WO2003028653A2

WO2003028653A2 - Sustained release pharmaceutical compositions

Info

Publication number: WO2003028653A2
Application number: PCT/US2002/031422
Authority: WO
Inventors: Michael Keith Taylor
Original assignee: Glaxo Group Limited
Priority date: 2001-10-03
Filing date: 2002-10-03
Publication date: 2003-04-10
Also published as: WO2003028653A3; AU2002337803A1

Abstract

A sustained release pharmaceutical composition having a plurality of multi-component pharmaceutical particles having a medicament/excipient matrix, the medicament/excipient fraction including a substantially hydrophilic medicament fraction and a substantially hydrophilic excipient fraction, the pharmaceutical particles being coated with at least one pharmaceutically acceptable coating material wherein the pharmaceutical particles exhibit a substantially linear dissolution profile and a duration of efficacy over at least a 12 hour period.

Description

SUSTAINED RELEASE PHARMACEUTICAL COMPOSITIONS

FIELD OF THE PRESENT INVENTION The present invention relates generally to pharmaceutical compositions. More particularly, the invention relates to improved sustained release pharmaceutical compositions and a process for preparing the same.

BACKGROUND OF THE INVENTION Sustained release pharmaceutical compositions that provide for delivery of a medicament over an extended period of time are well known in the art. Such compositions (or formulations) are typically employed to provide an effective concentration of the medicament to a desired region (e.g., stomach, deep lung) for an appropriate length of time. There are several advantages associated with sustained release pharmaceutical compositions. Among the advantages is the presence of a lower concentration of the medicament in the body for a longer period of time which lowers the incidence of toxicity for medicaments with a narrow therapeutic window, and often improves the overall effect. Further, patient compliance is improved when the dosing regimen is less complex and reduced; a patient is far more likely to take a single daily dose, than take two, three, or even four doses daily. This is particularly true for medicaments that are injected, inhaled or delivered by transmucosal diffusion.

Sustained release formulations have previously been produced by placing a coating material over micronized medicament particles. The coated medicament particles are then employed to provide a desired form of pharmaceutical composition, such as tablets, capsules, caplets and inhalable powder compositions. Illustrative is the coating processes and pharmaceutical compositions disclosed in PCT Pub. Nos. WO 00/28969 and WO 00/74657.

In the noted PCT publications, medicament core particles are coated with particles of coating material which are atomized by pulsed laser ablation, and bind to the core particles forming very thin film of the coating material on the core particles. The disclosed coating material, which is generally less than 1% by mass, comprises a biodegradable or biocompatable polymer (e.g., polylactic acid polymers). The coating materials purportedly delay medicament diffusion and dissolution until the coating material degrades or until the medicament diffuses through the non-degradable coating material. Still other coated particles are found in the art. References also refer to medicament particles being coated with a single layer, or alternating layers, of one or more coating materials, or describe the medicament may be interposed within the coating material, the selected coating depending on the desired release properties or profile. See, for example, U.S. Pat. No. 3,492,397 where the dissolution rate is said to be controlled by adjusting the wax/ethyl cellulose ratio of the applied spray coating; U.S. Pat. No. 4,752,470 where the controlled release characteristics for indomethacin are varied depending on the ratio of ethyl cellulose to hydroxypropyl cellulose in the coating; and U.S. Pat. Nos. 4,205,060 and 3,488,418 where it is indicated that the rate of dissolution of various medicaments can be controlled by varying the thickness of the coating applied to those drugs.

See also U.S. Pat. No. 5,026,559, which discloses a delayed and sustained-release pharmaceutical preparation comprising a multi-walled coated medicament having an inner wall microencapsular enteric coating, such as polymethacrylic acid/acrylic acid copolymer or cellulose acetate phthalate, a solid acid either incorporated in the enteric layer or layered over the enteric layer, and an outer wall microencapsulated control coating, such as polymethacrylic acid ester copolymer or ethyl cellulose. The solid acid purportedly delays medicament release by maintaining the enteric polymer in an impermeable state until the acid diffuses out of the drug or is neutralized. The multi-walled coated drug is admixed with an uncoated drug having immediate therapeutic properties upon dissolution in the stomach.

Sustained release profiles have also been achieved through particles having a matrix of drug and excipient matrix, in the absence of a coating or barrier layer. Examples of such particle matrixes are disclosed in US Patent Nos. 4,818,542, 6,254,854, 5,874,064, 6,136,295, 5,855,913, and 5,895,309, all of which are incorporated herein by reference. Still further references have described microparticles of active medicament which are mixed particles of a hydrophobic material under conditions which cause the hydrophobic material to be fused or affixed to portions of the surface of the active particles delaying the dissolution of the active material. Illustrative is the process disclosed in Published International Patent Application No. WO 02/43702 to Nectura.

There are several drawbacks and disadvantages associated with the Nectura process. A major drawback of the Nectura process is that it would be very difficult to control the amount of the hydrophobic coating material applied to the active particles and, hence, provide particles having a consistent, desired release profile.

The Nectura reference also mentions that the active particles may be suspended with particles of the hydrophobic in a solution of a liquid having a film forming agent dissolved therein, and spray dried. The film forming agent acts to bind the particles of the active and the particles of the hydrophobic material together, and may also act as a further barrier to the active substance. Like the other processes disclosed in the Nectura reference, this approach fails to provide adequate control of the amount of hydrophobic particles affixed to each active particle, which can, and in most instances will, result in particle to particle performance variation.

As will be appreciated by those ordinarily skilled in the art, there are several drawbacks associated with the "controlled release" particles mentioned above and the pharmaceutical formulations formed therefrom. A major drawback is that the initial dissolution rate of the conventional pharmaceutical compositions and, hence, medicament(s) is considerably high (i.e., substantial "burst" at on-set of dissolution), which is, in most instances, likely to cause adverse effects in vivo.

Also, the previously described particles may, in certain cases, be incapable of achieving a sustained release for a prolonged period of time allowing for twice a day, and more preferably, once a day delivery of an active, as compared to that same active in its micronized form (i.e., a micronized particle consisting solely of the active agent delivered to the lungs in formulation with a coarse carrier, such as lactose) that would have to be delivered more than twice a day.

