USRE47526E1 - Aerosolization apparatus with air inlet shield - Google Patents

Abstract

An aerosolization apparatus comprises a housing defining a chamber having a plurality of air inlets. The chamber contains an aerosolizable pharmaceutical formulation or is sized to receive a receptacle which contains an aerosolizable pharmaceutical formulation. A shield covers at least one of the air inlets or a portion of at least one of the air inlets. The shield prevents blockage of the air inlet by a user grasping the apparatus and inadvertently covering the air inlet. An end section is associated with the housing. The end section is sized and shaped to be received in a user's mouth or nose so that the user may inhale through the end section to inhale aerosolized pharmaceutical formulation that has exited the receptacle.

Description

This is a continuation of application Ser. No. 10/822,850 filed on Apr. 9, 2004, which claims the benefit of U.S. Provisional Application No. 60/461,679 filed Apr. 9, 2003, the entire disclosures of which are hereby incorporated by reference.

This application claims the benefit U.S. Provisional Patent Application Ser. No. 60/461,679 filed on Apr. 9, 2003, which is incorporated herein by reference in its entirety.

BACKGROUND

The need for effective therapeutic treatment of patients has resulted in the development of a variety of techniques for delivering a pharmaceutical formulation to a patient. One traditional technique involves the oral delivery of a pharmaceutical formulation in the form of a pill, capsule, or the like. Inhaleable drug delivery, where an aerosolized pharmaceutical formulation is orally or nasally inhaled by a patient to deliver the formulation to the patient's respiratory tract, has also proven to be an effective manner of delivery. In one inhalation technique, a pharmaceutical formulation is delivered deep within a patient's lungs where it may be absorbed into the blood stream. In another inhalation technique, a pharmaceutical formulation is delivered locally to a particular site, such as an infected lung. Many types of inhalation devices exist including devices that aerosolize a dry powder pharmaceutical formulation.

One type of inhalation device aerosolizes a pharmaceutical formulation that is stored in a capsule. For example, a dose or a portion of a dose of a dry powder pharmaceutical formulation may be stored in a capsule, and the capsule may be inserted into an aerosolization device which is capable of aerosolizing the pharmaceutical formulation. The aerosolization may be accomplished by causing the capsule to move within a chamber, for example by flowing air through the chamber using a user's inhalation pressure to generate the airflow. As the capsule moves within the chamber, the pharmaceutical formulation exits the capsule though one or more openings in the capsule, and the pharmaceutical formulation is entrained by the flowing air in an aerosolized form. The aerosolized pharmaceutical formulation may then be inhaled by the user, and a dose or portion of a dose of the aerosolized pharmaceutical formulation may be delivered to the user's respiratory tract.

The size and quality of the dose delivered to the user is dependent on the amount and condition of aerosolizable pharmaceutical formulation that exits the capsule. However, in conventional aerosolization devices, the amount and condition of the aerosolizable pharmaceutical formulation may vary from use to use and/or from user to user. For example, sometimes it is difficult to cause large amounts of the pharmaceutical formulation to exit the capsule when a user is unable to generate a high flow rate of air through the device. The inefficient release of pharmaceutical formulation can be costly and can result in the necessity for numerous operations of the device in order to achieve a desire dosage. In some circumstances, the pharmaceutical formulation exits the capsule in agglomerated form, the agglomerations being undesirably large for inhalation therapy.

Therefore, it is desirable to be able to aerosolize a pharmaceutical formulation in a consistent manner. It is further desirable to be able to aerosolize a pharmaceutical formulation in a manner that extracts an increased amount of the pharmaceutical formulation from a receptacle. It is also desirable to be able to aerosolize a pharmaceutical formulation in a more deagglomerated form.

SUMMARY

The present invention satisfies these needs. In one aspect of the invention, an aerosolization apparatus comprises a chamber that receives a receptacle, the chamber having a plurality of air inlets wherein at least one, but preferably not all, of the air inlets is shielded by a shielding member.

In another aspect of the invention, a handheld aerosolization apparatus comprises a housing defining a chamber having a plurality of air inlets, the chamber being sized to receive a receptacle which contains an aerosolizable pharmaceutical formulation; a shield which covers at least one but not all of the air inlets, whereby the shield prevents blockage of the at least one air inlet by a user grasping the apparatus; and an end section associated with the housing, the end section sized and shaped to be received in a user's mouth or nose so that the user may inhale through the end section to inhale aerosolized pharmaceutical formulation that has exited the receptacle.

In another aspect of the invention, a handheld aerosolization apparatus comprises a housing defining a chamber having a plurality of air inlets, the chamber being sized to receive a receptacle which contains an aerosolizable pharmaceutical formulation; a shield which covers a portion of but not all of at least one of the air inlets; and an end section associated with the housing, the end section sized and shaped to be received in a user's mouth or nose so that the user may inhale through the end section to inhale aerosolized pharmaceutical formulation that has exited the receptacle.

