WO2017100656A1 - Dry powder formulations of aspirin for inhalation - Google Patents

Abstract

The subject technology relates to pulmonary delivery of dry powder formulations of nonsteroidal anti-inflammatory drugs (NSAIDs), such as acetylsalicylic acid. The subject technology further relates to dry powder formulations of NSAIDs with an improved stability.

Description

DRY P0WBER FOR ULATIONS OF ASPIRI FOR OTALATiOH

Technical Field

jOOOl 1 The subject technology relates generally to pulmonary? delivery of dry powder formulations of nonsteroi al antiinflammatories (MSA!Ds), such as aspirin or A S A . The subject technology also relates generally to apparatuses and methods far delivery of substances, e.g., medication, to the lungs by inhalation for treating disease. The stibject technology further relates o dry powder formiiteiions of NSAlBs with an improved stability.

produces minimal side effects, j 00031 Dry powder i nha kf i on offers the pos-sifei lity of deli vering accurate and repr oducibie doses of a drug to the pulmonary vasculature, TeSko et «1, ¾yJPg le I M

Respiratory Care 50(9); 1209 (2005). Dry -powder formulations for inhalation tlierapy are described in U,S. Pat, No, 5,993,805 to- Sutton et al.: O.S. Pat, No. 6,92-1.6527 to Platz et a!,; WO 0000176 to Robinson et al; WO 9916419 to Tarara et al; WO 0000215 to ot et at; U.S. Pat. Mo. 5,855,913 to Banes et al; and U.S. Pat. N s. 6,136,295 and 5,874,064 to Edwards etal, j Θ004| Broad clinical application o dry po der inhalation delivery has been limited^' by di fficulties in generating dry powders of appropriate particle size, particle density, and dispersibility, keeping the dry powder stored in a dry state and developing a convenient, handheld device that effectively disperses -the resplrahle dry particles to he inhaled in ait In addition, the particle size of dry powders for inhal ation delivery is inherently li m i ted by the fact that smaller respirabie dry particles are harder to disperse in air. Dry powder formulations, while offering advantages over etnrabers&nte liquid dosage forriis and propellani-driven fo iulations, are prone to aggregation and low f wa ify* which considerably diminish dlspersiMity and the effici ency of dry powder-based in alation therapies. For example, inter-particle Van der Waals interactions and capiilary condensation effects are known to contribute to aggregation of dry particles, ffiekey. A, et al, E_nactors ¾^

Phar aceutical Technology, August, 1994. ffiOOSf To overcome such inter-particle adhesive forces, Baiycky ei al in U.S. Patent No. 7,182,961 teach production of so called "aerodyuamically light respirable particles," which have a vol ume median geometric diameter (VMGD) of greater than 5 microns (μη ) as measured using a laser dii¾ictjo» instaanent such as HEJLQS ( arnitaetored. by S mp tic* Princeton, N. J.). See Baryeky ^'et al, column 7, lines 42-65. Another approach to improve dispersiMlit of respirable particles of average particle size of less than 10 nra, involves the addition of water soluble polypeptide or addition of suitable excipients {including ami o acid exclpients such .as leucine) in an amount of 50% to 99.9% by weight of the total composition. Bijamal et al, US. Patent No, 6,582.729, However_* this approach reduces the amount of active agent that can be delivered using a fixed amount of powder . There fore, an increased amount of dr powder is required to achieve the intended therapeutic results, for exanipfe, multiple inhalations and/or Hequent adiainistration may be required . Sti ll other approaches invol ve the use of devices that apply mechanical forces, such as pressure from compressed gases, to the small particles to disrupt inter-particulate adhesion during or just prior to administration. See, e.g., U. S. Pat, os, 7,601,336 to Lewis etal, 6,737,044 to Dickinson et al 6,546,928 to Ashurst et al, or U.S. Pat. Applications 20090208582 to Johnston etal 0006| Despite the advances in dry powder fomnUation., there remains a need tor providin novel formulations of NSAlD's, such as aspirin, that are suitable for pulmonary delivery, and are Stable over a prolonged period of time. Given the known effectiveness of ASA for treating cardiovascular disease and more generally thromboemholic Cischentic) diseases such as stroke, there remains a need to develop dry powder formulations of ASA, which can effectively and rapidly deliver doses to the patient hi distress. De Caterina. Clinical use of ASA in ischemic heat disease: past, present and future. Gurr. Phar, Des. 18(33):S 15-23 (2012). ft has clearly been shown that antiplatelet therapy with ASA reduces the risk of serious vascular events, id AS A

? lias also been hown to be useful in th treatrnent ef acute ischemic stroke as well as tfaussierit ischemic events. ^'2¾e»gMing et ai. indications for Early ASA Use in Acute Ischemic Stroke, Stoke 31 '1240-1249 (2000); Warlow Coatroversjes Stroke: ASA ^'Should Be First-Line

Antiplatelet Therapy in the ^'Secondary Prevention of Stroke, Stroke 33:2137-2138 (2000).

However, gi ven the rapid first-pass metabolism of ASA, there remains a need for providing novel formulations of NSAIDs, such as ASA, that are suitable for .pulmonary^' delivery and therefore bypass first-pass metabolism and avoid gastrointestinal side effects_*

(00071 Another importan t characteristic of pharmaceutical, dry powders is their stability at different temperature and ^'humidify conditions. Unstable powders will absorb moisture from the environment and a glomer te, thus altering particle size distdbohO . of the powder. Thus, there remains a eed for novel foiiniiiations of MSAlD^{^}s, such as aspirin, that ill remain stable over a prolonged period of time.

SU MARY OF THE PiSCLOSUME fOiMJiJ The methods and com ositions of the present isclosure co.rap.rise dry particles that comprise cetylsalieyiic acid (aspirin, ASA), or a pharmaceutically acceptable salt thereof, as the active Ingredient, in. certain emb d ments, die dry particle are respirable. The dry particles may vary in size, e.g., a median aerodynamic diameter (MMAD) between about 0.5 μηι to about 10 μτη, between about 0.5 μητ. to about 5 μη¾ between about 1 pm to about 5 μηι, or between about 2.0 jtm to about 4 tun.

[0009 J The MMAD of the dry particles may change less than about 10% (or no greater than .10%) when stored at 30°C at 65% relative humidity fo about 4 weeks compared to the MMAD of the dry particles before storage, in another m odiment the MAD of the dry particles rosy change less than about 5% (or no greater than 5%) when stored at 30°C at 65% relative humidity for about 4 weeks compared to the MMAD of the dry particles before storage, in a third embodiment, die MMAD of the dry particles may change less than abou 10% (or.no greater than j 0%)* or less than about 5% (or so greater than ^·$%) after stored at 50°€ at 75% relative humidity for about 2 weeks compared to the MMAD of the dry particles before storage, in a fourth embodiment, the MMAD of the dry particles changes less than about 10% (or n greater than 30%), or less than about 5% (or no greater than 5%), when stored at 50°C for about 5 days compared to the MMAD of the dry parti cies before storage. jftOl if The MMAD of the dry particles ma change less than about 30% (or no greater than 30%), less than about 25% (or no g eater than 25%), less than about 20% (o no greater than 20%), less than about 15% (or no greater than 15%), less hai about 10% (or no greater than 10%), less than about 8% (o no greater than 8%), less than about 6% (or no greater than 6%), less than about 5% (or no greater than 5%), less than about 4% (or no greater tha 4%), less than about 3% (or no greater than 3%), or less than about 2% (or no greater than 2%), when stored at 30°C at 65% relative humidity for about 4 weeks, or after stored at 50*C at 75% relative humidity for about weeks, or ^'when stored at 50°C for about 5 days, compared to th MMAD of the dry particles before storage.

!0β11^'| The compositions of the present disclosure may also comprise a mixture of dry particles of different sizes,, wherein the composition comprises particles h ving an MMAD si e disiributiiM snck that said part cies: exhibit a DV9 less, than about 5: μ«ι. {or aboiit 5 jim), a DV50 less than about 3 μιη for about 3 .im), and a D^'VIO- less than about l pro (or about ϊ μΐίχ).

[0012 J D V9Q, DV50, and DV 10 of th dry particles of the present compositions ca change less th n about 10% (or so greater than IQ¾% or less than about 5% (or no greater t att 5¾ when stored at 30°C at 6 % relative humidity for about 4 weeks compared to the P90, D50 an Dl 0 of the dry particles before storage, respectively, in another embodiment, DV90, DV50 and DV 10 change less than about 10% (or no greater than. 10%), or less than about 5% (or HO greater than 5%), after stored at 50°C at 75% relative humidity for about 2 weeks compared to the D90, D5Q and D10 of the dry particles before storage, respectively . In still another embodiment, DV90, DV50 and DVlO change less than about 10% (or no greater than 10%), or less than about 5% (or no greater than 5%), after stored at SOX for about S days compared to the D90, D50 and DI of the dry particles before storage, respectively.

|001.3| When tested iti Next C3eneratio« Impaetor (NG¾ the percentages of particles deposited at Stages 5. 6 and 7 do not change greater than about 10%, or do not change greater than about 5%, when tested at time;, T^::s weeks (or Ϊ- 2 weeks) as compared with the percentages of particles deposited at Stages 5, 6 and 7 at time, T 0.

[0014] in the present pharmaceutical composition, acetyl sal icylic acid (or a pharmaceutically acceptable salt thereof) may be present at dose of about 90 mg or ess* about 80 rug o less, about 70 rag or less, about 60 mg or less, about 50.nig or less, aboiit 40 mg or less, about 30 mg or .less, about 20 mg or less, about .15 mg or less,, about .10 mg or less,, about 5 mg or less, or about 1 mg or less,

[0015J I»· the present pharmaceutical composition, aeetylsalieylic acid (or a pharmaceuticall acceptable salt thereof) may be present in an amount greater tha about 60% (w/w) of the dr particles, greater than about 70 (w/w) of the dry particles, greater than about 80% (w/w) of the dry particles, greater than about 85% (w/w) of the dry particles* greater than about 90% (w/ w) of the dry particles, greater than about 95% (w/w ) of the dry particles, greater than about 96% (w/w) of the dry particl es, greater than about 98% ( w/w) of the dry particles; greater than about 99% (w/w) of the dry particles, or about 100% (w/w) of the dry particles. f 801.6] The phartnaeeuiieal composition m y ftuther contain a plmrmaceti&a!ly acceptable excipient

[110171 The present disclosure also provides for method o treating thrombosis or redacing the risk of a thromboembolic event The method may comprise the step of administering to a subject in need thereof the present pharmaceutical composition, where the pharmaceutical composition comprises a therapeutically effective -dose of acetyisalieyilc acid, or a

pharmaceutically acceptable salt thereof In one embodiment, the pharmaceutical compositioa is delivered b a dry powder inhaler, jOO!Sf The present composition may be administered by inhalation, such as oral inhalation, and nasal inhalation, or other routes.

