42, wherein said first substance comprises a medicament selected from the group consisting of an analgesic, anginal preparation, antiallergic, antibiotic, antiinfective, antihistamine, anti- inflammatory, antitussive, bronchodilator, α₄ integrin inhibitor, diuretic, anticholinergic, adenosine 2a agonists, hormones, xanthine, vaccine, therapeutic protein, peptide, and combinations thereof.

52. The method of Claim 51 , wherein said first substance comprises a medicament selected from the group consisting of codeine, dihydromoφhine, ergotamine, fentanyl, moφhine, diltiazem, cromoglycate, ketotifen, nedocromil; cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines pentamidine; methapyrilene, beclomethasone, fluticasone, flunisolide, budesonide, rofleponide, mometasone, ciclesonide, triamcinolone, noscapine, albuterol, salmeterol, ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, terbutaline, isoetharine, tulobuterol or 4-hydroxy-7-[2-[[2- [[3-(2-phenylethoxy) propyl]sulfonyl]ethyl]amino] ethyl-2(3H)-benzothiazolone, 2R,3R,4S,5R)-2-[6-Amino-2-(lS-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2- ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol, (2S)-3-[4-({[4-(aminocarbonyl)-l- piperidinyl]carbonyl}oxy) phenyl]-2-[((2S)-4-methyl-2-{[2-(2-methylphenoxy) acetyl]amino}pentanoyl)amino] propanoic acid, amiloride; ipratropium, tiotropium, atropine, oxitropium; cortisone, hydrocortisone, prednisolone, aminophylline, choline theophyllinate, lysine theophyllinate, theophylhne, insulin or glucagon, and salts, esters, and derivatives and combinations thereof.

53. The method of Claim 52, wherein said first substance comprises a medicament selected from the group consisting of fluticasone, fluticasone propionate, 6α, 9α-difluoro- 11 β -hydroxy- 16α-methyl-3 -oxo- 17α-propionyloxy-androsta- 1 ,4-diene- 17 β - carbothioic acid S-(2-oxo-tefrahydro-furan-3-yl) ester, salmeterol, salmeterol xinafoate, albuterol base and sulfate, and combinations thereof.

54. The method of Claim 53, wherein said first substance comprises fluticasone propionate.

55. The method of Claim 42, wherein said first substance comprises an excipient selected from the group consisting of monosaccharides, disaccarides, polysaccharides, and combinations thereof.

56. The method of Claim 42, wherein said first substance comprises an excipient selected from the group consisting of simple amino acids, compound amino acids, and combinations thereof.

57. The method of Claim 55, wherein said first substance comprises an excipient selected from the group consisting of lactose, maltose, sucrose, starches, dextrins, dextrans, glucose, fructose and mannitol.

58. The method of Claim 57, wherein said first substance comprises mannitol.

59. The method of Claim 55, wherein said excipient comprises particles having an average geometric diameter in the range of approximately 50 to 200 μm.

60. The method of Claim 59, wherein said excipient particles have an average geometric diameter in the range of 50 to 100 μm.

61. The method of Claim 60, wherein at least 95% of the said excipient particles have a geometric diameter in the range of approximately 50 to 100 μm.

62. The method of Claim 42, wherein said first medium comprises an aqueous solution.

63. The method of Claim 42, wherein said first medium comprises an organic solution.

64. The method of Claim 63, wherein said organic solution comprises acetone.

65. The method of Claim 42, wherein said first medium comprises an aqueous- organic solvent mixture.

66. The method of Claim 42, wherein said subliming step comprises continuous extraction under vacuum.

67. A pharmaceutical composition obtained by co-dissolving at least one medicament with at least one crystallization inducing agent in a first medium to form a first solution, spray drying said first solution at a temperature in the range of approximately 35° C or greater, selectively subliming out said crystallization inducing agent, and harvesting the resultant crystalline medicament particles.

68. The pharmaceutical composition of Claim 67, wherein said spray drying temperature is less than approximately 60°C.

69. The pharmaceutical composition of Claim 67, wherein said medicament particles have a porous structure.

70. The pharmaceutical composition of Claim 67, wherein said medicament particles have a geometric diameter less than approximately 10 μm.