In another aspect of the invention, a handheld aerosolization apparatus comprises a housing defining a chamber having one or more air inlets, the chamber being sized to receive a receptacle which contains an aerosolizable pharmaceutical formulation; a shield extending around only a portion of transverse circumference of the housing, the shield covering at least one air inlets, whereby the shield prevents blockage of the at least one air inlet by a user grasping the apparatus; and an end section associated with the housing, the end section sized and shaped to be received in a user's mouth or nose so that the user may inhale through the end section to inhale aerosolized pharmaceutical formulation that has exited the receptacle.

In another aspect of the invention, a method of aerosolizing a pharmaceutical formulation comprises providing an aerosolizable pharmaceutical formulation in a chamber, the chamber having a plurality of air inlets; shielding at least one but not all of the air inlets from being blocked by a user grasping the chamber; aerosolizing the pharmaceutical formulation by flowing air through the chamber; and administering the aerosolized pharmaceutical formulation to the respiratory tract of a user during the user's inhalation.

In another aspect of the invention, a method of aerosolizing a pharmaceutical formulation comprises providing an aerosolizable pharmaceutical formulation in a chamber, the chamber having one or more air inlets; shielding only a portion of at least one of the air inlets from being blocked by a user grasping the chamber; aerosolizing the pharmaceutical formulation by flowing air through the chamber; and administering the aerosolized pharmaceutical formulation to the respiratory tract of a user during the user's inhalation.

DRAWINGS

These features, aspects, and advantages of the present invention will become better understood with regard to the following description, appended claims, and accompanying drawings which illustrate exemplary features of the invention. However, it is to be understood that each of the features can be used in the invention in general, not merely in the context of the particular drawings, and the invention includes any combination of these features, where:

FIG. 1A is a schematic sectional side view of a version of an aerosolization apparatus according to the invention in an initial position;

FIG. 1B is a schematic sectional side view of the version of an aerosolization apparatus shown inFIG. 1A at the beginning of an aerosolization process;

FIG. 1C is a schematic sectional side view of the version of an aerosolization apparatus shown inFIG. 1A during an aerosolization process;

FIG. 2 is a schematic sectional end view of a version of an aerosolization apparatus having an air inlet shield;

FIG. 3A is a schematic sectional side view of a version of an aerosolization apparatus in a rest position;

FIG. 3B is a schematic sectional side view of the version of an aerosolization apparatus shown inFIG. 3A just before capsule puncture;

FIG. 3C is a schematic sectional side view of the version of an aerosolization apparatus shown inFIG. 3A as the capsule is being punctured;

FIG. 3D is a schematic sectional side view of the version of an aerosolization apparatus shown inFIG. 3A just after capsule puncture;

FIG. 3E is a schematic sectional side view of the version of an aerosolization apparatus shown inFIG. 3A in use;

FIG. 4 is a schematic side view of a version of an aerosolization apparatus;

FIG. 5 is a schematic side view of a version of an inlet shield for use with an aerosolization apparatus;

FIG. 6 is a schematic side view of another version of an inlet shield for use with an aerosolization apparatus; and

FIG. 7 is a schematic side view of another version of an inlet shield for use with an aerosolization apparatus.

DESCRIPTION

The present invention relates to an aerosolization apparatus. In particular, the invention relates to an aerosolization apparatus capable of aerosolizing a pharmaceutical formulation contained in a receptacle, such as a capsule. Although the process is illustrated in the context of aerosolizing a dry powder pharmaceutical formulation for inhalation, the present invention can be used in other processes and should not be limited to the examples provided herein.

Anaerosolization apparatus100 according to the present invention is shown schematically inFIG. 1A. Theaerosolization apparatus100 comprises ahousing105 defining achamber110 having one ormore air inlets115 and one ormore air outlets120. Thechamber110 is sized to receive areceptacle125 which contains an aerosolizable pharmaceutical formulation. Thereceptacle125 has anopening130 thereinto that provides a communication between thechamber110 and the pharmaceutical formulation within thereceptacle125. Near or adjacent theoutlet120 is anend section140 that may be sized and shaped to be received in a user's mouth or nose so that the user may inhale through anopening145 in theend section140 that is in communication with thechamber outlet120.

Theaerosolization apparatus100 utilizes air flowing through thechamber110 to aerosolize the pharmaceutical formulation in thereceptacle125. For example,FIGS. 1A through 1C illustrate the operation of a version of anaerosolization apparatus100 where air flowing through theinlet115 is used to cause aerosolization of the pharmaceutical formulation and the aerosolized pharmaceutical formulation flows through theoutlet120 so that it may be delivered to the user through theopening145 in theend section140. Theaerosolization apparatus100 is shown in its initial condition inFIG. 1A. Thereceptacle125 is positioned within thechamber110 and the pharmaceutical formulation is secured within thereceptacle125. In the version shown, apartition150 blocks the forward end of thechamber110, and thepartition150 has the one ormore outlets120 extending therethrough.