10019| in certain embodiments, the present pharmaceutical composition is administer ed to a patient or subject in an emergency. In certain embodiments, a single dose, 2, 3, 4, 5, 6 or more doses of aeetylsahcylie acid, or a pharmaceutically acceptable salt thereof is administered to the subject. In certain embodiments, the method comprises (or consists essentially of or consists essentially of) the step of administering a single dose of the present composition, to the subject In certain embodiments, a single dose of acetyisalicylie acid (or a pharmaceutically acceptable salt thereof) may be about 90 mg or less, about 80 mg or less, about 70 mg or less, about 60 mg or less, about 50 nig or less, about 40 mg or less, about 30 mg or less, about 20 mg or less, about 15 .mg or less, about 10 mg or less, about 5 mg of less, or about 1 trig or less,

100201 Also encompassed by the present disclosure is a method of making dry particles that comprise acetyisalicylie acM, or a pharmaceutically acceptable salt thereof The method, may comprise the fallowing steps: (a) jet milling acetyisalicylie acid, or a pharmaceutically acceptable salt thereof, to particles with, a -size of no greate than about. 5 prn; (b) suspending the particles comprising aeetylsalicylic acid, or a pharmaceutically acceptable salt thereof in a solvent chosen from, hexane, heptane, or a mixture thereof; and. (c) spray drying the suspension. In certain embodiments, acetylsaticyJic acid, or a pharmaceutically acceptable salt thereof, is suspended in the solvent at about 20 t%, about 15 t%, about 10 wt.%, about 8 wt¾, about 6 wt%, about 5 wt%_;s about wt%_s about 3 wiH, about 2 wt%, about 1 wt¾_¾ abou 2 wl% to about wt%₅ about 2 wt% to about 15 wi%_} about 2 wt% to mi 10 wt¾_i5 about 2 wt% to about 5

BRIEF DESCRIPTIO O THE DRAWINGS f 0021] The patent or application file contains at least ne drawing executed hi color. Copies of this patent or patent application publteatio with color drawing(s) will be provided by the Office upon request and .payment of t e necessary fee, The accompanying drawings, which are included to provide further understanding of fee subject technology and are incorporated in and -constitute a part of this specification, illustrate aspec ts of the subject technology aiid together with the description serve to explain the principles of the subject technology, 0022| Figures 1 A and I B show laser diffraction dat , (Figure I A) and morphology (Figure j B) of milled control (BEEC-I 51 1 -024, .100% jet-milled. ASA), 1 0% ASA (BREC-151 I-03SA, spray dried from hexane), and 99.9, 0, 1 AS A Lecithin (BREC-1511 -038B, spray dried from hexane) formulations. f0023$ Figures 2 A and 2B show laser diffraction data (Fi ure 2 A) and morphology (Fi ure 2B) of spray dried EtOH based aspirin (BREC-1511-0201), and EtOfi based aspirin formulations 'containing distearoyl phosphatidylcholine (DSPC) (¾ EC- 1511-020 ) and lecitihi (8REC- I S1 1 -020L}.

|:ΘΘ24| Figures 3 A and 3B show laser diffraction data (Figure 3 ) and morphology' (Figure 38} of EtOH based aspirin (BREC- 151 1-0201, used for the comparison in this example), and spray dried EtOH based ASA containing lactose (BREClSi I -0200).

|0025| Figures 4A and 4B sho laser diffraction data (Figure 4 A) and morpholog (Figure 4B) of ASA sprayed from pure EtOH (BREC-15 1-0201) and the EtOH based ASA iorninlation containing anti-solvent . (H2O) (BREC-151 1-O20 ).

100261 Figures 5A and SB show laser diffraction data (Figure 5A) and morphology (Figare SB) of EtOH based 100% ASA (sprayed dried) high: GIL (gas to liquid) ratio (BREC-I51 1.-0201), middle G L ratio (BREC-15H-O20A), and low GIL ratio (BREC-151 I-020H).

[0027] Figure 6 shows laser diffraction data of 100% jet-nn ied ASA (BREC-151 1-024), BREC-151 1 -038A (spray dried from, hexane, 100 ASA), spray dried from hexane 99.9/0, 1 AS A/Lecithin. (BREC-i SJ I-038B) over the period of four weeks {time ø;, ek 1. eek 2,. -and week 4} at 30°€ and 65% relative humidity (KHK

[00281 Figure 7 shows laser diffraction data of BREC-1511 -0201, BREC-iSl 1-Q20K,. BREC-.1.511-020L oyer the period of four weeks (time 0, week I, week 2, and week 4) si 3Q°C and 65% relative .humidity ( H).

{00291 F!gore 8 sho s laser di»aetio«. dataof BREO-I5I 1-020D_? BREC- 1511-02011 BREC 3511 -020 ¾ over the period of lour weeks (ti me 0, week 1, week % arid week 4} at 30^¾C and 65% relative humidity (RH). fii030| Figure 9 shows the particle rm distribntiMi of BREC I Si 1-024 particles ¼sed ø«- MGI analysis (week 4, a 3iP€ and 65% RH). p03t{ Figure 1Θ shows the par eie size distribution, of BREC! 511 -038A particles based on NGi analysis (week , at 30^&C asd 65% RH).

[§032J Figure 11 shows the particle size distiibution of BRECl 5 ! I -03 SB particles based on JMGi analysis (week 4, at 30°C and 65% RH).

[ 331 -Figure 12 shows the particle ske distribution of BREC 15114320M particles based on NGI analysis (week 4, at 30°C and 65% RH). 03 Figure 13 shows the particle size distributio of BREC15! I~02GD particles based on MGI analysis (week -4, at 30°C and 65% RH).

[003S| Figure 1 shows the particle size distributio of BREC 1511 -0201 particles based on NGi analysis (week 4, at 30°C and 65% RH).

[Θ036| Figure 15 shows the particle size distribution of BREGI51.1-0201 particles based ori HGI analysis (week 4, at 30°C and 65% RH).

^'[00371 Figure 16.shows the particle si¾ distribution of BREC151 1 -020K particles based on HOI analysis (week 4, at 30°C and 65% RH). f 0038| Figure 17 show the particle size distf ibution of BREC 1511-020L particles based oft NGT analysis (week 4, at 30*C d 65% RH).

[0039J Figure 1 S shows particle morphology of BRECl 511 -024, HREC15 ! 1~038A, and 99. (U ASA/Lecithin EEC1511-Q38B MnrnMx s (at 2 weeks, at 50°C 75% RH).,.

|f040 Figure 19 is a surnrnary of RP~HPLC results ofBREClSll-i}24₅ BRECISl l-03iA₅ and BREC1511 -038B after 2 weeks at 50°C ?5% RH, 004.11 Figure 20 is a graph of par tick size distribution of BREC 1513 -024, BREC 1511- 038A, and BREC151 1-038B after 2 weeks at 50*075% RH.

[§0421 Figure 21 shows the particle size distribution of BRECl 51 1 -024 particles based on HOT analysis (after % weeks at 50^¾C/75% RH)_*

|0O43 Figure 22 shows the particle size disiribatioft of BRBC1511 -038A. particles based or* HGX analysis (alter weeks at 5(i⁰C/75%,RH).

|9044| Figure 23 shows the particle size distriburioii of BRECl 51 I-Q38B particles based on .MGI analysis (after 2 weeks at 50°C 75% RH),

|004S] Figure 24 shows laser diffraction data for (BRE VI 511 -052 A), Spray Dried 100% jet Miiied ASA (High FIow){BREC- 15 ! 1-052B), Spray Dried 100% Jet Milled ASA (High Flow, High Soiids)(BREC-lS1 1-052C), Spray Dried 100% Jet Miiied ASA (Bigh Flow, High Solids, High Tout)(B EC-1511-052D), and Spray Dried 99.9/0,1 Jet Milled. ASA/Le ithift (High Fl0w)(BREC~ 1 1 1 -052E),

(004 1 Figure 25 shows particle morphology of BREC~I5! i-052A, BREC~!511-0S2B, BREe 5U-052C BREC-1511-052D, and BREC-I511~052E (images were obtained using SEM),

[0047 J Figure 2.6 shows powder characteristics for each hatch (BREC- 15 i -052 A, BREG- Ι5Π-052Β, BREC-l n~052C, BREC- 5I1~0S2D₅ and BREC~15H-052E), DETAILED DESCRIPTION

{0048! tbe following detailed description, numerous specific details are set forth to provide a full dersta in of the subject technol ogy, ft w ill he apparent, however , to one ordinaril skilled i the art that the su ject technology may he practiced without some of these specific details, in other instances, well-know structures and techniques- have- not been shown in detail so as not to o scur the subj ct technology.

Thromboembolic Symptoms and ^'Ev nts

[9049] A thromboembolic event, such, as myocardial infarction, deep venous thrombosis, pulmonary embolism,, thrombotic stroke, or other ischemic event, can present with a- group of symptoms that allow a patient or clinic tan to prov ide an init ial therapy of ^'treatment for the event, i.e., immediately, of within about 5 seconds_* 10 seconds, 30 seconds or 1 , 5, 10 or 1.5 minute from the onset of the thromboembolic event. In certain situations, an 81 mg_} lo dose, or 'baby" ASA or a regular ASA (330 nig) may be orally administered in order to provide an. initial treatment for the patient. However, oral administration ma not act as quickly as necessary to provide a sufficient therapeutic effect and therefore, would not provide immediate protection to the patient. Pulmonary drug deli ver system and related methods or the present disclosure provide for as accelerated and more efficient pathway and treatment for reducing the risk of a thromboembolic event and/or providing treatment for a thromboembolic- event. For example, certain embodiments provide systems and methods of adt»ihisierij8g a non-steroidal anti- inflammatory drug (NSAID) by inhalation, such as by a dry powder inhaler (DPI) or a metered dose inhaler ( Df),

Delivery Mechanisms for Drugs

[90501 There are limi tations of administration of drugs by inh alation because the dosage of an inhaled drag, as well as the delivery timing, can often be difficult to precisely measure.

Usually, d powder inhalation is used to administer drugs that act specifically on the lungs, such as aerosolized anti-asthmatic drugs in metered-dose containers or administer gases used for general anesthesia. The present disclosure provides for accurate and reproducible delivery of ASA via a dry powder device. (0051 certain^■■embodiments, coating; of the .drug particles with surfactant., such as dipalmltoyl phosphatidylcholine (DPPC)* distearoyi phosphatidylcholine (PS PC) or soy lecithin can reprodudbl improve deliver of the drag from the. dry powder Inhaler device.