A further drawback is that the disclosed systems are often complex and produce compositions that tend not to be reproducibly manufactured with identical release profiles. Particularly, the coating process may modify the particle characteristics, such as crystalinity and morphology. Further, the above mentioned prior art particles may not always yield a desired medicament release profile. The profile of the particles is dependent on the matrix qualities, generally determined the drug to excipient ratio in the matrix, and the excipient materials used, as well as the particle morphology. All desired parameters in terms of particle size, morphology and medicament release profiles may not be achieved through modification of changing matrix component ratios, or production parameters.

Lastly, the coating technologies mentioned previously may yield wide particle to particle variance in compositional make-up. It would thus be desirable to yield a more controlled manner of manufacture to yield more homogeneously composed particles. It is therefore an objective of the present invention to provide a coated particle matrix which possesses suitable release profiles and morphologic qualities.

It is an object or alternative object of the present invention to provide sustained release pharmaceutical compositions that do not exhibit a high rate of initial dissolution (i.e., burst). It is a further or alternative object of the invention to provide sustained release pharmaceutical compositions that exhibit substantially linear dissolution profiles.

It is a further or alternative object of the invention to provide sustained release pharmaceutical compositions having superior physical and/or chemical stability.

It is a further or alternative object of the invention to provide homogeneously ^l structured particles having more precisely controlled amounts and thickness of the materials making up the particles, on a particle to particle comparative basis.

It is yet a further or alternative object of the invention to provide an improved method of preparing sustained release pharmaceutical compositions having superior medicament delivery and efficacy properties. It is a further or alternative object of the invention to provide a means of delivering sustained release pharmaceutical compositions having substantially linear dissolution profiles to the pulmonary system of a patient.

Tt is a further or alternative object of the present invention to provide a sustained release composition having favorable properties for pulmonary delivery. It is a further or alternative object of the invention to provide a method of coating sustained release pharmaceutical compositions during delivery of the compositions to the pulmonary system of a patient.

It is a further or alternative object of the invention to provide sustained release pharmaceutical compositions and methods for preparing same that substantially reduce or eliminate the aforementioned disadvantages and drawbacks associated with prior art pharmaceutical compositions and processes.

SUMMARY OF THE INVENTION The present invention relates to a composition of matter, a process for making such compositions, a method of using such compositions.

In accordance with the above objects and those that will be mentioned and will become apparent below, the sustained release pharmaceutical composition, in accordance with one embodiment of the invention, comprises a plurality of multi-component pharmaceutical particles having a medicament/excipient matrix, the medicament/excipient matrix comprising a substantially hydrophilic medicament fraction and a substantially hydrophilic excipient fraction, the medicament fraction comprising 1.0% to 50% (w/w) of said medicament/excipient matrix. The pharmaceutical particles are coated with at least one pharmaceutically acceptable coating material, the coating material comprising polylactic acid that is formed from a substantially homogeneous mixture of the polylactic acid and a solvent medium (e.g., acetone), the mixture being in a substantially liquid state with the polylactic acid substantially dissolved therein, wherein the pharmaceutical particles exhibit a substantially linear dissolution profile and a duration of efficacy over at least a 12 hour period. In one embodiment of the invention, the medicament fraction comprises a medicament selected from the group consisting of an analgesic, anginal preparation, antiallergenic, antibiotic, antiinfective, antihistamine, anti- inflammatory, antitussive, bronchodilator, α₄ integrin inhibitor, diuretic, anticholinergic, adenosine 2a agonists, hormones, xanthine, vaccine, therapeutic protein, peptide, and combinations thereof. In a preferred embodiment, the medicament fraction comprises ipratropium bromide. As indicated above, the medicament fraction preferably comprises 1.0% to 50% (w/w) of the medicament/excipient matrix. In a preferred embodiment of the invention, the medicament fraction comprises approximately 1.0% to 10% (w/w) of the medicament/excipient matrix. In the noted embodiment, the excipient fraction comprises 90% to 99% (w/w) of the medicament/excipient matrix and is selected from the group consisting of sugars, amino acids, inorganic salts, and combinations thereof. In a preferred embodiment, the excipient fraction comprises glycine.

In one embodiment of the invention, the coating material comprises approximately 1.0% to 50% (w/w) of each of the pharmaceutical particles. In a further embodiment, the coating material comprises approximately 5% to 30% (w/w) of each of the pharmaceutical particles. In yet a further embodiment, the coating material comprises approximately 12% to 17% (w/w) of each of the pharmaceutical particles.

In an alternative embodiment of the invention, the coating material comprises a pharmaceutically acceptable polymer having a molecular less thaii 160,000 and is selected from the group consisting of, polylactic-coglycolic acid (PLGA), polyglycolide (PGA), dipalmitoylphosphatidyl-choline (DPPC), dipalmitoylphophatidylethanolamine (DPPE), hyaluronic acid, and combinations thereof.

In one embodiment of the invention, the pharmaceutical particles have an aerodynamic diameter in the range of 1 - 10 μm. In a further embodiment, the pharmaceutical particles have an aerodynamic diameter in the range of approximately 2 - 8 μm. In yet a further embodiment, the pharmaceutical particles have an aerodynamic diameter in the range of approximately 0.5 - 3 μm.

The pharmaceutical particles of the invention exhibit a tap density less than 1.0 g/cm³, more preferably, the pharmaceutical particles exhibit a tap density in the range of approximately 0.2 - 0.5 g/cm³. In a preferred embodiment, the pharmaceutical particles exhibit a tap density in the range of approximately 0.2 - 0.5 g/cm³.

The pharmaceutical particles of the invention further exhibit substantially crystalline structures. In one embodiment of the invention, the pharmaceutical particles are also substantially porous. In a further embodiment, the pharmaceutical particles are hollow. In yet an additional embodiment of the invention, the pharmaceutical composition(s) described above, includes at least one pharmaceutically acceptable additive. In one aspect of the noted embodiment, the pharmaceutical composition similarly exhibits a substantially linear dissolution profile. In a further embodiment of the invention, the sustained release pharmaceutical composition includes a plurality of hydrophilic, multi-component particles having a medicament/excipient matrix, the medicament/excipient matrix having an ipratropium bromide fraction and a glycine fraction, the ipratropium bromide fraction comprising 1.0% to 50% (w/w) of the medicament/excipient matrix. The multi-component particles are similarly coated with at least one substantially hydrophobic coating material and exhibit a substantially linear dissolution profile.