Air or other gas is then caused to flow through aninlet115, as shown byarrows155 inFIG. 1B. For example, theairflow155 may be generated by a user inhaling160 through theopening145 in theend section140. Theairflow155 initially draws the receptacle toward thepartition150.Continued airflow155, as shown inFIG. 1C, causes thereceptacle125 to move within thechamber110. In the configuration shown, thereceptacle125 may contact thepartition150 at its forward end and then move about thesidewall165 of the capsule with its rearward end contacting thesidewall165. For example, the rearward end of thereceptacle125 may rotate and/or slide around thesidewall165 of thechamber110. This movement causes the pharmaceutical formulation in thereceptacle125 to exit through theopening130 and become aerosolized in theairflow155. The aerosolized pharmaceutical formulation is then delivered to the user's respiratory tract during the user'sinhalation160. In another version, compressed air or other gas may be ejected into aninlet115 to cause the aerosolizingair flow155, and the aerosolized pharmaceutical formulation is then inhaled by the user.

Theaerosolization apparatus100 also comprises an airinlet shielding member170. As shown inFIG. 1A, the airinlet shielding member170 comprises a coveringportion175 that at least partially covers one or more of theinlets115. The shieldingmember170 prevents blockage of the air flow by preventing at least one of theinlets115 from being blocked by a user's fingers or hand during use. Accordingly, if a user inadvertently grasps the apparatus in the area of theinlets115, the user will the shieldingmember170 rather than one or more of theinlets115 and air will still flow through into thechamber110. As can be seen inFIGS. 1B and 1C, theair flow155 takes a more tortuous path in the region of the shieldingmember170. Accordingly, in one version, it is preferred that the shielding member not cover all of theinlets115 in that such coverage will increase the flow resistance within the apparatus. In another version, it is desirable to increase the flow resistance through the apparatus and coverage of all or a plurality of the inlets is desirable. The cross-section of a version of anaerosolization apparatus100 is shown inFIG. 2. In this version, the shieldingmember170 covers less than half of theinlets115. In this configuration, adequate air flow through the device is assured independent of user finger positioning. By cover it is meant overlap in the radial or outward direction.

A version of anaerosolization apparatus100 comprising a shieldingmember170 is shown inFIGS. 3A through 3E. In this version, thehousing105 of theaerosolization apparatus100 comprises abody205 and aremovable endpiece210. Theendpiece210 may be removed from thebody205 to insert areceptacle125 in thechamber110 which is formed when thebody205 and theendpiece210 are connected together. Theendpiece210 comprises apartition150 that is dome-shaped215 and that blocks the forward end of thechamber110, and the partition215 has the one ormore outlets120 extending therethrough. Examples of aerosolization apparatus with apartition150 and chamber configuration are described in U.S. Pat. No. 4,069,819 and in U.S. Pat. No. 4,995,385, both of which are incorporated herein by reference in their entireties. Theinlets115 comprise a plurality of tangentially orientedslots220. When a user inhales160 through theendpiece210, outside air is caused to flow through thetangential slots220 as shown byarrows225 inFIG. 3E. Thisairflow225 creates a swirling airflow within thechamber110. The swirling airflow causes thereceptacle125 to contact thepartition150 and then to move within thechamber110 in a manner that causes the pharmaceutical formulation to exit thereceptacle125 and become entrained within the swirling airflow. In one specific version, thechamber110 comprises a taperedsection230 that terminates at anedge235. During the flow of swirling air in thechamber110, the forward end of thereceptacle125 contacts and rests on thepartition150 and a sidewall of thereceptacle125 contacts theedge235 and slides and/or rotates along theedge235. This motion of the capsule is particularly effective in forcing a large amount of the pharmaceutical formulation through one ormore openings130 in the rear of thereceptacle125.