Pharmacokinetics of AS

|0052j For example, harmacokinetic: studies show that after oral administr tion of aspirin the peak plasma levels of acetyl salicylic acid (ASA), the active ingredient, arc achieved after about 20 ruin at s, after which the pl asma levels rapidly decline due to the relatively shor elimination half-life (15-20 minutes). By comparison, plasma levels of the primary

pharmacologically active metabolite salicylate, increase for a period of about.45 minutes following administration of ASA. and remain elevated for much longer due to its sigmfieanfly longer elimination half-life (2-3 hr) (Dressman etal, 2012. Bio atver Monograph for

i^ffl^i¾g-Eg|g _.Sgjd 0 JPQgIge_.I_.g L S . doi 10.1002/}ps.23I2).

P053| Following administration of an oral dose of aspirin, peak, plasma level s of salicylic acid, the primary metabolite of ASA, are typically achieved after about 1-2 hours, and ASA is generally undetectable within 1-2 hours after administration. Aspirin Comprehensive

Prescribing information,

I¾¾fe i<¾¾l¾s ¾L¾he¾ - retrieved 1 1 /22/ 15. The rate of absorption from the G I tract i s. dependent on aniurifeef of factors including the dosage form, presence or absence of food, gastric pi as well as other factors. jOG f ASA. is used by millions of people to achieve desit&Me effects, a id by many people , baby (Bi rng dose) ASA is often used daily. The principal effect of ASA is to impair the function of cyclooxygena.se en ytnes (specifically,, COXI a d COX2 enzymes}. By inhibiting COX I, ASA can irreversibl inhibit platelet aggregation, which decreases: the risk of blood dots. Additionally* the impairment of the CQX2 enzyme can reduce inflammation, stiffness, and pain in the body by inhibiting prostaglandins and thromboxanes. As such, individuals at high risk for heart attack, stroke, or with inflammation often take ASA to address symptoms and effects of these conditions. As noted, AS can effectively reduce the likelihood of such myocardial events and reduce pain and inflammation, with dose as small as a baby ASA. However, due at least i part to its iahib on of€0X1, ASA can increase the risk ofMeextitig and cause damage to or ans such as the stomach, md ^'intesti»es* which can be painful.

Dry Powder Inhaler Technology

|OT55| Deli v ery of a drag by mhalaiion in. the early stages of an eme.rge.ney situation, c n also provide a fast-acting, effective form of preliminary treatment for certain medical conditions. For example, in one embodiment, upon receiving a complaint of a symptom of a thromboembolic event, a patient can be administered, by DPI, a therapeutic amount of a NfSAID. The SAlD can address problems associated with, or provide an initial, rapid treatment for, thromboembolic event

(FPP). Higher FPFs are more desirable when producing a inhalable drag formulation.

[00S7J Therefore, in various embodiments, a method for treating disease, e.g., by reducing the risk of a tliromboeiiiboiic event, can be provided, which comprises administering a NSAID, such as a -salicylate, b DPI or D For example., the method, can comprise administering ASA by a DPI or MDL The administered dose can be less than 25 mg of ASA. Further, in various embodimen ts, the administered dosage can be less than 20. mg of AS A. The

administered dosage can he less than 15 mg of ASA, less than 1.2 m of ASA, less than 10 mg of ASA, less than 8 mg of ASA, less than 5 mg of AS A, less than. 2,mg of ASA or less than 1 mg of AS A, In other embodiments, the dosage of ASA can be from about :2 mg to about 30 mg, about 4 mg to about 25 mg of ASA, about 6 mg to about 20 mg of ASA, about 8 mg to about 15 mg of ASA, about 10 mg to about 13 mg of ASA, about 1 mg,. about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6.mg, about ? mg, about 8 mg, about 9 mg, about 10 mg, aboiit 1 1 mg, about 12 t . about 13 rsg. about 14 ma, about 15 mg, about 16 ma, about 17 tag, about I S mg. about 39 mg.. or about 20 rag of ASA. Such dosages can. be bioeqoivaleiit when, compared to typical dosages of about 81 mg to about 325 mg, while demonstrating few negative side effects.

Alternatively, the dose of ASA can be less than about 80 mg. from about 1 mg to about 75 mg, .from about^' 2 mg to about 60 mg_:} from about 5 mg to -about 40 mg, from about 10 mg to about 30 from about 12 m to about 25 mg, or from about 15 mg to about 20 mg.

{00581 The dosages or dosage ranges described herein may be single dose or a daily dose.

|il0591 Thus, a NSAID, such as ASA, can he administered by DPI or MDI in a single dose or multiple closes tbaf are much less than a traditional oral dose of ASA. which can provide a equivalent treatment with fewer negative side effects. Further, systems (devices) of

administering such treatments are also provided. f006¾f !m some embodiments, a NSAID, such as aspirin, can be administered by DPI or MDI in multiple inhalation, doses. For example, e ASA ma be inhaled in 1-6; 2-6, 3-6, 4-6, 2-3, 2, 3, 4₅ 5, or 6 doses. The number of inhalations m be dependent on the amount of ASA present in each chamber of the DPI and/or the total amount of ASA to be delivered. For example, 25mg, 30 mg, 35 mg, 40mg, 50 tng, 25-40 mg, 25-50 rag of ASA may be delivered to the subject in 2 to 3 inhalations by DPI. The thromboembolic eveht may be myocardial iniarciiou, deep venous thrombosis, pulmonary embolism, or thrombotic stroke. The dose of the NSAID drug can b administered as a preliminary treatment in response t any symptom of a thromboembolic event Tile NSAID .may be ASA and ma be administered in a- single dose or in multiple doses, e,g„ 2, .3, 4, 5, 6, 7, 8, 9 or 10 or greater. f 00613 In some embodiments, the NSAID, in particular;- ASA, can be formulated to include pharmaceutically acceptable excipients that are effective to improve aerodyuamic performance, .bioavailability and/or phamiacokineties as compared to prior art methods of administration.

I (I062| The DPI or MDI apparatus can have moutbpiece and an actuation member for making avai lable the NSAID for mhalation by a patient to reduce the risk of the thromboemboli c event. 0 3 For exam le, according to one embodiment, a metho of reducing the risk of a thromboembolic event is provided and can comprise adroitusteririg dose of a nonste oidal and- iutlanrmatory drug by a dr powder inhaler. The dose can be effective to reduce a risk of a thromboembolic event in a patient. The dry powder inhaler can have a mo^'uttpiece and an actuation, .member for making available the dose of the non-steroidal ariti ni½inr»atory drug for inhalation by the patient to reduce the risk of tbe thromboembolic event.

Nonsteroidal A«ts nfMmmatnr rags CNSAIBS)

£110641 NSAIDs, such as ASA, can provide various -beneficial effects and contribute to reducing the risk of a cardiovascular disease (such as thrombosis). However, the use of NSAIDs, such as ASA, m a clinical, setting has -traditionally been limited to oral administration. Oral administration -of ASA, for example, can result ih-the loss or inaciivation of approximately 2/3 of the oral dosage due to the first pass effect in. the gut and liver. While one third of the dosage reaches the systemic blood stream and provides the desired effect, the negative side effects created by the lull dosage often deter patient from using ASA on. a regular or dally basis. jftOeSJ Further, in many situations, such as m emergencies, oral administration of NSAIDs, such as AS A, may be inappropriate because it may take too long for the drug to become effective. An alternative administration method and systems can be -implemented that utilize a lower dosage and provide a more direct delivery mechanism to the systemic blood stream. Thus, the methods and systems of the present disclosure allow fo the beneficial effects of NSAIDs, such as ASA, to be achieved on both a regular basis as well as in emergency situations, while minimizing previous drawbacks associated with the use of NSAIDs. j 00661 » certain embodiments. NS AIDs can be used in various methods at¾d systems. Irs some embodiments, NSAIDs can include salicylates_* i.e., the salts and esters of salicylic acid, which have anti-platelet action. Further, NSAIDs can also include one or more of the following compounds listed in Table 1.

Table I As kiB (Asp tt Is a brand. name; fc chemical Is called ASA)

Celecoxib (Celebrex)

Dexdetoproferi ( erai)

Diclofenac (Vo!tare¾ C&taf!arn, Y oltaiea- R)

Diflttnisal (Dolo ld)

Etodolac (Lodine, Lodine XL)

Btoricoxlb (Algix)

Penoprofea (Fetiopron, alfma)

j iidoni6thaciR (1 ndoei a , Imfocin $ R, ladoc m IV)

Ketoprofen (Ac ron, Orudis, Qriivail, Keteflam)

Ketorolac (Toradol, Sprix, Toradol IV flM._f Toradol IM)

Lic feloRe (imder development)

Comoxicaai (Xeffa)

Loxo rofeii (Loxonift,. toxoamc , Oxeno)

Luffliracox tb (Prex tge)

Meciofeaamic acid (Meclomen)

efeiiariilc acid (Poustei)

Meloxicam ( ova¾ Mel ox, Recoxa, Mobile)

abm etoPe (Re lafen)

Naproxen. ( Aleve, Anaprox, M Idol Extended Relief, Na rosyn Naprelasi)

N½esati¾e (SaKde, fSTknafox, es lid)

Qxaporozm (Daypro, Daytttn, Durapro )

Parecoxib (Dynastat)

a llndac (C ί ί noril )

Tenaxicam ( obi flex)

Tolfenamic acid (Cloiairs. Rapid, Tidbil)

VaMecoxib (Bextra) |iM7| Other alternatives cm also be used iastea of a NS Al D fe some methods or systems disclosed lierem,. Such alternatives include as Piavi (elopidogrel), COX-2 inhibitors, other remedies such, as Nattokinase (an zyt (EC 3A21 ,62, extracted ami purified .from a Japanese food called natto)}. Further, other .drugs that provide different beneficial effects, such as being effecti ve to reduce a risk of a cardiovascular di sease (such as thrombosi s) in a patient can also be used in some embodiments. Thus, the discussiors of methods aod systems shall apply

generally to these various alternatives^ althougb for discussion purposes., the present disclosure often refers t aspirin. It is contemplated that the methods, effects, rmac kinetic data, and other considerations relating to aspirin can be equally applie o other NSAIDs, according to some embodiments.