In the noted embodiment, the coating material similarly comprises a pharmaceutically acceptable polymer having a molecular less than 160,000 and is selected from the group consisting of polylactic acid (PLA), polylactic-coglycolic acid (PLGA), polyglycolide (PGA), dipalmitoylphosphatidyl-choline (DPPC), dipalmitoylphophatidylethanolamine (DPPE), hyaluronic acid, and combinations thereof. The coating material preferably comprises approximately 1.0% to 50%) (w/w) of each of the pharmaceutical particles. In a preferred embodiment, the coating material comprises polylactic acid (PLA). The pharmaceutical particles similarly exhibit a tap density less than 1.0 g/cm³, more preferably, in the range of approximately 0.2 - 0.5 g/cm³, even more preferably, in the range of approximately 0.2 - 0.5 g/cm³. The pharmaceutical particles also have an aerodynamic diameter in the range of 1 - 10 μm.

The pharmaceutical particles further exhibit substantially crystalline structures. In an additional embodiment, the pharmaceutical particles are also substantially porous. In a further embodiment, the pharmaceutical particles are hollow.

In yet additional embodiments, the pharmaceutical composition includes one or more pharmaceutically acceptable additives that provide beneficial properties to the aerosolibility, dispersability and/or dissolution profile. The process for preparing a sustained release pharmaceutical composition, in accordance with the invention, comprises: (a) providing medicament material; (b) providing excipient material; (c) providing at least one pharmaceutically acceptable coating material; (d) introducing the medicament and excipient materials or particles into a first solution; (e) substantially dissolving the medicament and excipient particles in the first solution to form a core material; (f) spray drying the core material to form multi- component binary particles having a medicament/excipient matrix, the medicament/excipient matrix having a medicament and an excipient fraction; (g) introducing the coating material into a second solution; (h) substantially dissolving the coating material in the second solution to form a coating material solution; (i) introducing the binary particles into the coating material solution; (j) mixing the binary particles in the coating material solution, preferably for at least 30 minutes; and (k) spray coating the binary particles to coat the binary particles with at least one layer of the coating material.

In one embodiment of noted process, the medicament material and excipient material are substantially hydrophilic. The coated binary particles are also porous, substantially crystalline and exhibit a substantially linear dissolution profile. In yet a further embodiment of the invention, a method for the delivery of a pharmaceutical composition of the invention to the pulmonary system of a patient is provided, comprising: (i) providing a pharmaceutical delivery device with a pharmaceutical composition (as described herein) disposed therein (ii) aerosolizing the pharmaceutical composition; (iii) dispersing the aerosolized pharmaceutical composition into a plume; (v) emitting the aerosolized pharmaceutical composition from the delivery device; and (vi) delivering the plume to the pulmonary system of the patient.

In an additional embodiment of the invention, the method for the delivery of a pharmaceutical composition of the invention to the pulmonary system of a patient comprises: (i) providing a pharmaceutical delivery device having a pharmaceutical composition disposed therein, the pharmaceutical composition comprising a plurality of multi-component pharmaceutical particles (as described herein) and at least one coating material; (ii) introducing a propellant flow within the delivery device; (iii) aerosolizing the pharmaceutical composition into the propellant flow whereby the pharmaceutical particles are coated with the coating material, (iv) dispersing the aerosolized pharmaceutical composition from the delivery device; and (v) delivering the aerosolized pharmaceutical composition to the pulmonary system of the patient. The advantages of this invention include the formation and delivery of sustained release pharmaceutical compositions that exhibit one or more of the following attributes, (i) substantially linear, uniform dissolution profiles, (ii) superior stability, (iii) superior medicament delivery and efficacy characteristics and (iv) superior flow and aerosolibility characteristics, as well as alternative or additional advantages apparent from the description and disclosure herein.

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:

FIGURES 1 and 2 are scanning election micrographs of porous pharmaceutical particles according to the invention; FIGURES 3 and 4 are graphs of dissolution profiles for pharmaceutical particles with varying amounts of coating material according to the invention;

FIGURE 5 is an x-ray diffractogram showing the x-ray diffraction profiles of a core particle and pharmaceutical particles having 5 and 30% (w/w) of PLA coating according to the invention; and FIGURE 6 is a dynamic vapor sorption trace of a pharmaceutical composition comprising coated pharmaceutical particles according to the invention, and

FIGURE 7 is a graph of bronchoprotection over time of a pharmaceutical composition comprising coated, multi-component binary particles according to the invention.

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. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only, and is not intended to limit the scope of the invention in any manner. All publications, patents and patent applications cited herein, whether supra or infra, are hereby incorporated 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 coating material" includes a mixture of two or more such coating materials; reference to "a solvent medium" includes mixtures of two or more such solvents, and the like.

Throughout this specification, the terms "core particles," and "core particulate materials" will be used interchangeably, as will the terms "coating material" and "coatings." These interchangeable terms are intended to have the same meanings as used herein.

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. 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.

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

Definitions

By the term "medicament", as used herein, is meant to mean and include any substance ύ.e., compound or composition of matter) which, when administered to an organism (i.e., 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 bioactive agents, as well as biopharmaceuticals (e.g., peptides, hormones, nucleic acids, gene constructs, etc.), including, but not limited to, analgesics, e.g., codeine, dihydromorphine, ergotamine, fentanyl or morphine; 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; antimstamines, e.g., methapyrilene; anti- inflammatories, e.g., beclomethasone (e.g., as the dipropionate ester), fluticasone (e.g., as the propionate ester), flunisolide, budesonide, rofleponide, mometasone (e.g., as the furcate ester), ciclesonide, triamcinolone (e.g., as the acetonide) or 6a, 9 -difluoro- 11 β-hydroxy- 16 -methyl-3-oxo- 17α-propionyloxy-androsta- 1 ,4-diene- l7β-carbothioic acid S-(2-oxo-tetrahydro-furan-3-yl) ester; antitussives, e.g., noscapine; bronchodilators, e.g., albuterol (e.g., as free base or sulphate), salmeterol (e.g., as ^l 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 hydrochlori.de), rimiterol, terbutaline (e.g., as sulphate), isoetharine, tulobuterol or 4-hydroxy-7-[2-[[2-[[3-(2-phenylethoxy) propyl]sulfonyl]ethyl]amino]ethyl-2(3H)-benzothiazolone; adenosine 2a agonists, e.g., 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 (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) acetyljamino} 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 budesonide.