The one ormore openings130 in the rear of thereceptacle125 in the version ofFIGS. 3A through 3E are created by apuncturing mechanism250 that is slidable within thebody205. Thepuncturing mechanism250, shown in its rest position inFIG. 3A, comprises aplunger255 attached at itsforward end260 to apuncture member265, which in the version shown is aU-shaped staple270 having two sharpenedtips275. Thepuncturing mechanism250 further comprises aseating member280 which contacts theplunger255 and/or thepuncture member265 and is slidable relative to theplunger255 and thepuncture member265. To create theopenings130 in thereceptacle125, the user applies aforce285 to theplunger255, as shown inFIG. 3B, such as by pressing against anend surface290 of theplunger255 with the user's finger or thumb. Theforce285 causes the plunger to slide within thebody205. A slight frictional contact between theplunger255 the arear section295 of theseating member280 causes theseating member280 to also slide within thebody205 until aforward seating surface300 of theseating member280 contacts thereceptacle125, as shown inFIG. 3B. Theforward seating surface300, which may be shaped to generally match the shape of thereceptacle125, secures thereceptacle125 between the seatingmember280 and thepartition150. The continued application offorce285 causes theplunger255 and thepuncture member265 to slide relative to theseating member280, as shown inFIG. 3C, to advance the puncture member135 throughopenings305 in theforward seating surface300 and into thereceptacle125. Upon the removal of theforce285, aspring310 or other biasing member urges thepuncturing mechanism250 back to its rest position. For example, thespring310 may contact ashoulder315 in thebody205 and press aflange320 on theplunger255 toward arim325 in thebody205. The frictional engagement between the plunger355 and theseating member280 also returns the seatingmember280 to its retracted position when the plunger is returned to its retracted position.

In the version ofFIGS. 3A through 3E, the shieldingmember170 is an integral portion of theendpiece210. Accordingly, in this version, if the user installs theendpiece210 and then uses theaerosolization apparatus100 without adjusting his or her grip on theendpiece210, none of theinlets220 will be covered by the user. The provision of the shieldingmember170 on theendpiece210 has additional advantages. For example, the shieldingmember170 can serve to lengthen and/or widen theendpiece210 thereby reducing the risk of a user choking on theendpiece210 if theendpiece210 were to become inadvertently disconnected from the body of the apparatus.

In one version, thereceptacle125 comprises a capsule. The capsule may be of a suitable shape, size, and material to contain the pharmaceutical formulation and to provide the pharmaceutical formulation in a usable condition. For example, the capsule may comprise a wall which comprises a material that does not adversely react with the pharmaceutical formulation. In addition, the wall may comprise a material that allows the capsule to be opened to allow the pharmaceutical formulation to be aerosolized. In one version, the wall comprises one or more of gelatin, hydroxypropyl methylcellulose (HPMC), polyethyleneglycol-compounded HPMC, hydroxyproplycellulose, agar, or the like. Alternatively or additionally, the capsule wall may comprise a polymeric material, such as polyvinyl chloride (PVC). In one version, the capsule may comprise telescopically ajoined sections, as described for example in U.S. Pat. No. 4,247,066 which is incorporated herein by reference in its entirety. The interior of the capsule may be filled with a suitable amount of the pharmaceutical formulation, and the size of the capsule may be selected to adequately contain a desired amount of the pharmaceutical formulation. The sizes generally range from size 5 to size 000 with the outer diameters ranging from about 4.91 mm to 9.97 mm, the heights ranging from about 11.10 mm to about 26.14 mm, and the volumes ranging from about 0.13 ml to about 1.37 ml, respectively. Suitable capsules are available commercially from, for example, Shionogi Qualicaps Co. in Nara, Japan and Capsugel in Greenwood, S.C. After filling, a top portion may be placed over the bottom portion to form the a capsule shape and to contain the powder within the capsule, as described in U.S. Pat. No. 4,846,876, U.S. Pat. No. 6,357,490, and in the PCT application WO 00/07572 published on Feb. 17, 2000, all of which are incorporated herein by reference in their entireties.

In another version, theaerosolization apparatus100 may be configured differently than as shown inFIGS. 1A through 1C and 3A through 3E. For example, thechamber100 may be sized and shaped to receive thereceptacle125 so that thereceptacle125 is orthogonal to the inhalation direction, as described in U.S. Pat. No. 3,991,761. As also described in U.S. Pat. No. 3,991,761, thepuncturing mechanism250 may puncture both ends of thereceptacle125. In such version, the non-circular cross-section may be provided along a sidewall that contacts the ends of the capsule. In another version, the chamber may receive the receptacle in a manner where air flows through the receptacle as described for example in U.S. Pat. No. 4,338,931 and in U.S. Pat. No. 5,619,985. In another version, the aerosolization of the pharmaceutical formulation may be accomplished by pressurized gas flowing through the inlets, as described for example in U.S. Pat. No. 5,458,135, U.S. Pat. No. 5,785,049, and U.S. Pat. No. 6,257,233, or propellant, as described in PCT Publication WO 00/72904 and U.S. Pat. No. 4,114,615. All of the above references being incorporated herein by reference in their entireties.

A version of anaerosolization apparatus100 having anendpiece210 comprising an airinlet shielding member170 is shown inFIG. 4. In this version, the shieldingmember170 comprises two covering portions175 (only one shown in the view ofFIG. 4) and twoopen portions180 between the diametrically opposed coveringportions175. Alternatively, there could be three, four, or more coveringportions175 separated byopen portions180. In the version shown, the user would grasp the apparatus by contacting the coveringportions175 and would therefore not block theair inlets115. In one version, space would be provided between the coveringportion175 and the outer surface of theinlets115 under the coveringportion175 in order to create a manifold airflow portion below the coveringportion175.