100681 The subject technology relates to respirah!e dry powders aud dry particles that comprise an NSAIB, such as AS A, as an active ingredient

\ϋ069\ i n one aspect, the dry particles of the subject technology are comparatively small, and preierably are dispersible. The size of the dr particles can be expressed is a vari ety of ways that are conventional in the art, such as, fine particle fraction (FPE), volumetric median ...geometric- -diameter ( VMGDj, or mass median aerodynamic diameter (MMAD). (Ι 7β In one embodiment, the respirab! dr particles of the subjeet technology can have an MMAD of about 5 μηι or less., about 0,5 μικ to about S pm, about I uia to about 5 μη¾ about 4 pro or les (e.g., about 1. μικαο about 4 μτη), about 3.8 um or less (e.g÷ about I μ-ra to about 3.8 μι»), about 3.5 μ«ι or less (e.g. about 1 μηι to about 3.5 μηι), about 3,2 x,m or less (e.g. about 1 μηι to about 3,2 μηι), about 3 μηι or less (e.g. about 1 μχ to about 3,0 μηι), about 2,8 μηι or less (e.g. about 1 μητ to- about 2.8 μχη), about 2.2 μηιοτ less (e.g. about I p to about 2,2 pm), about 2.0 pin or less (e.g. about 1 μηι to about 2.0 pin) or about 1.8 er or less (e.g. about i micron t about 1 >% μη.ί),

[Θ071] Alternatively or m ddi ion, the dry powders and dry particles- of the subject technology have a FPF of the total dose of less than 5.0 μηι (FPF JfD < 5.0 μηι) of at least about 20%, at least about 30%, at least about 45%, preferably at least about 40%,. al least about 45%, at least about 50%, at least about 60%, at least about 65% or at least about 70%. Alternatively or its ad ition, the dry powders and dry particles of the subject technology have a FPF of the emitted dose of less than 5.0 μπι (FPF B < 5,0 μ-ra) of at least about 45%, preferably at least about 50%, at least about 60%,. at least about 65%, at least about 70%, at least about 75%, at least about §0%, or at least about 85%,

[00721 D 10 represents tfee particle diameter corresponding to 10% cunmlative (from 0 t 100%) uuderslze particle size distribution. other w rds, if D 1.0 is A urn, we can say 10% of the particles in the tested sample are smaller than A micrometers, or the percentage of parti cles smaller than A micrometer is 10%. D50 represents the particle diameter corresponding, to 50% cumulative undersize particle size distribution, 090 represents the particle diameter

corresponding to 90% cumulative understKe particle size distribution_* As used herein, D1.0 and D(v0, J ) are interchangeable; D30 and D(v0,S) are interchangeable; D9 and (v0.9) are interchangeable,

[00731 la one embodiment tfee respirable dry powders and dry particles of the subject technology can have, a water or solvent content of les than, a out 15% by weight of the respirable dry particle, lor example, the respirable dry particles of die su ject technology can have a water or solvent c onten t of less than about 15% by weight, less than about 13 % by weight, less than about 11.5% by weight, less tha about 10% by weight, less than about 9% by weight, less than about 8% by weight, less than about 7% by weight, less than about 6% by weight, less than about 5% by weight, less than about 4% by weight, less than about 3% b weight, less than about 2% b weight, less than about 1% by weight or be anhydrous. The respirable dry partic les of the subject technology can have a w ater or solvent content of less than about 6% and greater than about i%, less than about 5.5% and greater than about 1,5%, less than .about 5% and greater than, about 2%, about 2%, about 2_t5%_s about 3%_s about 3.5%, about 4%, about 45% about 5%.

10074 J Depending on the specific applications of the dry powders described herein, the dry powder and particles may contain a varying percentage Of active Ingredient in the composition, for example, the dry particles may contain.3% or more, 5% or snore,, 10% or more, 15% or more.20% or more, 25% or more, 30% or more, .35% or more, 40% or more, 50% or more, 60% or ore, 70% or o , 75% or niaf¾_s 80% or mam,, 85% or more, 9Q% or more. Or 95% or more (weight ' ercentage) of the active ingredient (e.g., ASA)_*

Delivery and Treatment with Dry Powders 075J According to some embodiments disclosed herein, absorption of NSAIDs

administered by DPI or MDl through the pulmonary capillaries and epithelium may provide an immed ate y effective treatment to address symptoms of thromboembolic events. f 00761 in .accordance with some emb diments, the dry powder administration of the MS A13¾ such as a salicylate like ASA, can he highly porous and demonstrate a sponge-like morphology or be a component of a carrier particle. The particles cm also demonstrate a spheroidal shape, by which the shape and porous surface can serve to decrease the area of contact between particles, thereby leading to less particle agglomeration and more effective distribution throughout the !trag. ^'Dry powder technologies, such as FulmoSpherei . may be implemente in embodiments of the methods and systems disclosed herein.

[0077) The absolute geometric diameter of the particles measored at I bar using the HHLOS system is not critical provided that the particle's envelope density is sufficient such that the MMAD is in one of the ranges- listed herein, wherei MMAD is VMGD times the square root, of the envelope density (MMAD ~ V GD*sqrt (envelope density)). If it is desired to deliver a high unit dose of ^'salt using a fixed volume-dosing container, then, particles of higher envelop densit are desired. High envelope densi ty allows for more mass of powder to be contained within the fixed vqlu e-dosifig container. Envelope densities may be greater than. ®,l gfcaf, greater than 0.25 g/cm - , greater than 0.4 g/cm³, greate than 03 g/eitr , and greater than 0.6 g/cm^.

[00781 The respirable dry po wders and particles of the subject technology ca he employed in compositions suitable far drug delivery vi the respirator system. For example, such compositions can incl ude blends of the respirable dry particles of the subject technol ogy and one or mo e other dry particle or powders, such as dry particles or powders that contain another acti ve agent, or that consist of or consist, essentially of one or more pharmaceutically acceptable exci ienis. (00791 espirable dry powders and dry particles suitable for use in the methods of the su jec ^'technology cm travel through the u er airways (Sue.* the oropharynx aud larynx), die lower airways, which include the trachea followed by bifurcations into the bronchi and bronchioli, and through die terminal bronchioli which in torn divide into respiratory bronchiole leading then to the ultimate respiratory ¾one, the alveoli or ihe deep Sung, In one embodiment of the subject technology, most of .the mass of respirable dry powders or particles deposit the dee lung, in another embodiment of the subject technology, deliver is primarily to the central airways. In another embodiment, delivery* is to the tipper airways. j 00801 The respirable dry particles or dry powders of the subject technology can he deli vered by Inhalation at various parts of the breathing cycle fag._* laminar flo a mid-breath). An advantage of the hi gh disperslhi!ity of the dry powders and dry particles of die subject technology is the abilit to target deposition in the respiratory tract. For example, breath controlled delivery of nebulised solutions is a recent development in liquid aerosol deliver (Dalby ef l in Inhalation Aerosols, edited by Hickey 2007, p. 437). In this case, nebulized droplets are released only dining certain portions of the breathing cycle. For deep lung delivery, droplets are released In the beginning of the inhalation cycle, while for central airway deposition, drey are released later in the inhalatiaii. jOOSlf The dry powders of this . subject: technology^' provide -advanta es ^· for targetiug the timing of drug delivery i n the breathing cycle and also specific locati n in the human rang.

Because the respirable dry powders of the subject, technology can be dispersed rapidly, such as wi thin a fraction of a typical inhalation maneuver, the timing of the powder dispersal can be controlled to deliver an aerosol at specific times within the inhalation. j 0§82| Wi th a highly dispersibie powder, the complete dose of aerosol can be dispersed at die beginning portion of the inhalation,. While die patien s inhalation flow rate ramps u to the peak inspiratory flow rate, a highly dispersibie powder will begin to disperse already at: the beginnin of the ramp up and could completely disperse a dose in the first portion of the inhalation ; Since the air that is inhaled at the beginning of the inhalation will ventilate deepest into the lungs, dispersing the most aerosol into the first part of the inhalation is preferable fo deep lung deposition. Similarly, for central deposition, dispersing the aerosol at high concentration into the air which will ventilate the central airways ears be achieved by sa i dispersion of the dose Bear the mid to end. of die inhalation. This can be accomplished^' by a number of mechanical and other means such as a switch operated by time, pressure or flow rate that diverts the patient's inhaled air to die powder to be dispersed only after the switch conditions are met (I083| Suitable intervals between doses that provide the desired thera eut c effect cart be determined based on the se verity of the condition, overall well-being of the subject and the subject's tolerance to respirabie dr particles and dry powders as well as other considerations. Based on these and other considerations, a clinician can determine appropriate intervals between doses, Generally, respitabfe dry particles and dry powders are administered once, twice or three Mines a day , as needed;:

[0084J in some embo iment ie amount of NSA1D deli vered to the respiratory tract (e,g,_f lungs, respiratory airway) is about §.00 ! mg/kg body weight/dose to about 2 mg/kg body weight/dose, about 0.002 mg/kg body weight/dose to about 2 mg kg body weight/dose, about 0.005 mg kg body weight/dose to about 2 mg/kg body weight/dose, about 0.01 mg/kg bod weight/dose to about 2 mg/kg body weight/dose, about 0,02 mg/kg body weight/dose to about mg/kg body weight/dose, about 0.05 mg kg body weiaht/dose to about 2 mg/kg bodv

weight/dose, about 0.075 mg kg body weight/dose to about 2 mg kg body weight/dose, about 0.1 mg/kg body weight/dose to about 2 mg/kg bod weight/dose, about 0.2 mg/kg body weight/dose to about mg/kg bod weight/dose, about 0.5 mg/kg body weight/dose to about 2 mg/kg body weight/dose., or about 0,75 mg/kg body weight/dose to about 2 mg/kg body weight dose,.

|O085 In certain embodiments, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about SS% at least about 90%, at least about 95%, or at least about 99%, of the administered ASA reaches the systemic circulation of a, subject within about 60 minutes upon administration,, or within about 40 miniates upon administration, or within aboiit 30 minutes upon administration, or withi about 20 minutes upon administration, . or within about 15 minutes upon administration., or within about 5 minutes upon administration. 0Θ | In certain embodiments;, the m thod and delivery devices described herei ca deliver ASA, and pharmacologically active metabolic byproduct of ASA thereof, to the systemic circulation, at levels that are substantially the same, or higher as compared to those delivered b oral administration of about 30 -MO rag of ASA, specifically, 40 mg, 50 mg,. 60 mg, 80 mg or 160 mg.

administration, or within about 5 minutes upon administration.

[6089J If desired or indicated, the respirahle dry particle and dr powders described herein can be administered with one or more other therapeutic agents. The other therapeutic agents can be administered by an suitabl route, such as orally, parenisrally (e.g., intravenous, intraarterial, intramuscular, or subcutaneous injection), topically, by inhalation (e.g., intrabronehiaL intranasal of oral inhalation, intranasal drops), reetally, vaginally, and die like. The respirahle dry particles and dry powder can be administered before, substantially concurrently ith, or subsequent to administration of the other iherapentic agent.. Preferably, the respifitble dry particles and dry powders and the other therapeutic agent are administered so as to provide substantial overlap of their pharmacologic activities. |-0β 0| Tile -compositions ami methods of the present disclosure provide for a method for treating (including prophylactic treatment^' or reducing the risk) of a cardi ovascular disease (such as thrombosis), comprising administering to the respirator tract of a subject in weed thereof an effective amount of respirable dr particles or dry powder, as described herein.