By the term "excipient", as used herein, it is meant to mean substantially inert materials that are nontoxic and do not interact with other components of a composition in a deleterious manner including. The term "excipient" thus includes, but not limited to,

π sugars, amino acids and inorganic salts, such as lactose, mannitol, maltose, dextrose, phenylalanine, leucine, glycine, a calcium salt and/or combinations thereof.

By the term "pharmaceutical composition", as used herein, it is meant to mean a combination of at least one medicament and one or more added components or elements, such as an "excipient."

By the term "coating material", as used herein, it is meant to mean a substantially hydrophobic polymer or phospholipid having a molecular weight less than 160,000, including, but not limited to, polylactic acid (PLA), polylactic-coglycolic acid (PLGA), polyglycolide (PGA), dipalmitoylphosphatidyl-choline (DPPC), dipalmitoylphosphatidylethanolamine (DPPE) and hyaluronic acid.

By the terms "polylactic acid" and "PLA", as used herein, it is meant to mean and include a racemic mixture of D and L enantiomers, including, but not limited to, poly(lactic) acid, poly(D,L-lactide,) poly(D,L-lactic) acid, and the stereo enantiomers, poly-L-lactide, poly(D-lactide), poly(L-lactide), poly-L(-)lactide, poly(D-lactic) acid and poly(L-lactic) acid.

By the term "solvent medium", as used herein, it is meant to mean a substance capable of dispersing one or more other substances, including, but not limited to, H₂O, acetone, methylene chloride, tetrahydrofuran, ethyl acetate, chloroform, hexafluoroisopropanol, ethyl alcohol, and other like solvents. By the term "sustained release", as used herein, it is meant to mean a controlled, modified, delayed or extended delivery of a medicament or phaπnaceutical composition to an organism.

By the term "linear dissolution profile", as used herein, it is meant to mean a near zero order medicament release profile. By the term "propellant", as used herein, it is meant to mean a carrier gas employed to expel a substance (e.g., medicament) in a substantially aerosolized form including, but not limited to air and fluids capable of generating a propulsive force. The propulsive force of the propellant may be generated by the patient's inhalation effort, by mechanical, electrical, or chemical means, or inherent in the rapid expansion of a fluid upon transitioning to gaseous phase. Such fluids include pressurized low boiling point materials, such as chlorofuoroalkanes, e.g., P-11 and P-12, hydrofluoroalkanes, e.g. HFA- 134a and HFA-224, carbon dioxide (CO₂), argon, and nitrogen, which transition into gaseous phase upon exposure to atmospheric pressure, as well as materials that are liquids at room temperature and pressure, and which may be heated beyond their gas transition point and then released. 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 composition to a patient, including, but not limited to, dry powder inhalers, metered dose inhalers, nebulizers, piezoelectric vibrating spray assemblies, and any other suitable delivery system for delivering pharmaceutical compositions through the nose or mouth. Such inhalers include 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 Rotodisc™ 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 Boehringer Engelheim and the Airmax™ device by Baker-Norton; and the Dura and

Inhaled Therapeutic active delivery systems, which are incorporated by reference herein.

The term "pharmaceutical delivery device" further includes those systems and apparatus disclosed in U.S. Pat. Nos. 3,591,090; 4,333,450; 4,512,341; 4,566,452; 4,657,007; 4,649,911; 5,027,809; 5,512,341; 5,186,166 and 5,653,233, which are also incorporated by reference herein.

As will be appreciated by one having ordinary skill in the art, the present invention substantially reduces or eliminates the disadvantages and drawbacks associated with conventional sustained release pharmaceutical compositions and methods for producing same. As discussed in detail herein, the pharmaceutical compositions employing the unique pharmaceutical particles of the invention can be readily employed to provide controlled systemic or local medicament delivery to the pulmonary system via aerosolization. The pharmaceutical compositions can also be employed in capsules and compressed into tablets.

The pharmaceutical compositions, in accordance with one embodiment of the invention, comprise a plurality of unique pharmaceutical particles; each of the pharmaceutical particles comprising a co-precipitated, multi-component core material (i.e., "binary particle") having a pharmaceutically acceptable coating material disposed thereon. In alternative embodiments of the invention, the coated binary particles are substantially crystalline and porous. In an alternative embodiment, the coated binary particles are also hollow. A key advantage of the unique pharmaceutical particles of the invention is that they exhibit a substantially linear dissolution profile and, hence, do not exhibit a high rate of initial dissolution (i.e., burst). The pharmaceutical particles are thus capable of extending or lengthening the duration of bronchoeffectiveness of the medicament fraction (i.e., medicament), as compared to the medicament fraction alone. As discussed in detail herein, the multi-component binary particles comprise a medicament fraction and an excipient fraction, which, in accordance with the invention, form a medicament/excipient matrix during the initial dissolution phase. In additional embodiments of the invention, the pharmaceutical compositions include one or more pharmaceutically acceptable additives, such as a surfactant or a wetting agent (e.g., gum acacia), which provide beneficial properties to the aerosolibility, dispersability or dissolution ("therapeutic release") profile of the pharmaceutical particles and or pharmaceutical compositions formed therefrom.

According to the invention, the medicament fraction is preferably water soluble (i.e., hydrophilic) and comprises at least one of the following: an analgesic, anginal preparation, antiallergenic, antibiotic, antiinfective, antihistamine, anti- inflammatory, antirussive, bronchodilator, α₄ integrin inhibitor, diuretic, anticholinergic, adenosine 2a agonists, hormones, xanthine, vaccine, therapeutic protein, peptide, and combinations thereof. In a preferred embodiment of the invention, the medicament fraction comprises ipratropium bromide. According to the invention, the medicament fraction comprises approximately

1.0% to 50%, preferably, approximately 1% to 10% (w/w) of the medicament/excipient matrix (i.e., binary particle). In a preferred embodiment of the invention, the medicament fraction comprises approximately 3% to 5% (w/w) of the binary particle composition. The excipient fraction of the medicament/excipient matrix, which is similarly preferably water soluble (i.e., hydrophilic), comprises at least one of the following: a sugar, amino acid or inorganic salt. More preferably, the excipient fraction comprises lactose, mannitol, maltose, dextrose, phenylalanine, leucine, glycine, a calcium salt and/or combinations thereof. Most preferably, the excipient fraction comprises glycine.

According to the invention, the excipient fraction comprises approximately 90% to 99%o (w/w) of the medicament/excipient matrix. In a preferred embodiment of the invention, the excipient fraction comprises approximately 95%) to 97%> (w/w) of the binary particle composition.