Other versions of anendpiece210 which comprises a shieldingmember170 are shown inFIGS. 5, 6, and 7. These versions show different arrangements for the coveringportions175 and theopen portions180 associated with the shieldingmember170. In the version ofFIG. 5 a series of longitudinalopen portions180 is provided. In the version ofFIG. 6, one or more circumferentially extendingopen portions180 are provided. In the version ofFIG. 6, an open portion is also provided that extends circumferentially around thebase185 of and under theendpiece210. While such open portion at the base185 may be used in combination with one or more additionalopen portions180, it has been discovered that it may be disadvantageous to provide the open portion at the base185 as the onlyopen portion180. A user can easily occlude all or a portion of an open portion at the base185 which can lead to inconsistent air flow through the device. In addition, air flowing through an open portion at the base185 can encourage endpiece disconnection from the body.

In a preferred version, the invention provides a system and method for aerosolizing a pharmaceutical formulation and delivering the pharmaceutical formulation to the respiratory tract of the user, and in particular to the lungs of the user. The pharmaceutical formulation may comprise powdered medicaments, liquid solutions or suspensions, and the like, and may include an active agent.

The active agent described herein includes an agent, drug, compound, composition of matter or mixture thereof which provides some pharmacologic, often beneficial, effect. This includes foods, food supplements, nutrients, drugs, vaccines, vitamins, and other beneficial agents. As used herein, the terms further include any physiologically or pharmacologically active substance that produces a localized or systemic effect in a patient. An active agent for incorporation in the pharmaceutical formulation described herein may be an inorganic or an organic compound, including. without limitation, drugs which act on: the peripheral nerves, adrenergic receptors, cholinergic receptors, the skeletal muscles, the cardiovascular system, smooth muscles, the blood circulatory system, synoptic sites, neuroeffector junctional sites, endocrine and hormone systems, the immunological system, the reproductive system, the skeletal system, autacoid systems, the alimentary and excretory systems, the histamine system, and the central nervous system. Suitable active agents may be selected from, for example, hypnotics and sedatives, psychic energizers, tranquilizers, respiratory drugs, anticonvulsants, muscle relaxants, antiparkinson agents (dopamine antagnonists), analgesics, anti-inflammatories, antianxiety drugs (anxiolytics), appetite suppressants, antimigraine agents, muscle contractants, anti-infectives (antibiotics, antivirals, antifungals, vaccines) antiarthritics, antimalarials, antiemetics, anepileptics, bronchodilators, cytokines, growth factors, anti-cancer agents, antithrombotic agents, antihypertensives, cardiovascular drugs, antiarrhythmics, antioxicants, anti-asthma agents, hormonal agents including contraceptives, sympathomimetics, diuretics, lipid regulating agents, antiandrogenic agents, antiparasitics, anticoagulants, neoplastics, antineoplastics, hypoglycemics, nutritional agents and supplements, growth supplements, antienteritis agents, vaccines, antibodies, diagnostic agents, and contrasting agents. The active agent, when administered by inhalation, may act locally or systemically.

The active agent may fall into one of a number of structural classes, including but not limited to small molecules, peptides, polypeptides, proteins, polysaccharides, steroids, proteins capable of eliciting physiological effects, nucleotides, oligonucleotides, polynucleotides, fats, electrolytes, and the like.