.[00.91 J Cardiovascular diseases include, for example, atherosclerosis, coronary artery disease (CAD), angina pectoris (commonly known as "angina"), thrombosis, ischemic heart disease, coronary insufficienc _* peripheral vascular disease, myocardial infarction,, cerebrovascular disease (such as stroke), transient ischemic attack, arierioioscierosis, small vessel disease, elevated cholesterol, intermittent claudication or hypertension.

[00921 respirabl dry particles and dry powders can he administered to the respiratory tract of a subject in need thereof using -any suitable method, such as instillation techniques, and/or an inhalation, device, such as a dr powder inhaler (DPI) or metered dose inhaler (1VID1), A number of DPis are available, such as, the inhalers disclosed is U. 5. ^'Patent No. 4,995,385 and 4,069,81 , Spinhai«st<¾' (Fisor^ !Loyigbbor ttgfe, il. .), Rotalmlers®, DisMtaler and Diskus® (QiaxoSmith liue, Research Triangle ^'Technology .Park, North^' Carolina), FlowCapss®,

TwinCaps®, XCaps (Jiovione, Lo res, Portugal), Inhalators® (Boejhr^'ingeringemeim, Germany), Aerolizer® (Novartis, -Switzerland), and others known to those skilled in the art. 093| Generally, inhalation devices (e,g., DPis) are able to deliver a maximum amount of dry powder or ry particles in a single inhalation, which is related to the capacity of the blisters, capsules (e.g. size 000, 00., OE, 0, 1, 2, 3, and 4_S with respective vehuBeirie capacities of 1 7mi, 950μΙ, ?70μΙ, 680μ1, ^:4^'8ϋμ1, 360μΙ, 270.μ1, and.200μ1> or other means that contain the dry particles or dry powders within the Inhaler. Accordingly, delivery of a desired dose or effective amount may require two or more inhalations. Preferably,, each dose that is administered to a subject in need thereof contains m effective amount of respirahle dry particles or dry powder and is administered using no more than about 4 inhalations. For example, each dose of respirable dry particles or dry powder can he administered in a single inhalation or 2, 3, or 4 inhalations. The respirable dr particles and dr -powders are preferably administered in a single, breath-activated step using breath-activated DPI. When this type of device is used, the energy of the subject's inhalation both, disperses the tesphable dr particles and draw them into the respiratory tract. ( 0 41 For dry powder inflates, oral cavit deposition is donnnated by inertia! impaction and $o characterized, by the aerosol's Stoles number (DeHaan ei al Journal of Aerosol. Science. 35 .(3), 309-331, 2003). For equivalent inhaler geometry, breathing pattern and oral cavity geometry, .the Stokes number, and so the oral cavity deposition, is primarily affected by the aerodynamic size of t he inhaled powder. Hence, factors that contribute to oral deposition, of a powder include the size distribution of the individual particles and the dispersihility of the powder. If the MM AD of the individual particles is too large^ e.g. above 5 μττι, then

increasing, percentage of powder will deposit in the oral cavity. Likewise, if a powder has poor dispersibilsty, it is an indication that the particles will leave the dry powder inhaler and en ter the oral cavity as agglomerates. Agglomerated powder will perform aerodynamical ly like an individuai particle as large as the agglomerate, therefore even if the individual particles are small ( .g._t ΜΜΑΌ of about 5 μιπ or less), the size distribution of the inhaled powder may have an MAD of greater than about 5 prn, leading to enhanced oral cavity deposition, f e095J The respirable dry powders and particles of the subject technology can be employed in compositions suitable for drug delivery via the respirator system. For example, such compositions can include blends of the respirable dry paiticies of the subject technology and one or more other dry particles or powders, such as dry particles or powders that contain, another active agent, or that consist of or consist essentially of one or more pharmaceiiticaiJy acc eptable exeipients,

METHODS FOR PREPARING OKY PO BEES AND PRY PARTICLES 0O 6| The respirable dry particles and dry powders cars be prepared using any suitabl method. Many suitable methods for preparing respirable dry powders and particles are conventional in the art, and include single and double emulsion solvent evaporation, spray drying, milling (e.g._t milling), blending, solvent e traction_s solvent evaporation, phase Separation, simple and complex eoacervation, inter facial polymerization, .suitable methods that involve the use of supercritical carbon dioxide (COi), and other suitable methods, Respirable dry particles can be made using methods for making microspheres or microcapsules known in the art. These methods can be employed under conditions that result in the formation of respirable dry particles with desired aerodynaniic properties (eg,., aerodynamic diameter and geometric diameter), If desired, respirable dry particles wit desired properties, such as siae and density, cm be selected using mutable methods, such as sieving.

Spray Drying

|Q097j Inlialafele dry panicles can be produced by spray drying. Suitable spray drying techniques are described, fer example, by _h Masters in "Spray Drying fMndbaok^*', John Wiley & Sons, New York (1984); and spra drying techniques developed by B^'UCHI Laborator Equipment or GEA Mho drying technology. Geueralty, du ing spray drying,; hear froni a hot gas such as heated air or nitrogen is used to evaporate a sol vent f om droplets formed by atomizing a confiniiotis liquid feed_* If desired, the sp ay drying or Other instruments, e.g., j&t milling instrument, used to prepare the :dry particles can i clude an Mint- geometri c particl e sizer that determines a geometric diameter of the respirable dry parti cles as th ey are being produced., and/or an inline aerodynamic particle si¾e.r that determines the aerod namic diameter of the respirable dry particles as they are bein produced.

|0098J For spray drying,, solutions, emulsions or suspensions that contain the components of the dr particles to he produced, in a suitable sol vent (e.g., aqueous .solvent, organic so ent, aqueous-organic mixture or emulsion) are distributed to a drying vessel via an atomization device. For example, a nozzle or a rotary atomizer may be used to distribute the solution or suspensio to the drying vessel For example, a rotary atomizer having a 4* or 24-vaned wheel may be used. Examples of suitable spray dryers that can be outfitted wit either a. rotary atomizer or a nozzle, include, Mobile Minor Spray Dryer or the Model PSD* I, both

manufactured by ro, Inc. (Denmark). Actual spray drying condittons will var depending, in part, on the composition of the spray drying solution or suspension and material flow rates. The person of ordinary skill will be able to determine appropriate conditions based on the

compositions of the sol ution, emulsion or suspension to be spray dried, the desired particle properties and other factors. In general, the inlet temperature to the spray dryer is about 100^eC to about 300*0* and. preferably is about 220°C to about 285°€, The spray drye outlet temperature will vary depending upon such factors as the feed temperatur and the properties of the material s being dried. Generally* the outlet temperature is about 50°G to about 150°C, preferably about 9tFC to about 120*0 or about 98*C to about 108°C If desired, the respirable dry particles that are produced can be fractionate by volumetric sl¾e, for example, rising a sieve, or fraetioned by aerodynamic size* for example, using a cyclone, and/or ferther separated, according to density using techniques known to those of skill, in the art j0099| To prepare the respirable dry particles of the subject technolo y, generally, a solution, emulsion or suspension that contains the desired components of the dry powder (i.e.. a feed stock) is prepared and spra dried under suitable conditions. Preferably; the dissolved or suspended solids concentration in the feed, stock is at least about I g/L, at least about 2 g/L, at least about 5 g/L, at least about 10 g L, at least about 15 g/L, at least about 20 g/L, at least about 30 g L, at least about 40 g/L, at least about 50 g/L, at least about.60 g L, at least about 70 g/L, at least about B0 g/L, at feast about 90 g/L* or at least about 100 g/L, The feedstock, can be provided by^■ preparing a single Solution, or suspension by dissolvin or suspending suitable components (kg.., salts, exdpients, other active ingredients) in a suitable solvent. The solvent, emulsion or suspension can be prepared using any suitable methods, such as bulk mixing of dry and/of liquid components, or static mixing of liquid components to form a combination. For example, a hydrophiile component (e,g.,. an aqueous solution) and a hydrophobic component (e.g., an organic solution) can be combined using a static mix r- to form a combination. The

-combination can then be t mized to produce droplets, which are dried to form respirable dry particles. Preferably, the aiom ng step is performed immediately after the components are combined in the static mixer,

£00.100] In one embodiment, respirable dry particles tha comprise ASA can be prepared b spray dry ing. Spra drying is a commonly used method of drying a li uid feed thr ough a hot gas. It is a method whereby solutions or slurries can be rapidly dried to particulate form. by atonuzing: the liquid in a heated chamber, lypieaily, the hoi gas can be air aithough when preparing chemically sensitive materials such as pharmaceuticals, and where solvents such as ethanol ate- ^'used, and oxygen-free atmosphere is required arid so nitrogen task will typically be used. Spray drying is frequently used in the food preparation industry and has become an important method for the dehydration of fluid foods such as milk* coffee, and egg powder. The process is also adaptable to preparations of pharmaceutical and chemical formulations. ff M ] The liquid feed varies depending on the material being dried an is not limited to food ^'or phajrmaceutical products, and may be a solution, colloid or suspension. The process is a one-step rapid method that typically eliminates additional processing. By eontrolimg process conditions particles of the desired size can be reprodacibiv formed. In some cases, excipients can be included with the active pharmaceutical ingredient suc that a complex particle of API and excipient can be produced in a single step process. In other cases, an active pharmaceutical particulate preparation cars be produced in a first spray-dryin process, and mat product then modified fay the subsequent addition of one or more pharmaceutically acceptable excipienrs. In some cases it is possible to add excipients by a subsequent spray-crying process, Ol 02] In some spray-drying methods the liquid feed is um ed through an atorni¾er nozzle, or array of nozzles, that produce tine droplets that are nt oduc d into th main drying chamber.. Atomizers can vary there being rotary, single fluid, two-fluid, and ultrasonic designs. These different designs provide a variety of advantages, applicability and disadvantages depending on the particular spra drying process required. The hot dry ing gas can be passed as a concurrent or connier-current B w to the atomizer direction. The concurrent flow enables the particles to have a lower residence time within the system and the particle separato thus operates more efficiently, in some systems the particle separator is a cyclone device. The counter-current flow method enables a greater residenc time of the particles in the chamber.. Therefore, in general a spf ay-drying method will consist of the steps of pre-conceritration of liquid^ atomization, drying m hot gas atniosphe.re_s separatio of the dried powder from moist gas, cooling, and then packaging of the finished product. Θ0Ϊ 1⁾3] In one embodiment of the present disclosure, feed solutions with aspirin

concentrations of either 2% w/w, or 3% w w were prepared by adding aspirin to the appr opriate solvent followed by stirring until a homogeneous solution was obtained. A BUCHI spray dryer model B-290 Advanced was used in ah experiments. The unit was equipped with a two fluid nozzle. The high-performance cyclones were used to collect tire dried product. The spray-drying unit was operated in open cycle,, with the aspirator blowing nitrogen at 100% of capacity, corresponding to a flow rate of the dry nitrogen of approximately 40 kg per hour. The flow rale of atomization nitrogen was adjusted to 40 mm or 50 mm in the rotameter, depending on the particular trial. Before feeding the stock solution, the spray dryer was stabilized the solvent During the stabilisation period, the solvent flow rate was adjusted m orde to - iv^ the target outl et temperature, After stabilization of the outlet temperature, the feed of the spray dry er was commuted f om the solvent to the product .solution (inlet t m e atu e was then readjusted to maintain the outlet temperature in ^'the target value): At the end of the stock solution, the feed was once more commuted to solvent;, in order to rinse the feed Hue and carr out. a controlled shutdown.