According to the invention, the medicament fraction can also comprise a substantially hydrophobic medicament, such as a fluticasone. Similarly, the excipient fraction can comprise a substantially hydrophobic excipient. The coating material, in accordance with the invention, preferably comprises a substantially hydrophobic polymer or phospholipid having a molecular weight less than 160,000, including, but not limited to, polylactic acid (PLA), polylactic-coglycolic acid (PLGA), polyglycolide (PGA), dipalmitoylphosphatidyl-choline (DPPC), dipalmitoylphosphatidylethanolamine (DPPE) and hyaluronic acid. In a preferred embodiment of the invention, the coating material comprises polylactic acid (PLA).

Preparation of the pharmaceutical particles of the invention will now be discussed in detail. In one embodiment of the invention, the medicament fraction, which comprises core particles thereof, and the excipient fraction, which similarly comprises core particles thereof, are placed in a first solution or medium. In this embodiment, the first solution comprises H₂O.

The first solution and core medicament and excipient particles are then heated to a temperature of approximately 90° C and slowly stirred (e.g., 30 rpm) until the core particles are substantially dissolved. More preferably, the core particles are heated and stirred until they are completely dissolved. In a preferred embodiment, the core particles (i.e., solids) comprise approximately

1% to 10% (w/v) of the first solution. More preferably, the core particles comprise approximately 4% to 6% (w/v) of the first solution.

The core material is then preferably subjected to spray drying. In accordance with the invention, the core material formed thereby comprises binary particles having a medicament/excipient matrix. After the spray drying step, the coating material (e.g., PLA) is placed in a second solution, heated to a temperature of approximately 90° C and slowly stirred until the PLA is substantially dissolved, more preferably, completely dissolved. According to the invention, the second solution includes at least one of the aforementioned solvent mediums. In a preferred embodiment of the invention, the solvent medium substantially comprises acetone.

Preferably, the coating material comprises approximately 0.02% to 1.25% (w/v) of the second solution. More preferably, the coating material comprises approximately 0.1% to 0.6% (w/v) of the second solution. After the coating material reaches the desired dissolved state, the binary particles are introduced into the second solution. The second solution (with the binary particles therein) is then heated to a temperature of approximately 90° C and slowly stirred for a period no less than 30 min. to insure adequate coating on each of the binary particles.

Preferably, the binary particles comprise approximately 1.0% to 5.0% (w/v) of the second solution. More preferably, the binary particles comprise approximately 2.0% to

3.0% (w/v) of the second solution.

The binary particles are then subjected to a conventional spray coating process or step to produce the unique pharmaceutical particles (i.e., substantially continuously coated binary particles) of the invention. As will be appreciated by one having ordinary skill in the art, various additional conventional coating processes, such as solvent extraction, spray drying and vapor deposition can also be employed to produce the coated pharmaceutical particles of the invention.

According to the invention, the multi-component binary particles can also be subjected to multiple spray coating steps to provide multiple layers of the coating material. In additional envisioned embodiments of the invention, the layers may comprise different coating materials to provide a desired dissolution profile.

In an alternative embodiment of the invention, discussed in detail below, the binary particles are coated during expulsion of the propellant composition (including at least one coating material) by a pharmaceutical delivery device. Preferably, the coating material comprises at least 1%> (w/w), preferably approximately 1% to 50% (w/w) of the pharmaceutical particle. More preferably, the coating material comprises at least approximately 15% (w/w) of the pharmaceutical particle. Most preferably, the coating material comprises approximately 15% to 50%)

(w/w) of the pharmaceutical particle.

The coated multi-component binary particles produced by the process described above preferably exhibit porous structures (designated 5 in Fig. 1 (5% PLA coating) and

Fig. 2 (30% PLA coating). In an alternative embodiment, the coated particles are also hollow.

According to the invention, the coated multi-component binary particles exhibit sustained release characteristics or attributes. More preferably, the coated particles and, hence, pharmaceutical compositions made therefrom, exhibit a substantially linear dissolution profile. Even more preferably, the coated particles exhibit a lengthening of the duration of bronchoeffectiveness of the medicament compared to the delivery of the medicament alone.

In a further embodiment of the invention, the first solution comprises a mixture of H₂O and at least one solvent medium. In a preferred embodiment of the invention, the solvent medium comprises acetone.

According to the invention, the solvent medium can comprise approximately 1% to

100% (v/v) of the first solution. More preferably, the solvent medium comprises approximately 45% to 55% (v/v) of the first solution. Applicants have found that producing the hydrophilic core materials from a first solution which includes both water and solvent medium, particularly a non-aqueous medium, such as acetone, pre-disposes the binary particles to pore formation and the unique pharmaceutical particle morphology upon subsequent exposure to the solvent medium used in the second solution and subsequent spray drying process. Although the exact mechanism for this is not clear, it is believed that the formation of pores may be from dehydration or from extraction of residual solvent medium remaining in the particles from the first solution during the second spray drying process.

In the instances where the core materials are solid walled hollow particles, the use of a water/solvent medium containing first solution may, in some instances, yield porous or pitted binary particles as a result of the coating process employed in producing the pharmaceutical particles. In other instances, exposure of the medicament and excipient materials particles to the first solution for an extended period of time directly produces "porous" pharmaceutical particles. The degree of porosity has been found to be directly related to the percentage of the solvent media in the first solution (i.e., fconc. = fporosity). As indicated, the coating process and materials of the invention modify the sustained release profile and characteristics of the core material (i.e., binary particles). Applicants have, however, surprisingly found that the coating process and materials of the invention do not adversely decrease the degree of porosity of the resultant pharmaceutical particles (i.e., porosity of pharmaceutical particles is substantially the same as the binary particles). Indeed, it has been found that the coating process, in most instances, enhances the degree of porosity of the pharmaceutical particles.

As will be appreciated by one having ordinary skill in the art, the porosity provides additional, significant advantages. For example, it is well known that porous particles with a relatively large diameter are particularly suitable for inhalation therapy. Due to their large diameter, porous particles also exhibit better flow characteristics.

According to the invention, the core medicament and excipient particles that are employed to produce the core material of the invention preferably have an aerodynamic diameter less than 10 μm. Preferably, the core particles have an aerodynamic diameter in the range of 0.5 - 10 μm. More preferably, the core particles have an aerodynamic diameter in the range of approximately 1 - 6 μm.