Examples of active agents suitable for use in this invention include but are not limited to one or more of calcitonin, amphotericin B, erythropoietin (EPO), Factor VIII, Factor IX, ceredase, cerezyme, cyclosporin, granulocyte colony stimulating factor (GCSF), thrombopoietin (TPO), alpha-1 proteinase inhibitor, elcatonin, granulocyte macrophage colony stimulating factor (GMCSF), growth hormone, human growth hormone (HGH), growth hormone releasing hormone (GHRH), heparin, low molecular weight heparin (LMWH), interferon alpha, interferon beta, interferon gamma, interleukin-1 receptor, interleukin-2, interleukin-1 receptor antagonist, interleukin-3, interleukin-4, interleukin-6, luteinizing hormone releasing hormone (LHRH), factor IX, insulin, pro-insulin, insulin analogues (e.g., mono-acylated insulin as described in U.S. Pat. No. 5,922,675, which is incorporated herein by reference in its entirety), amylin, C-peptide, somatostatin, somatostatin analogs including octreotide, vasopressin, follicle stimulating hormone (FSH), insulin-like growth factor (IGF), insulintropin, macrophage colony stimulating factor (M-CSF), nerve growth factor (NGF), tissue growth factors, keratinocyte growth factor (KGF), glial growth factor (GGF), tumor necrosis factor (TNF), endothelial growth factors, parathyroid hormone (PTH), glucagon-like peptide thymosin alpha 1, IIb/IIIa inhibitor, alpha-1 antitrypsin, phosphodiesterase (PDE) compounds, VLA-4 inhibitors, bisphosponates, respiratory syncytial virus antibody, cystic fibrosis transmembrane regulator (CFTR) gene, deoxyreibonuclease (Dnase), bactericidal/ permeability increasing protein (BPI), anti-CMV antibody, 13-cis retinoic acid, macrolides such as erythromycin, oleandomycin, troleandomycin, roxithromycin, clarithromycin, davercin, azithromycin, flurithromycin, dirithromycin, josamycin, spiromycin, midecamycin, leucomycin, miocamycin, rokitamycin, andazithromycin, and swinolide A; fluoroquinolones such as ciprofloxacin, ofloxacin, levofloxacin, trovafloxacin, alatrofloxacin, moxifloxicin, norfloxacin, enoxacin, grepafloxacin, gatifloxacin, lomefloxacin, sparfloxacin, temafloxacin, pefloxacin, amifloxacin, fleroxacin, tosufloxacin, prulifloxacin, irloxacin, pazufloxacin, clinafloxacin, and sitafloxacin, aminoglycosides such as gentamicin, netilmicin, paramecin, tobramycin, amikacin, kanamycin, neomycin, and streptomycin, vancomycin, teicoplanin, rampolanin, mideplanin, colistin, daptomycin, gramicidin, colistimethate, polymixins such as polymixin B, capreomycin, bacitracin, penems; penicillins including penicllinase-sensitive agents like penicillin G, penicillin V, penicillinase-resistant agents like methicillin, oxacillin, cloxacillin, dicloxacillin, floxacillin, nafcillin; gram negative microorganism active agents like ampicillin, amoxicillin, and hetacillin, cillin, and galampicillin; antipseudomonal penicillins like carbenicillin, ticarcillin, azlocillin, mezlocillin, and piperacillin; cephalosporins like cefpodoxime, cefprozil, ceftbuten, ceftizoxime, ceftriaxone, cephalothin, cephapirin, cephalexin, cephradrine, cefoxitin, cefamandole, cefazolin, cephaloridine, cefaclor, cefadroxil, cephaloglycin, cefuroxime, ceforanide, cefotaxime, cefatrizine, cephacetrile, cefepime, cefixime, cefonicid, cefoperazone, cefotetan, cefmetazole, ceftazidime, loracarbef, and moxalactam, monobactams like aztreonam; and carbapenems such as imipenem, meropenem, pentamidine isethiouate, albuterol sulfate, lidocaine, metaproterenol sulfate, beclomethasone diprepionate, triamcinolone acetamide, budesonide acetonide, fluticasone, ipratropium bromide, flunisolide, cromolyn sodium, ergotamine tartrate and where applicable, analogues, agonists, antagonists, inhibitors, and pharmaceutically acceptable salt forms of the above. In reference to peptides and proteins, the invention is intended to encompass synthetic, native, glycosylated, unglycosylated, pegylated forms, and biologically active fragments and analogs thereof. Active agents for use in the invention further include nucleic acids, as bare nucleic acid molecules, vectors, associated viral particles, plasmid DNA or RNA or other nucleic acid constructions of a type suitable for transfection or transformation of cells, i.e., suitable for gene therapy including antisense. Further, an active agent may comprise live attenuated or killed viruses suitable for use as vaccines. Other useful drugs include those listed within the Physician's Desk Reference (most recent edition).

The amount of active agent in the pharmaceutical formulation will be that amount necessary to deliver a therapeutically effective amount of the active agent per unit dose to achieve the desired result. In practice, this will vary widely depending upon the particular agent, its activity, the severity of the condition to be treated, the patient population, dosing requirements, and the desired therapeutic effect. The composition will generally contain anywhere from about 1% by weight to about 99% by weight active agent, typically from about 2% to about 95% by weight active agent, and more typically from about 5% to 85% by weight active agent, and will also depend upon the relative amounts of additives contained in the composition. The compositions of the invention are particularly useful for active agents that are delivered in doses of from 0.001 mg/day to 100 mg/day, preferably in doses from 0.01 mg/day to 75 mg/day, and more preferably in doses from 0.10 mg/day to 50 mg/day. It is to be understood that more than one active agent may be incorporated into the formulations described herein and that the use of the term “agent” in no way excludes the use of two or more such agents.