(0011 1 Respitahie particles can also be produced by Jet-milling. See, e.g., techniques ^•developed by Apex Process T chnolog or ietphanna SA, Jet milling, is a process of using highly compressed air or other gasses. usually in a vortex -motion, to impact ine particles against each other in a chamber , -'et mills are capable of reducing so lids to particle sizes in the low-micron to su raicron range. The grinding energy Is created fey gas strearns 1mm horizontal grinding air nozzles. Particles in the ftuidized bed created b the gas streams are accelerated towards the center of the mill, colliding whh slower moving particles. The gas streams and the particles carried in them create violent turbulence and as the particles collide with one another they are pulverized,

1 010 1 Wet polishing is a process that combines a technology to attain a small particle size (either a bottom up technique such as controlled crystallization or nanocty staliization or top down technique such as high shear mixing or high pressure homogenizaiion) with a suitable isolation technology (for example spray drying or filtration with a drying process). Thes combinations can be used to tune the particle size and morphology to meet specific drug delivery needs. The method allows control of particle size distribution with tight spans and in-process sampling, and .maintains -crystalline state (little or no amorphous content),

Excipiettts

{Θ0Ϊ 061 Partic les described herein can be encapsulated, e.g. , by a pharmaceutical exe ipient such as lactose, sugar, or a polymer, §0107] in addition, particles described herein can be mixed and/or coated with arious pharmaceutically acceptable excipients. Excipients can be included in order to improve aerodynamic erform nce of the active drug, to improve bioa vailability, i ncrease stability*, to modulate H, to provide sustained release properties, to rovide taste-masking of an irritating: drug and/or to improve pharmacokinetic performance,

|00108| With dry powder foriMilations, exeipients can also provide a. carrier function to reduce clamping of the acti ve pharmaceutical ingredient and to improve so spension of the formulation m the airflow as the pharmaceutical preparatioii is being inhaled. Such carriers can include substances such as, hut not limited to, sugars sugar alcohols such as glucose, saccharose, lactose and f uctose, starches or starch derivatives, oligosaccharides such as dextrins, cyckuiextrins and their derivatives, polyvinyipyu lidine, al inic acid, tylose, silicic acid, cellulose, cellulose derivatives, sugar alcohols suc as mannitol ^'or sorbitol calcium carbonate, calcium phosphate, lactose, lactitol, dextetes, dextrose, tnaltodextrin, saccharides including ruonosacchaxides, disaeehafides, poiysaechariies suga alcohols suc as arabinose, ribose, mannose, sucrose, trehalose, maltose and dextran.

[00109} in some cases, an excipient can be provided in order to coat the active p rm ceutical ingredient., t us "masking" it. Masking s especially useful when the unmodified active pharmaceutical is irritating r otherwise unpleasant to the recipient. For example, in some cases it has been s hown thai coating a bi tter molecule with a. hydrogenaied oil and^■ surfactant combination is effective to covet the otherwise unpleasant taste of the active ingredient.

Particle Si«e Analysis

[00110] The diamete of the resprrable dry particles, for example, their VM iD, cap be measured using an electrical zone sensing instrument such as a ultisizer lie, (Coulter

Electronic., Lut n, Beds, En land), or a laser diffraction instru ent such, as a HELOS system: (Synipatec, Princeton, HI}. Other iustratnents for measuring particle geometric diameter are well kno wn In the art. The di ameter of resptrable dry particles in. a sample will range depending upon factors such as particle composition and methods of synthesis, ^'the itstribution of size of respirable dry particles in a sample can be selected to permit, optimal deposition within targeted sites within the respiratory system, fOOlIlj Experimentally, aerodynamic diameter can be determined using time of flight (TOF) measurements. For example, an instrument such as the Model 3225 Aerosizer DSP Particle Size Analyzer (Amherst Process Instrument, Inc.* Amherst, MA) can. be used to rneasnre aerodynamic diameter. The Aerosizer measures the time taken for individual respirable dry particles to pass between two fixed laser beams. f0O112] Aerodynamic diameter can also be experimentally determined directly using conventional .^■gravitational settling methods, in which the time required for a sample of respirable dry parEictes to settle a certain distance is measured. Indirect methods for measuring the mass median aerodynamic diameter include the Andersen Cascade Impactor (AO) and the multi-stage liquid impinger (MSLI) methods. Another method, of measurin the aerodynamic diameter is with a N x t Generation Impactor (NGI), The NG^'I operates on similar principles of menial impaction as the ACi The NG! may have multiple stages, e,g„ seven stages and can be c librated at How rates of ^'30_f.60, and 100 LPM. In contrast to the ACI, or which the impactor stages are stacked the stages of the NOI are all in one plane. Collection cups are used to collect the pariicies below each stage of die GL U.S. Patent No, 8,61.4,255, The methods and instruments for measuring particle aerodynamic diameter are well known in the art

£001.131 Fine particle fraction .(EPF) can he used as one wa to characterize the aerosol performance of a dispersed powder. Fine particle fraction describes the s ze distribution of airborne respirable dry particles. Gravimetric analysis, using a Cascade impactor, is one method of measuring the size distribution, or fine particle fraction, of airborne respirable dry particles. The Andersen Cascade Impactor (ACi) is an eight-stage impactor that can separate aerosols into nine distinct fractions based on aerodynamic size. The size cutoffs of each stage are dependent upon the flow rate at which the AG is operated., The ACI is made up of u ti le Stages consisting of a series of nozzles (i.e. , a jet plate) and an impaction ..surface (i.e., an. impaction disc). At each stage an aerosol stream passes tiiroirg the nozzles and impinges upo the sarface. Respirable dry particles in the aerosol stream with a large enough inertia will impact upon the plate. Smaller respirable dfy particles that do not have enough inertia to i pact o the plate will remain in the aerosol stream and be carried to the next stage. Each successive stage of the ACi has a thgker aerosol velocity in the nozzles so that smaller respi.taMe dry particles can be

■collected at eaeii successive stage. fiil J If desired, a two-stage collapsed AC! can also e used to measure fin particle fraction, The two-stage collapsed ACI consists of only the top two stages -of the eight-stage ACI and allows for the collection of two separate powder fractions. Specifically, a two-stage collapsed ACI is calibrated so that the fraction of powder that is collected on stage one is composed of respirable dry particles that have an aerodynataic diameter of less than 5.6 μηι and greater tha 3.4 μηι. The fraction of powder passing stage one and depositing on a collection filter is th us composed of respi rable dry particles having n aerodynamic diameter of less than 3.4 urn. The airflow at such a calibration Is approximately 60 L niin. f rtnuiation produced by the methods described herein, can be effectively delivered at airflow rates ranging from about 20L asin to about 60 L/m . 00115} An ACI can be used to approximate the emit e dose, which herein is cali d gravimetric recovered dose and analytical recovered dose, "Gravimetric recovered, dose" is defined as the ratio of the powder weighed on all s tage filters of the AC ! to the nominal dose, "Analytical recovered dose" is defined as the ratio of the powder recovered from rinsing all stages, all stage filters, and the induction port of the ACi to the nominal dose. The FPF TP (<5,0) is the ratio of the interpolated amount of powder depositing below 5.0 pro on the AC! to the nominal dose , The FPF D (<$.ø) is the ratio of the interpolated amount of powder depositin below 5.0 pro on the ACI t either the gravimetric recovered dose or the analytical recovered dose. j 001161 Another way to approximate emitted dose is to determine how mne powder leaves its container, e.g. capsnle or ^' lis er_* upon actuation, of a dry powder inhaler (DPI). This takes into account the percentage leaving the capsule, but does not take into account any powde depositing on the DPI. The emitted dose is the ratio of the we ght of the. ^'capsule w h the dose: before inhaler actuation to the weight of the capsule after inhaler actuation.. This measurement can also be called the capsule emitted powder mass (CEPM), 01i7j A Multi-Stage Liquid Impinger (MSLI) is another device that can he used to measure particle size distribution or fine particle fraction, 'the Multi-stage liquid Impinger operates on the same principles as the ACI, although instead of eight stages, MSLI has fi ve. Additionally , each MSLI stage consists of an eihanol-wetted glass -frit instead of a solid plate. The wetted stage is used to prevent particle bounce and re-e¾n-ainment which can occur when using the AO . U.S. Patent No. 8,614,255; fOO^'l 181 The subject technology also relates to respitahle dry powder or respirahle dr particles produced using any of the methods described herein..

Particl Stability

100! 191 One characteristic of pharmaceutical dry powders is whether they are stable at differeni temperature and hiunidity conditions. Unstable powders will absorb moisture f om the environment and agglomerate, thus altering particle size distribution of the powder.

[00120] in certain embodiments, the dry particles of the present composition have an MMAD (or DIG, D50 and/or D90) which varies less than about 30%,, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 8%, less than about 6%, less than about 4%, less than about 3%_i: less than about 2%_s or less than about 1 ¾, ailer the composition is stored at 30°C at 5% relative humidity for about 4 weeks, or stored at S^'0°C at 75% relative humidity for about 2 weeks, or stored at 50°C tor about S days.

{001.21} The stability of AS A formulations ma be tested under different eoBfiitioas that varied, in storage time, temperature as well as hernidity, f 00122] h one embodiment under various temperature, time, and humidity conditions, milled ASA suspended in hexane and spray dried exhibits a high stability.

110123] in one embodiment, ASA is sus nded, in hexane having the chemical formula OSH^'M prior to spray drying. lit another embodiment, ASA is suspended in heptane prior to spray drying. In further embodiment, ASA is suspended in heptane or hexane isomer, in yet another embodiment, ASA is suspended in heptane or hexane derivative prior to spra drying.

{00124} ASA may be suspended in a non-polar solvent or a liquid -comprising a non-polar sol v ent Noa-lirniting examples o f non-pol ar solvents include hexane, 2~methylpe«tane* 2,3- dimedrylbuiaoe, 2,2-dimeihyIbutane, heptane, pentane, cyciopentane, cyclohexane, benzene, toluene, i,4~dioxane, e orofomv diethyl ether, and diehlororaeihane. |0§325] Other solvents might be sui table for ASA suspension, m addition to bexarse, heptane, and derivatives thereof^* solvents that ASA Is insoluble in (e.g.., an anti-solvent)^ and that have vapor pressare and boiling poitrt suitable for evaporation processed like spray dryin may also be suitable.