In a further embodiment of the invention, the core particles also have geometric diameters that are substantially equal to the noted aerodynamic diameters (e.g., aerodynamic and geometric diameters less than 10 μm).

The core medicament and excipient particles can be produced in any appropriate fashion, into appropriately sized particles by any suitable method of particle formation.

The suitable methods include, but are not limited to, micronization, milling, spray drying and solvent/anti-solvent crystallization. In a preferred embodiment of the invention, micronization or milling is employed to produce the core particles of the invention.

The coated pharmaceutical particles formed in accordance with the invention preferably have an aerodynamic diameter in the range of 1 - 10 μm. For local applications, the coated particles preferably have an aerodynamic diameter in the range of approximately 2 - 8 μm. For systemic delivery, the coated particles preferably have an aerodynamic diameter in the range of approximately 0.5 - 3 μm.

In a preferred embodiment of the invention, the size and shape of the coated pharmaceutical particles formed in accordance with the invention are substantially equal to the size and shape of the core particles employed to produce the pharmaceutical particles.

The properties of the core particles are thus virtually unchanged.

As indicated, the coated pharmaceutical particles are also "low density". By the term "low density", as used herein, it is meant to mean a particle having a tap density less than 1.0 g/cm³. Accordingly, in one embodiment of the invention, the pharmaceutical particles have a tap density less than 0.8 g/cm³. In an alternative embodiment, the pharmaceutical particles have a tap density in the range of approximately 0.2 - 0.5 g/cm³.

As indicated, the pharmaceutical particles produced in accordance with the invention are also substantially crystalline, as evidenced by the x-ray diffractogram shown in Fig. 5. As will be appreciated by one having ordinary skill in the art, the noted crystallinity is generally indicative of good physical and chemical stability.

The selection of core medicament and excipient particle size, coating material(s) and percentage (i.e., thickness) of the coating material will, of course, vary depending upon the particular pharmaceutical composition (i.e., application). As will be appreciated by one having ordinary skill in the art, such parameters can be selected and adjusted to prepare coated pharmaceutical particles having particular physical or pharmaceutical properties. The choice of the noted parameters will, in many instances, depend upon the particular core material (i.e., binary particle) to be coated and/or the particular coating material to be employed. The preparation of the core material (i.e., binary ρarticle(s)) can also be varied depending upon the particular thickness of the coating material to be applied. In some instances, it may also be necessary to reduce the core material to a desired uniform particle size or consistency prior to, or following, the application of the coating material. The core particles and/or the coated pharmaceutical particles can also be subjected to other conventional processes, such as sieving, to further improve the uniformity of the core particles or coated pharmaceutical particles. As will be appreciated by one having ordinary skill in the art, the pharmaceutical compositions of the invention can be conveniently filled into a bulk storage container, such as a multi-dose reservoir, or into unit dose containers such as capsules, cartridges or blister packs, which may be used with an appropriate pharmaceutical delivery device. The noted devices and aforementioned pharmaceutical delivery devices, which contain a pharmaceutical composition of the invention, are deemed novel and, hence, form a further aspect of the invention.

The pharmaceutical compositions of the invention are particularly suitable for use with multi-dose or reservoir-type dry powder inhaler devices. The lower limit of powder delivery, which may be accurately metered from a multi-dose reservoir-type device, is typically in the range of 100 to 200 micrograms. The pharmaceutical compositions of the present invention are therefore particularly advantageous for highly potent and, hence, low dose medicaments that require a high ratio of excipient for use in a multi-dose reservoir- type device. 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. As will be appreciated by one having ordinary skill in the art, the precise dose administered will depend on the age and condition of the patient, the particular medicament employed and the frequency of administration. Accordingly, in one embodiment of the invention, the invention includes the delivery of a pharmaceutical composition of the invention to the pulmonary system of a patient comprising: (i) providing a pharmaceutical delivery device with a pharmaceutical composition (as described herein) disposed therein (ii) introducing or inducing a propellant flow within said delivery device; (iii) aerosolizing the pharmaceutical composition in the propellant flow; (iv) dispersing the aerosolized pharmaceutical composition into a plume;

(v) emitting the aerosolized pharmaceutical composition from the delivery device; and (vi) delivering the plume to the pulmonary system of the patient. in an alternative embodiment of the method of the present invention, the delivery device further comprises a source of aerosolization energy that is independent of patient inhalation effort. The noted method further includes the step of releasing this aerosolization energy to create a propellant that aerosolizes the pharmaceutical composition.

In a preferred embodiment of the invention, at least 40% of the pharmaceutical composition is emitted from the delivery device. In a further embodiment of the invention, the fine particle fraction of the emitted dose is at least 40%.

In the methodology described above, the pharmaceutical composition preferably primarily comprises a plurality of "coated" pharmaceutical particles formed as hereinbefore described. In a further embodiment of the delivery method of the invention, the pharmaceutical composition comprises two distinct components; a plurality of core binary particles (i.e., pharmaceutical particles) and at least one of the aforementioned coating materials, which are disposed in the delivery device.

The noted embodiment of the delivery method thus comprises: (i) providing a pharmaceutical delivery device having a pharmaceutical composition disposed therein, the pharmaceutical composition comprising a plurality of multi-component pharmaceutical particles and at least one coating material; (ii) introducing a flow of propellant within said delivery device; (iii) aerosolizing the pharmaceutical composition into the propellant flow whereby the pharmaceutical particles are coated with the coating material; (iv) dispersing the pharmaceutical composition from the delivery device; and (v) delivering the pharmaceutical composition to the pulmonary system of the patient. According to the invention, the noted aerosolization and dispersion of the pharmaceutical composition can also occur substantially simultaneously.

In the noted delivery method embodiment, the coating material is preferably solubilized in the propellant or a suitable solution thereof. The pharmaceutical particles (preferably, not solubilized) are disposed therein.

EXAMPLES The example that is set forth herein is for illustrative purposes only and is not meant to limit the scope of the invention(s) in any way.

Example 1 20 gm of core ipratropium bromide (IPB) and glycine particles were placed in 400 ml of a 50:50 solution of H₂0 and acetone. The geometric diameter of the core particles was approx. 3 μm. The weight percent of the respective fractions was 4% (w/w) ipratropium bromide and 96%> (w/w) glycine.