The pharmaceutical formulation may comprise a pharmaceutically acceptable excipient or carrier which may be taken into the lungs with no significant adverse toxicological effects to the subject, and particularly to the lungs of the subject. In addition to the active agent, a pharmaceutical formulation may optionally include one or more pharmaceutical excipients which are suitable for pulmonary administration. These excipients, if present, are generally present in the composition in amounts ranging from about 0.01% to about 95% percent by weight, preferably from about 0.5 to about 80%, and more preferably from about 1 to about 60% by weight. Preferably, such excipients will, in part, serve to further improve the features of the active agent composition, for example by providing more efficient and reproducible delivery of the active agent, improving the handling characteristics of powders, such as flowability and consistency, and/or facilitating manufacturing and filling of unit dosage forms. In particular, excipient materials can often function to further improve the physical and chemical stability of the active agent, minimize the residual moisture content and hinder moisture uptake, and to enhance particle size, degree of aggregation, particle surface properties, such as rugosity, ease of inhalation, and the targeting of particles to the lung. One or more excipients may also be provided to serve as bulking agents when it is desired to reduce the concentration of active agent in the formulation.

Pharmaceutical excipients and additives useful in the present pharmaceutical formulation include but are not limited to amino acids, peptides, proteins, non-biological polymers, biological polymers, carbohydrates, such as sugars, derivatized sugars such as alditols, aldonic acids, esterified sugars, and sugar polymers, which may be present singly or in combination. Suitable excipients are those provided in WO 96/32096, which is incorporated herein by reference in its entirety. The excipient may have a glass transition temperatures (Tg) above about 35° C., preferably above about 40° C., more preferably above 45° C., most preferably above about 55° C.

Exemplary protein excipients include albumins such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, hemoglobin, and the like. Suitable amino acids (outside of the dileucyl-peptides of the invention), which may also function in a buffering capacity, include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, tyrosine, tryptophan, and the like. Preferred are amino acids and polypeptides that function as dispersing agents. Amino acids falling into this category include hydrophobic amino acids such as leucine, valine, isoleucine, tryptophan, alanine, methionine, phenylalanine, tyrosine, histidine, and proline. Dispersibility-enhancing peptide excipients include dimers, trimers, tetramers, and pentamers comprising one or more hydrophobic amino acid components such as those described above.

Carbohydrate excipients suitable for use in the invention include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol), pyranosyl sorbitol, myoinositol and the like.

The pharmaceutical formulation may also include a buffer or a pH adjusting agent, typically a salt prepared from an organic acid or base. Representative buffers include organic acid salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid, Tris, tromethamine hydrochloride, or phosphate buffers.

The pharmaceutical formulation may also include polymeric excipients/additives, e.g., polyvinylpyrrolidones, derivatized celluloses such as hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylmethylcellulose, Ficolls (a polymeric sugar), hydroxyethylstarch, dextrates (e.g., cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin), polyethylene glycols, and pectin.

The pharmaceutical formulation may further include flavoring agents, taste-masking agents, inorganic salts (for example sodium chloride), antimicrobial agents (for example benzalkonium chloride), sweeteners, antioxidants, antistatic agents, surfactants (for example polysorbates such as “TWEEN 20” and “TWEEN 80”), sorbitan esters, lipids (for example phospholipids such as lecithin and other phosphatidylcholines, phosphatidylethanolamines), fatty acids and fatty esters, steroids (for example cholesterol), and chelating agents (for example EDTA, zinc and other such suitable cations). Other pharmaceutical excipients and/or additives suitable for use in the compositions according to the invention are listed in “Remington: The Science & Practice of Pharmacy”, 19^thed., Williams & Williams, (1995), and in the “Physician's Desk Reference”, 52^nded., Medical Economics, Montvale, N.J. (1998), both of which are incorporated herein by reference in their entireties.

“Mass median diameter” or “MMD” is a measure of mean particle size, since the powders of the invention are generally polydisperse (i.e., consist of a range of particle sizes). MMD values as reported herein are determined by centrifugal sedimentation, although any number of commonly employed techniques can be used for measuring mean particle size. “Mass median aerodynamic diameter” or “MMAD” is a measure of the aerodynamic size of a dispersed particle. The aerodynamic diameter is used to describe an aerosolized powder in terms of its settling behavior, and is the diameter of a unit density sphere having the same settling velocity, generally in air, as the particle. The aerodynamic diameter encompasses particle shape, density and physical size of a particle. As used herein, MMAD refers to the midpoint or median of the aerodynamic particle size distribution of an aerosolized powder determined by cascade impaction.

In one version, the powdered formulation for use in the present invention includes a dry powder having a particle size selected to permit penetration into the alveoli of the lungs, that is, preferably 10 μm mass median diameter (MMD), preferably less than 7.5 μm, and most preferably less than 5 μm, and usually being in the range of 0.1 μm to 5 μm in diameter. The delivered dose efficiency (DDE) of these powders may be greater than 30%, more preferably greater than 40%, more preferably greater than 50% and most preferably greater than 60% and the aerosol particle size distribution is about 1.0-5.0 μm mass median aerodynamic diameter (MMAD), usually 1.5-4.5 am MMAD and preferably 1.5-4.0 μm MMAD. These dry powders have a moisture content below about 10% by weight, usually below about 5% by weight, and preferably below about 3% by weight. Such powders are described in WO 95/24183, WO 96/32149, WO 99/16419, and WO 99/16422, all of which are all incorporated herein by reference in their entireties.