[00136]. The following test parameters can be wed for stability testing of dry powders.

[00127] Appearance and Color - The appearance f me content, of the container and the appearance of the container and closure system (i.e., the val ve and its components and the inside of the container) should conform to their respective descriptions as an indication of the drug product integrity. If any color is associated with the formulation, (either present initially of from, degradative processes occurring during shelf life), then a quantitati ve test with appropriate acceptance -criteria should be established for the drag product.

[001281 Identification - Specific identification tests are recommended to verify- the identify of the dmg substance in the drug product, Chromatographic retentio time alone is not an adequate method to ensure the identity of the drug substance in the drug product. If the drug substance is ehirai then at least one of the methods used for identification should be specific for Ibis property.

[00129] Microbial Limits - Th microbial quality should be controlled, by appropriate tests and acceptance criteria for total aerobic count, total yeast and mold count, and freedom front designated indicator pathogens. Acceptance criteria will be reflective of the data for the

.submitted batches (e.g., clinical, preclinical, biobatch, primary stability, production) but at a minimum should meet the acceptance criteria, proposed in the Pharmacopeia! Forum (1996, Vol .22, p., 3098). Furthermore_.,, appropriate testing will, be done to show that the drug product does not support the growth of microorganisms and that microbial quality is maintained throughout the expiration period,

[00 i 3§] Water or Moisture Content - Testing for the presence of water in the container may be performed, particularl for suspension formulations. Water or moisture should be strictly limited to prevent changes in particle size dist buti n_:, moronic- form, and other changes such as crystal growth or aggregation,. (00131] .Dehydrated Alcohol Content ~ if alcohol is used as a cosolvent in the fomruiation, a specs lie assay with -acceptance criteria, for this, e eipieni will be used,

{00132] impurities and Degradation Products - The levels of degradation products an

«Bpttftt.es wil l be determined by means of stability indicating methods. Acceptance criteria will be set for individual and total degradation products and impurities. For identification and

qualificatio thresholds, refer to the appropriate guidance, individual impurities or degradation- products appearing at levels 0.10 percent or greater will be specified. Specified impurities and degradation products are those, either identified or unidentified, that are indi vidually listed and limited in the drug product specification,

{00133} Dose Content 1 Jnif orraity - Because of the complexity of the discharged dose, the medication available at the mouthpiece of the actuator will be thoroughly analyzed for an

Individual container, among containers, and among batches. This test may be regarded as providing an overall performance evaluation of a batch, assessing the formulation, the

ffianufacriring process, the valve_*, -and the actuator. The numbe of actuations per determinatio should not exceed the number of actuations in the ni m nm dose approved in die labeling. A stability indicating method will be used. The amount of drug substance discharged sh ul be expressed both as the actual amount and as a percent of label claim from the actuator.. The U SP Unit Spray .sampling apparatus may be used. This test is designed to demonstrate the uniformity of medication per actuation or dose, consistent with the label claim, discharged from the mouthpiece of a sample of an appropriate number of containers from a batch (n = 10 is recommended). The primary purpose is to ensure dose unifo mit within discharges from multiple containers of a batch. The following acceptance criteria are recommended; The amount of active ingredient per detei n atioB is not ©tt side. of 80-120 percent of label clai for more than one often containers, none of the determinations is outside of 75-125 percent of the label claim, and the mean is not outsid of 83™ 115 percent of label claim, if two or three of the ten determinations are outside of 80- 120 percent of tire label claim, none is outside of 75·· 125 percent of label claim, and the mean is not outside of 85-1.15 percent of label claim, an

additional 20 containers should be sampled (second tier). For the second tier of testing, of a batch, the amount of active ingredient per determination is not outside of 80-120 percent of the label claim for mar e than 3 of all 30 determinations, none of the: 30 eternimatipns s .outside of 75- 125 percent of label claim, an d the m an Is wi tti ¾5~115 percent of label claim.

[00134] Particle ize Distribution - One form of c ontrol which is more cr itical for rabafation aerosols ihm for most other conventional, drug products is particle size distribution, of die delivered dose. This parameter is dependent on the formulation, the valve, an the mouthpiece. The optimum aerodynamic particle size distribafion for most inhalation aerosols has generally been recognized as being in the range of 1 -5 microns. From a pharmaceutical viewpoint, the most important parameter for an inhalation product is usually the aerodynamic particle siz distribution, of the outgoing aerosol. The aerodynamic particle size distrlbattOn is influenced by the characteristics of the spray oCthe dru product, as well as other factors, and is not solely determined by the size of th individual dru substance particles initially SttSpeuded m the formulation, A multistage cascade intpactor fractionates and collects particles of one or more drag components by aerodynamic diameter throitgh serial multistage impactions. Such a device with all associated accessories should allow determination of siz distribution throughout the whole dose including, in particular* the small particle size traction of the dose. It also provides mfomiation that allows for the com lete mass balance of the total labeled dose to be determined. However, to minimiz distortions and to e sure reproducibility, it is important to specify certain- conditions such as information on the calibration of the equipment, flow rate, duration, the size and shape of the expansion chamber, or inlet stern, the selecti on of impaction surfaces, and the method, accessories^ and adapters by which the inhalation aerosol is introduced into a specified impactor. These important parameters should be selected to obtain a complete, profile of the dose. Additionally, criteria should be provided n the application for the qualification of each cascade impactor. It is recommended that all cascade irapactors used in support of the drag product in the application be of the same design. Other criti cal variables that should be specified and controlled in such a test procedure are relative humidity and temperature, Particles may undergo changes during their passage into or through the cascade impactor depending on humidity and temperature conditions. The most common problems associated with humidity are hygroscopic growth and aggregation of particles. Creating atmospheres of controlled temperature and relative humidity b introducing: equilibrated air into the system can minimize variability from these sources. The number of actuations needed to determine particle size disrribarion by multistage cascade impactor should be kept to the minimum justified by the sensitivi ty of the analytical method use to quantitate the deposited iwg substance. The amount of drug substance deposited on the critics! stages of the cascade irnpactor should be sufficient for reliable assay, but not so excessive as to bias the results by masking individual actuation variation, The aerodynamic particle size .distribution analysis and the mass balance obtained (drug substance deposited on surfaces from the valve to the cascade irnpactor -filter) should be reported. The total mass of drug collected on ail stages and accessories is recommended to be between 85 and 115 percent of label claim on a per actuation basis. in addition* data may also be presented m terms of the percentage of the mass .found on the various stages aod accessories relative to the label olaitn. Acceptance criteria may be proposed in terms of appropriate groupings of stages and/or accessories. However, if this approach is used, at a minimum there should be three to four groupings to ensure future bateh-to-batch consistency of the particle size distribution.

Fertbermore, acceptance criteria expressed n terms of mass median aerodynamic -diameter (MM AD) and geometric standard deviation (GSD) alone, as well as in terms of respirable fraction, respirable dose, or fine particle mass are not considered adequate to characterize- the particl size distribution of the whole dose.

(00135} Microscopic Evaluation - Microscopic examination provides information on the presence of large particles* changes in morphology of the drug substance particles, extent of agglomerates_* crystal growth, and foreign particulate matter over time. Additionally:, where the crystalline form of the drug substance can affect the bioavailability, performance, stability, or other properties of the drug roduct* microscopic evaluation or other appropriate methods are recommended to control and monitor the morphic form if changes are observed on stability.

(001361 Spray Pattern and Plume Geometry - Characterization of spray pattern and plume geometr are important for -evaluating the performances of the valve and the actuator. Various factors can affect the spray pattern and phone geometry, including the size and shape of the actuator orifice, the design .of the actuator, the size of the metering chamber, the size of the stem ori fice of the valve, the vapor pressure in the container, and t he nature of the formulation.

(00137] The following examples of specific aspects for carrying out the prese t disclosure are offered for illustrative-purposes only- and are not intended to limit the scope of the present disclosure in anv wa v EXA PL S

Particle Size Analysis

|00138| Particle size analysis was carried out asaig laser diffraction and light microscopy.

|00I3^| A. Malvern Masters izet 2000 equipped with a Seiroceo 21)00 Sample Dispersion ^'Unit was used to measure the .geometric particle size of the samples. For each measurement approximately 50~100mg of powder was loaded into the micro volume tray. Measurement ^•parameters can be found in the table below. 3 replicates are run per sample an the average of die three replicates is reported to 3 decimal, places.

Morphology

Scanning electron microscopy

|00140J Field emission .scanning. electron, microscopy (FB-SEM, FEI, Sirion, USA) was used to examine the morphology and surface appearance of various ASA particles. The samples were attached to specimen stubs with two-sided adhesive tape and Pi-coated with a ^'.sputter coater (BAL-TEC, SC 005₅ Germany) at 30 mA for 150 s. The coated microcapsules were examined using a $Me» SEM: at 10 kV with a 1.5 « resolution according m previously reported method (Rosenberg et at, 1 85).

H LC analysis: Equipment 0141J The HJ*LO column was Phen rne»ex Lima 3o C I .8(2) ^'$0msa_t 4.o jxm₅ w¾ic¾ caiised the drug to elate at - 1.3 minutes.

R im T im ] 5. mia_; {Isoeratic}

[001421 The particle size measurement Is taken by quantifying deposition amounts by HPLC and entering these values into a program CODAS - Copley Inhaler ^'resting Data Analysis Software j00!43j Batches of aspirin fomiutatkm, anu!¾etered using either a jet -rattled, or solution based approach were evaluated for the general characteristics, as well as fisr the stabilit studies (see . Examples 1 -5), For some of the aspirin (ASA) formulations of the present disclosure, ASA was jet milled to <5 μηι and suspended at 2 wt in hexane, followed, by spray drying,

Addi tionally , the inventors also tested the impact of mehiding lecithin into the forra¾!¾tiof», Thus, properties of jet milled ASA, which was suspended at 2wt% in hexane, and then spray dried in the presence or absence of lecithin were evaluated in Example 1. P0I4 J General manufacturing and yield characteristics of jet-milled control (BREC 1511 - 024, 1.0:0% jet-milled ASA), spray dried from he ane, 1.00% ASA (BRBC151 1-038A), arid spray dried from hexane 99,9/0, 1 ASA Lecithio (BREC 151.1 -038B) are depicted, in Table 2 (Example i ).