71. The pharmaceutical composition of Claim 67, wherein said crystallization inducing agent comprises menthol.

72. The pharmaceutical composition of Claim 67, wherein said co-dissolving step is performed at a temperature in the range of 20°C to 40°C.

73. The pharmaceutical composition of Claim 67, wherein said medicament is selected from the group consisting of an analgesic, anginal preparation, antiallergic, antibiotic, antiinfective, antihistamine, anti-inflammatory, antitussive, bronchodilator, α₄ integrin inhibitor, diuretic, anticholinergic, adenosine 2a agonists, hormones, xanthine, vaccine, therapeutic protein, peptide, and combinations thereof.

74. The pharmaceutical composition of Claim 73, wherein said medicament is selected from the group consisting of codeine, dihydromoφhine, ergotamine, fentanyl, moφhine, diltiazem, cromoglycate, ketotifen, nedocromil; cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines pentamidine; methapyrilene, beclomethasone, fluticasone, flunisolide, budesonide, rofleponide, mometasone, ciclesonide, triamcinolone, noscapine, albuterol, salmeterol, ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, terbutaline, isoetharine, tulobuterol or 4-hydroxy-7-[2-[[2-[[3-(2-phenyiethoxy) propyl]sulfonyl]ethyl]amino]ethyl-2(3H)-benzothiazolone, 2R,3R,4S,5R)-2-[6-Amino-2- (lS-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)- tetrahydro-furan-3,4-diol, (2S)-3-[4-({[44-(aminocarbonyl)-l- piperidinyl]carbonyl}oxy)phenyl]-2-[((2S)-4-methyl-2-{[2-(2-methylphenoxy)acetyl] amino}pentanoyl)amino] propanoic acid, amiloride; ipratropium, tiotropium, atropine, oxitropium, cortisone, hydrocortisone, prednisolone, aminophylline, choline theophyllinate, lysine theophyllinate, theophylhne, insulin or glucagon, and salts, esters, and derivatives and combinations thereof.

75. The pharmaceutical composition of Claim 74, wherein said medicament is selected from the group consisting of fluticasone, fluticasone propionate, 6a, 9α-difluoro- 11 β -hydroxy- 16c.-methyl-3 -oxo- 17 -propionyloxy-androsta- 1 ,4-diene- 17 β-carbothioic acid S-(2-oxo-tetrahydro-furan-3-yl) ester, salmeterol, salmeterol xinafoate, albuterol base and sulfate, and combinations thereof.

76. The pharmaceutical composition of Claim 75, wherein said medicament comprises fluticasone propionate.

77. The pharmaceutical composition of Claim 67, wherein approximately 5% to 10% w/w of said crystallization inducing agent is co-dissolved with said medicament.

78. The pharmaceutical composition of Claim 77, wherein approximately 10% w/w of said crystallization inducing agent is co-dissolved with said medicament.

79. The pharmaceutical composition of Claim 67, wherein said first medium comprises an aqueous solution.

80. The pharmaceutical composition of Claim 67, wherein said first medium comprises an organic solution.

81. The pharmaceutical composition of Claim 80, wherein said organic solution comprises acetone.

82. The pharmaceutical composition of Claim 67, wherein said subliming step comprises continuous extraction under vacuum.

83. The pharmaceutical composition of Claim 67, wherein said pharmaceutical composition includes at least one excipient selected from the group consisting of monosaccharides, disaccarides, polysaccharides, and combinations thereof.

84. The pharmaceutical composition of Claim 83, wherein said excipient is selected from the group consisting of lactose, maltose, sucrose, starches, dextrins, dextrans, glucose, fructose and mannitol.

85. The pharmaceutical composition of Claim 83, wherein said pharmaceutical composition comprises approximately 0.1 to 99.9% w/w of said medicament and 99.9 to 0.1% w/w of said excipient.