The core particles and H₂0/acetone solution were mixed until the core particles were completely dissolved. The core material (i.e., binary particles) were then spray dried under the following conditions:

Atomization pressure: 3 bar Inlet temperature: ~ 100°C

Atomization nozzle: 7 mm Outlet temperature: ~ 47- 50°C

Solution pump rate: 15 ml/min Entrainment air flow: ~ 20 CFM

The core material yielded by the noted spray drying process was approximately 58%».

Polylactic acid (PLA) was then placed in an acetone solution in varying amounts to provide the following % PLA dissolutions: 1%, 5%, 10%, 15%, 30% and 50%. Referring to Table I, two groups of samples were prepared. The first group, comprising samples Al - Fl, were subjected to a 15 min. dissolution period. The second group, comprising samples A2 - F2, were subjected to a 2 hour dissolution period.

TABLE I

The core materials (i.e., samples Al - Fl, A2 - F2) were then spray coated under the following conditions: Atomization pressure: 3 bar Inlet temperature: ~ 80°C Atomization nozzle: 7 mm Outlet temperature: ~ 54 - 56°C Solution pump rate: 15 ml/min.

Referring now to Table II, there is shown the dissolution data for samples prepared with 5%, 15%, 30%, and 50% PLA dissolutions.

TABLE II

Dissolution Profiles

Referring now to Figs. 3 and 4, there shown the dissolution profiles for each of the samples (i.e., sustained release pharmaceutical compositions) identified in Table I. Referring first to Fig. 3, it can be seen that dissolution of the PLA in the range of 15%> to 50% (for 15 min.) produced substantially linear and uniform dissolution profiles, and a modulated release rate as compared to IPB alone (i.e., neat IPB control). Dissolution less than 15% produced dissolution profiles with a high rate of dissolution at the on-set of dissolution (i.e., a burst), which, as discussed above, is similar to the profiles exhibited by prior art coated particles.

Referring to Fig. 4, a two (2) hour dissolution of the PLA similarly resulted in substantially linear and uniform dissolution profiles at 15% to 50%> PLA dissolution. As illustrated in Fig. 4, the total amount of drug (i.e., IPB) released was also greater than the samples subjected to the 15 min. dissolution period.

Crystallinity A core binary particle and core particles having 5%> and 30% (w/w) PLA coatings were subjected to x-ray diffraction. Referring to Fig. 5, the x-ray diffractogram reflects that the core particle (designated CP) and the particles having 5% and 30%> (w/w) PLA coatings, designated 5PLA and 30PLA, respectively, exhibited crystalline structures. This demonstrates that the spray coating process utilized to generate the coated particles did not alter the desired crystalline structure of the core particle.

Stability

Core binary particles having a 30%o (w/w) coating of PLA were also exposed to 2 cycles of elevated temperature (~ 40°C) and humidity (75% RH) for approximately 20 hours to assess the stability of the coated pharmaceutical particles. Referring to Fig. 6, there is shown a dynamic vapor solution trace for the coated particles (designated 30PLA), which reflects a negligible weight change during the first cycle and no weight change during the second cycle. The noted data thus indicates that the coated pharmaceutical particles and, hence, sustained release pharmaceutical compositions produced therefrom are very stable under adverse conditions.

Duration of Effect

Buxco Whole Body Plethysmography airway resistance measurement, as described in Chong, et al., Measurement ofBronchoconstriction Using Whole-body Plethysmograph: Comparison of Freely Moving Versus Restrained Guinea Pigs, J. Phcol.Tox. Methods 39, pp. 163-168, (1998), was used to determine duration of effect of the coated core particles, as compared to negative and positive controls. All formulations were presented in a micronized lactose blend.

The coated core particles comprised multi-component core particles having a medicament/excipient matrix, comprising 96% (w/w) glycine, 4% (w/w) ipratroprium bromide with a coating of 15%> (w/w total particle) PLA disposed thereon

(15%PLA/IPB/glycine). 20 mg of the 15%PLA/IPB/glycine particles were formulated in a blend that included 16g coarse lactose carrier and 4g micronized glycine.

The positive control comprised multi-component core particles having an uncoated matrix comprising 96% (w/w) glycine and 4% (w/w) ipratroprium bromide. 4mg of the IPB/glycine particles were formulated in a blend that included 16g coarse lactose and 4g micronized glycine. The negative control (i.e., placebo formulation) comprised a formulation of 20% micronized glycine (uncoated). 4g of the glycine particles were formulated in a blend that included 16g coarse lactose carrier.

The 15%PLA/TPB/glycine particles were administered in a coarse lactose/micronized glycine blend, and subsequently challenged at 2, 6, 10, 16 and 24 hours with a bronchoconstricting agent, i.e., methacholine. Doses for guinea pig studies were based on weight adjustments and human dosage regimens, i.e., 1 microgram doses. Dosing for the Buxco whole body plethysmography study was based on adjustments to a 1 microgram IPB dose depending on the dissolution rate of the engineered particles. The dissolution rates of the 15%PLA/IPB/grycine particles were 20% compared to neat IPB. Based on these results, the dosages of the noted 15%PLA/IPB/glycine particles were increased five-fold to insure equivalent doses were available.

Referring now to Fig. 7, there is shown a graph that demonstrates that the 15%PLA/IPB/glycine particles afford, statistically, significantly more bronchoprotection as compared to the negative and positive controls at the 10, 16 and 24 hour timepoints.

Indeed, the noted data indicates that the duration of effect for the 15%PLA/IPB/glycine particles has been extended from 6 hours (IPB/glycine particles) to 24 hours in this animal model of bronchoconstriction. The coated core particles of the invention thus provide an extended duration of effect (or efficacy) as compared to the medicament (i.e., IPB) alone.

SUMMARY

From the foregoing description, one of ordinary skill in the art can easily ascertain that the present invention provides a cost efficient means of forming sustained release pharmaceutical compositions that exhibit (i) substantially linear, uniform dissolution profiles and do not exhibit a "burst" at on-set of dissolution, (ii) superior stability, (iii) superior medicament delivery and efficacy properties and (iv) excellent flow and aerosolibility characteristics.

Throughout the specification and 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 pharmaceutical composition, comprising: a plurality of multi-component pharmaceutical particles having a medicament/excipient matrix, said medicament/excipient matrix comprising a substantially hydrophilic medicament fraction and a substantially hydrophilic excipient fraction, said medicament fraction comprising 1.0% to 50% (w/w) of said medicament/excipient matrix, said pharmaceutical particles having at least one pharmaceutically acceptable coating material disposed on the outer surface thereof, said coating material comprising polylactic acid, said polylactic acid being formed from a substantially homogeneous mixture of said polylactic acid and a solvent medium, said polylactic acid and solvent mixture being in a substantially liquid state with said polylactic acid substantially dissolved therein, wherein said pharmaceutical particles exhibit a substantially linear dissolution profile and a duration of efficacy over at least a 12 hour period.