Although the present invention has been described in considerable detail with regard to certain preferred versions thereof, other versions are possible, and alterations, permutations and equivalents of the version shown will become apparent to those skilled in the art upon a reading of the specification and study of the drawings. For example, the cooperating components may be reversed or provided in additional or fewer number. Also, the various features of the versions herein can be combined in various ways to provide additional versions of the present invention. Furthermore, certain terminology has been used for the purposes of descriptive clarity, and not to limit the present invention. Therefore, any appended claims should not be limited to the description of the preferred versions contained herein and should include all such alterations, permutations, and equivalents as fall within the true spirit and scope of the present invention.

Claims (21)

What is claimed is:

1. A handheld An aerosolization apparatus comprising:

a housing having at least two air inlets, the inlets configured and dimensioned to produce a swirling airflow;

an endpiece comprising a perforated member and an aerosolized pharmaceutical formulation outlet partition having one or more outlets, the endpiece being connectable to the housing to define a chamber, the chamber being sized to receive a capsule which contains an aerosolizable pharmaceutical formulation, the endpiece further comprising a shield which covers at least one air inlet two but not all of the air inlets, wherein the shield comprises at least one covering portion, whereby the covering portion prevents blockage of at least one air inlet by a user grasping the apparatus; and

a puncturing mechanism disposed within the housing for creating one or more openings in only one end of the capsule, the puncturing mechanism comprising an alignment guide a seating member and a puncture member, wherein the alignment guide seating member comprises a surface which advances to contact and align secure the capsule between the seating member and the partition while the alignment guide and puncture member are is advanced into the capsule to create an opening in the capsule, and wherein the surface comprises one or more protrusions for contacting the capsule.

2. An apparatus according toclaim 1 wherein the shield comprises at least two covering portions intermediate to two open portions.

3. An apparatus according toclaim 1 wherein the shield comprises at least four covering portions intermediate to at least four open portions.

4. An apparatus according toclaim 1 wherein the shield covering portions and open portions are displaced from said air inlets.

5. An apparatus according toclaim 1 wherein the endpiece is removably connected to the housing and wherein the endpiece may be removed from the housing to provide access to the chamber.

6. An apparatus according toclaim 1 wherein the shield extends longitudinally along the apparatus.

7. An apparatus according toclaim 1 wherein the shield extends transversely along the apparatus.

8. An apparatus according toclaim 1 wherein the chamber is elongated and wherein the capsule is may be received lengthwise within the elongated chamber.

9. An apparatus according to claim 1 in combination with the capsule wherein the capsule contains an aerosolizable pharmaceutical formulation comprising an active agent.

10. An apparatus according to claim 9 wherein the active agent comprises tobramycin.

11. An apparatus according to claim 9 wherein the active agent comprises ciprofloxacin.

12. An apparatus according to claim 9 wherein the active agent comprises amphotericin B.

13. An apparatus according to claim 9 wherein the active agent comprises an anti-infective.

14. An apparatus according to claim 9 wherein the active agent comprises an anti-asthma agent.

15. An apparatus according to claim 9 wherein the active agent comprises a bronchodilator.

16. An aerosolization apparatus comprising:

a housing having air inlets;

an endpiece comprising a partition having one or more outlets, the endpiece being connectable to the housing to define a chamber, the chamber being sized to receive a capsule which contains an aerosolizable pharmaceutical formulation, the endpiece further comprising a shield which covers at least two but not all of the air inlets, wherein the shield prevents blockage of at least one air inlet by a user grasping the apparatus; and

a puncturing mechanism disposed within the housing for creating one or more openings in only one end of the capsule,

wherein the endpiece is sized and shaped to be received in a user's mouth or nose so that the user may inhale through the end section to aerosolize the pharmaceutical formulation.

17. An apparatus according to claim 16 wherein the shield comprises at least two covering portions intermediate to two open portions.

18. An apparatus according to claim 16 wherein the shield comprises at least four covering portions intermediate to four open portions.

19. An apparatus according to claim 16 wherein the inlets are configured to produce a swirling airflow.

20. An apparatus according to claim 16 in combination with the capsule wherein the capsule contains an aerosolizable pharmaceutical formulation comprising tobramycin.

21. An apparatus according to claim 16 in combination with the capsule wherein the capsule contains an aerosolizable pharmaceutical formulation comprising ciprofloxacin.

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