86. The pharmaceutical composition of Claim 85, wherein said pharmaceutical composition comprises approximately 1 to 20%> w/w of said medicament and 50 to 99% of said excipient.

87. The pharmaceutical composition of Claim 83, wherein said excipient comprises substantially crystalline excipient particles formed by

(a) co-dissolving said excipient with at least one crystallization inducing agent in a first medium to form a first solution,

(b) spray drying said first solution at a temperature in the range of approximately 35°C to 180°C, (c) selectively subliming out said crystallization inducing agent, and

(d) harvesting the resultant crystalline excipient particles.

88. A pharmaceutical composition obtained by dissolving a first substance with a primary medium to form a dissolved substance medium, adding at least one crystallization inducing agent in a first medium to said dissolved substance medium to form a first solution, spray drying said first solution at a temperature in the range of approximately 35°C to 180°C, selectively removing said crystallization inducing agent, and harvesting the resultant crystalline particles.

89. A method of forming crystalline pharmaceutical particles, comprising:

(a) placing a first substance in a primary medium to form a base substance medium;

(b) adding at least one crystallization inducing agent in a first medium to said base substance medium to form a first solution; (c) spray drying said first solution at a temperature in the range of approximately

35°C to l80°C; (d) selectively subliming out said crystallization inducing agent; and

(e) harvesting the resultant crystalline particles.

90. The method of Claim 89, wherein said primary medium comprises an aqueous solution.

91. The method of Claim 90, wherein said first substance comprises a medicament.

92. The method of Claim 91 , wherein said medicament is soluble in said aqueous solution.

93. The method of Claim 91 , wherein said medicament is insoluble in said aqueous solution.

94. The method of Claim 90, wherein said first substance comprises an excipient.

95. The method of Claim 94, wherein said excipient is soluble in said aqueous solution.

06. The method of Claim 94, wherein said excipient is insoluble in said aqueous solution.

97. The method of Claim 90, wherein said first substance comprises a combination of at least one medicament and at least one excipient.

98. The method of Claim 97, wherein said excipient is soluble in said aqueous solution and said medicament is insoluble in said aqueous solution.

99. The method of Claim 97, wherein said excipient is insoluble in said aqueous solution and said medicament is soluble in said aqueous solution.

100. The method of Claim 97, wherein said excipient and medicament are soluble in said aqueous solution.

101. The method of Claim 97, wherein said excipient and medicament are insoluble in said aqueous solution.

102. The method of Claim 89, wherein said primary medium comprises an organic solution.

103. The method of Claim 102, wherein said first substance comprises a medicament.

104. The method of Claim 103, wherein said medicament is soluble in said organic solution.

105. The method of Claim 103, wherein said medicament is insoluble in said organic solution.

106. The method of Claim 102, wherein said first substance comprises an excipient.

107. The method of Claim 106, wherein said excipient is soluble in said organic solution.

\ 08. The method of Claim 106, wherein said excipient is inso^'l uble in said organic s solution.

109. The method of Claim 102, wherein said first substance comprises a combination of at least one medicament and at least one excipient.

110. The method of Claim 109, wherein said excipient is soluble in said organic solution and said medicament is insoluble in said organic solution.

111. The method of Claim 109, wherein said excipient is insoluble in said organic solution and said medicament is soluble in said organic solution.

112. The method of Claim 109, wherein said excipient and medicament are soluble in said organic solution.

113. The method of Claim 109, wherein said excipient and medicament are insoluble in said organic solution.

114. The method of Claim 89, wherein said primary medium comprises an aqueous-organic solvent solution.

115. The method of Claim 89, wherein said crystalline particles have a geometric diameter in the range of approximately 2 to 5 μm.

116. The method of Claim 89, wherein said crystallization inducing agent comprises menthol.

117. The method of Claim 89, wherein said first medium comprises an aqueous solution.

118. The method of Claim 89, wherein said first medium comprises an organic solution.

119. The method of Claim 118, wherein said organic solution comprises acetone.

120. The method of Claim 89, wherein said first medium comprises an aqueous- organic solvent solution.