2. The pharmaceutical composition of Claim 1, wherein said medicament fraction comprises a medicament selected from the group consisting of an analgesic, anginal preparation, antiallergenic, antibiotic, antiinfective, antihistamine, anti- inflammatory, antitussive, bronchodilator, α₄ integrin inhibitor, diuretic, anticholinergic, adenosine 2a agonists, hormones, xanthine, vaccine, therapeutic protein, peptide, and combinations thereof.

3. The pharmaceutical composition of Claim 2, wherein said medicament fraction comprises ipratropium bromide.

4. The pharmaceutical composition of Claim 1 , wherein said medicament fraction comprises approximately 1.0% to 10% (w/w) of said medicament/excipient matrix.

5. The pharmaceutical composition of Claim 1, wherein said excipient fraction comprises an excipient selected from the group consisting of sugars, amino acids, inorganic salts, and combinations thereof.

6. The pharmaceutical composition of Claim 5, wherein said excipient fraction comprises glycine.

7. The pharmaceutical composition of Claim 1, wherein said excipient fraction comprises 90% to 99% (w/w) of said medicament/excipient matrix.

8. The pharmaceutical composition of Claim 1, wherein said coating material is substantially hydrophobic.

9. The pharmaceutical composition of Claim 1, wherein said coating material has a molecular weight less than 160,000.

10. The pharmaceutical composition of Claim 1 , wherein said coating material comprises a polymer selected from the group consisting of polylactic-coglycolic acid

(PLGA), polyglycolide (PGA), dipalmitoylphosphatidyl-choline (DPPC), dipalmitoylphophatidylethanolamine (DPPE), hyaluronic acid, and combinations thereof.

11. The pharmaceutical composition of Claim 1, wherein said coating material comprises approximately 1.0% to 50% (w/w) of each of said pharmaceutical particles.

12. The pharmaceutical composition of Claim 11 , wherein said coating material comprises approximately 5% to 30% (w/w) of each of said phaπnaceutical particles.

13. The pharmaceutical composition of Claim 11 , wherein said coating material comprises approximately 12% to 17% (w/w) of each of said particles.

14. The pharmaceutical composition of Claim 1, wherein said solvent medium comprises acetone.

15. The pharmaceutical composition of Claim 1 , wherein said pharmaceutical particles have an aerodynamic diameter in the range of 1 - 10 μm.

16. The pharmaceutical composition of Claim 15, wherein said pharmaceutical particles have an aerodynamic diameter in the range of approximately 2 - 8 μm.

17. The pharmaceutical composition of Claim 15, wherein said pharmaceutical particles have an aerodynamic diameter in the range of approximately 0.5 — 3 μm.

18. The pharmaceutical composition of Claim 1 , wherein said pharmaceutical particles have a tap density less than 1.0 g/cm³.

19. The pharmaceutical composition of Claim 18, wherein said pharmaceutical particles have tap density less than 0.8 g/cm³.

20. The pharmaceutical composition of Claim 18, wherein said pharmaceutical particles have a tap density in the range of approximately 0.2 - 0.5 g/cm³.

21. The pharmaceutical composition of Claim 1 , wherein said pharmaceutical particles are substantially crystalline.

22. The pharmaceutical composition of Claim 1, wherein said pharmaceutical particles are substantially porous.

23. The pharmaceutical composition of Claim 1 , wherein said pharmaceutical particles are hollow.

24. The pharmaceutical composition of Claim 1, wherein said pharmaceutical composition includes at least one pharmaceutically acceptable additive.

25. The pharmaceutical composition of Claim 1, wherein said pharmaceutical composition exhibits a substantially linear dissolution profile.

26. A pharmaceutical composition, comprising: a plurality of pharmaceutical particles, said pharmaceutical particles comprising substantially hydrophilic, multi-component particles having a medicament/excipient matrix, said medicament/excipient matrix including an ipratropium bromide fraction and a glycine fraction, said ipratropium bromide fraction comprising 1.0% to 50% (w/w) of said medicament/excipient matrix, said multi-component particles being coated with at least one substantially hydrophobic coating material, wherein said multi-component particles exhibit a substantially linear dissolution profile.

27. The phannaceutical composition of Claim 26, wherein said pharmaceutical particles are substantially porous.

28. The pharmaceutical composition of Claim 27, wherein said pharmaceutical particles have a tap density less than 1.0 g/cm³.

29. The pharmaceutical composition of Claim 28, wherein said pharmaceutical particles have tap density less than 0.8 g/cm³.

30. The pharmaceutical composition of Claim 28, wherein said pharmaceutical particles have a tap density in the range of approximately 0.2 - 0.5 g/cm³.

31. The pharmaceutical composition of Claim 26, wherein said pharmaceutical particles are hollow.

32. The phaπnaceutical composition of Claim 26, wherein said coating material comprises a pharmaceutically acceptable polymer having a molecular weight less than 160,000.

33. The pharmaceutical composition of Claim 32, wherein said coating material comprises a polymer selected from the group consisting of polylactic acid (PLA), polylactic-coglycolic acid (PLGA), polyglycolide (PGA), dipalmitoylphosphatidyl-choline (DPPC), dipalmitoylphophatidylethanolamine (DPPE), hyaluronic acid, and combinations thereof.

34. The pharmaceutical composition of Claim 33, wherein said coating material comprises polylactic acid (PLA).

35. The pharmaceutical composition of Claim 26, wherein said coating material comprises approximately 1.0% to 50% (w/w) of each of said pharmaceutical particles.

36. The pharmaceutical composition of Claim 26, wherein said pharmaceutical particles have an aerodynamic diameter in the range of 1 - 10 μm.

37. The pharmaceutical composition of Claim 26, wherein said pharmaceutical particles are substantially crystalline.

38. The pharmaceutical composition of Claim 26, wherein said pharmaceutical composition includes at least one pharmaceutically acceptable additive.

39. The pharmaceutical composition of Claim 26, wherein said pharmaceutical composition exhibits a substantially linear dissolution profile.