^■[00145] Given its high solubility and its approval for inhalation use eihaxiol (EtOH} ^'has been described to be a sui able solvent to dissolve aspifirr ASA .fomruiadofts obtained through, spray drying of EtOH-based solutions (obtained by wet polishing) were also evaluated for particle size stability as well as general characteristics (Example 2). Moreover, since previous studies have shown that coating of th dra particles with surfactant, in particular a surfactant such as dipalmiloyJ phosphatidylcholine (ΕίΡΡϋ), distearoyl phospbatidylebolin (DSPC) r lecithin, inaproves delivery of the drug from, the dr powder inhaler device (Morales et al. Ther Deliv, 2(5);623-4 i (201 ), EtOH based ASA foraiaiations containing DSPC or lecithin were also evaluated. Q0146J The follo ing EtOH based ASA. formulations ere generated and tested; spray dried EtOH: based aspirin (BREC-020i)_i BtQH based^■ formulations contammg distearoyl

phosphatidylcholine (DSPC) (8REC~020K), and lecithm (BREC-020L}. Table 3 contains general features of the .manufacturin : process for each fori.»ulatio« As evident by % yield., similar yields were obtained for all formulations. However, as evident by particle size analysis (using Malvern laser diffraction Masters zer 2000), formulations containing DSPC or leciihin displayed greater particle size, compared to pure (100%) ASA (in EtOH).

[00147] These results demonstrated that aspirin formulations obtained by spray drying from EtOH based solutions containing pure ASA exhibit smaller particle size and no change in morphology as compared with the aspirin formulations obtained by spray drying from EtOH based solutions containing surfactants, such as DSPC or leciihin,

{00:14$] In one of the ASA formu a ions evaluated i the present disclosure, lactose was used as a nucleation agent in order to improve crystallization. Jet milled lactose was suspended in 0,2wt% in m EtOH solution containing ASA and then spray dried. General manufacture, yield, and particle size characteristics of spray dried EtQB based aspirin (BEEC~Q20X used for the comparison), and spray dried EtOH based ASA containing lactose (BREC-020D are shown in Table 4. The addition of nucieation agent did not influence particle ske. DIO (0.6) and D50 ^'(2,0) were equal for both oHU la ioas, while D90 differe slightly (see Table 4)<

[00149} Another ASA formulation evaluated in the present disclosure includes the addition of anti-solvent to the formulation. I s Example 4, the inventors ex mined the particle size of ASA sprayed from pure EtOH (BREC-0203) aad compared to the one containing, anti-solvent (¾Q) (BR.EC-151 l~O20M)_f This analysis revealed similar particle distribution among tile two formulations (see Table 5 and figure A),

[00150} Additional parameter that can influence particle size is the ga to liquid (G/L) ratio. Generally, decreasing G/L ratio results in larger particles.. In the present disclosure* the inventors tested 3 possi ilities regarding the G/L ratio of spray (hied from EiOH 100% ASA (BREC 1511- 0201). The 3 possibilities included high G L ratio (BREC 151 1-0201), middle G/L ratio

(B REC151 1-020A), and low G/L ratio (BREC IS 1 1 -0201:1). The general features of each compound are depic ted in Table 6. Eval uatioa of particle size showed that both increasing and decreasing the G/L ratio leads to a decrease in particle si¾e (Figure 5 A).

[00151 J Next, the accelerated stability study of the samples was earned out. Bulk stability, particle size stability, and aerosol stability of ASA formulations described in Examples 1-5 were studied,

[00152] Bulk powder aliqnots were prepared under dry conditions and placed in amber glass jar, after, whic they were sealed with desiceastiii. Mylar bags.. The hulk stability study ineorpot e a 4-week analysis of samples at 30°C and 65% relative humidity (RE),

[001531 The following nine formulations were prepared according to the protocol d. escribe in Example 1 : 100% jet-milled ASA (BREC 133 1-024), BRECI51 L03gA (spray dried from hexahe 100% ASA), spray d ied from hexane 99.9 0 J ASA/Leclthk (BEECl 51.1-03 SB), spray dried from EtOH 100% ASA CBREC-0201), spray dried from EtOH 99.9/0.1 ASA Lecithin

(BRECIS! 1-020 , spray dried from. EtOH 90.4/0.6ASA/DSPC (BKBC151 I -020L), spray dried ftoni EtOH 95/5 AS A/Lactose (BREC 153 1-0200), spra d ied from EtOH 45/55 ΕίΟΗ/ΒαΟ (HRECJ 5i 1 -020M), and spray dried from EiOH 100% ASA Low G L (BREC~1511 -02ΘΗ). I §015 J Ei iPLC assay showed that there was .ad significant J oss of potency or increase iii degradants over the period of 4 weeks {Table 7). Also, under the 65% relative humidity conditions, none of the 9 formulations contained any measorable water, no was there any uptake detected.

[ O1S5) Particle size stability oyer the period of 4 weeks for formulations generated from each distinct approach milling (Figure 6), EtO! solutions (Figure 7), and Et0H solutions/In line mixin (Figure 8). Particle size analysis at each step (0 week, t week, 2 ^'weeks, and 4 weeks) was carried out using Malvern particle size analyzer, jO0l56} Of the 9 formulations tested, spray dried milled ASA from hexane (BRBC-151 1~ 038A) exhibited the greatest particle size stability over 4 weeks of analysis, not only its comparison to powders generated from EtOH (BREC-151 1-020Ϊ, BREC- ! 51 1-02QK, BREC- 151 1-020L, BREC-151 l~02 D, and BREC-15 ί 1-020H (Figures 7 and 8» and in line mixing solutions (BREC151 1-020M, Figure 8), but also in comparison to other powders obtained from milling approach, Including jet nulled ASA. (BREC-l 511-024, Figure 61 and jet milled ASA, suspended in hexane with lecithin (Figure 6). The profile of particles obtained at time 0 (30€ and 65% relative humidity (RH)) for spray dried milled ASA suspended in hexane (BREC-151 1 - 038A) was the following: D(v0.1) - 0.9 pm; D (vO.5) ^2.3 μΐ«; Ό (v 0.9) -= ,5 pm; D [3,2] pro =1 ,6; and Β 4 ,3] pm. ^:::: 2,5 ιη (Figure 6). The profile Of partic les obtained at 4 weeks (30°C and 65% .relative humidity (RH)) for spray dried milled ASA suspended in 100% hexane (BREC- 151 1-038A) was the following: D(vO.l) - 0.9 pm; D (vQ.5) =2.3 pm; D (v0.9) = 4.6 pm; D [3,2] =1.7 pm; and B[4,3] = 2.6 pm (Figure 6). As shown in Figure 6, BREC-15 ! I -03^'8^'A exhibited excellent stability ove the period of four weeks, where the particle size distribution changed less than 10% over time, j 00157] The profile of particles obtained at time 0 Q(FC and 65% rel ative humidity (RH)) for spray dried milled AS A suspended in hexane with lecithin (BREC-l 511 -038B) was the following: D(v0, l ) - 0.9 pm: D (vO.5) =2.0 pm; D (v0,9) =3.9 m;∑ [3,2] =1.6 pm; and Ό{4,3 = 2.2 pm (Figure 6). The prof le of particles obtained at 4 weeks (30°C and 65% relative humidity (RH)) for spray dried milled ASA suspended in hexaae with lecithin (BREC-15 Π-0.38Β) was the

43. Mlo ingi O(vO J) - 1.0 ; D (vO.S) -2.4 pm; D (v0.9) 4.6 μίη; D p,2] - 1.7 m; and D[4₅3^ ™ 2,6 μηι (Figure 6). o 158) in contrast to jet milled ASA suspended n hexa te, ail other formulations showed: m increase hi particle size -over time. Moreover, addition of lecithin (BREC-15 i i-020K} or DSPC (BREC-11 3 -020L) to the powders obtained from ΕίΟίΙ solutions exhibited similar particle size stability compared to «eat ASA. Similarly, addition of lactose (BREC- 1511 -020D), gentler, atoniizatiaa (BEEC-151 1-Ό20Η), ¾nd i line mixing approach (BREC-151 1.-020M), did not lead to inmroved particle stability compared to the baseline sample (BREC-151.1-0201).

|0O^'i 59] TaJcen together, particle size stability 'Studies provide that spray dried milled AS A suspended in hexarse. as well as spray dried milled ASA suspended in hexane with lecithin, displays excellent stability over the prolonged period (at about 30°C and 65% -relative humidity (RH}). where the particle si¾e distribution changed less han. 10% over time. Moreover, particle size grew for all samples except BREC151 1-038A (milled ASA suspended in Hexane and spray dried).

|0016ffj Following the particle sixe stabilit analysis, aerosol performance -assay was carri ed out using a low resistance dry powde inhaler device. The aerodynamic particle size distributions Of BRECiSi 1-024. B ECl-Sl 1-03SA, BRieiSl 1-038B, BREClSl 1-020M,. BREClSl i-02QD, BREClSl WJ20H, BREClSl 1-0201, BREC15U-O20K, and BREClSl J-020L emitted from the dry powder inhaler (DPI) were measured- with an eight-stage next generation pharmaceutical impactor (NGI). The NG.1 is a partiele-classifying cascade hnpactor for testin metered-dose, ^■dry-powder, and similar inhaler devices. One unique feature of KG! is a micro-orifice collector (MOC) that captures in a collection cup extremely small particles normally collected on th final filter in other i pactors. The particles captured, in the MOC cup can be analyzed in the same manner as the particles collected is the other i pactor stage cups (Mat l et L Jonrnal of

Aerosol Medicine, v. _:} (2003),

[00161 j Particle size distributions at week 0 and week 4 were compared determining mass median, aerodynamic diameter ( MAD), geometric standard deviation (OSD), eniiited fraction (EF), tine particle fraction (EPF) <5 micron, and fine particle dose (FPD). Table 8 and Table 9 provide a .summary of findings of aerodynamic properties fox each, formulation, whereas Figure 9 (BRECl Si i. -024), Figure 10 (BREC1511-03gA¾ re 1 I (BRECIS 3 1~038B)_S Figure 1.2 (B ECI Sl ! -OlOM), Figure 13 (BRECI SI I-020D Figure 14 (BEECl S ! l-OaOHX Figure 15 (BRECl.5 ^'ϊ 1-0201), Figure 16 (BRECI Sl I-020K), and Figure 17 (BREC 151 1. -020L) show detailed particle size distribution at week 0 and week 4 based on NGl analysis,

|Θ0162| Aerosol performance studies revealed that spray dried rallied ASA suspended in hexane (BREC 151 I-038A) (Figure 10), mm spray dried milled ASA. suspended in hexane with lecithin (BRECl 51 1-038B) (Figure 1 1 % inaintamed the same aerosol properties during tire 4 weeks, or did not exhibit a significant aerosol property shift -during the 4 weeks. Oft the contrary, BREC 1511-024, BREClSi t~020M, and BREC15 H -020L displayed a large shift m properties, with dramatic increase in. MMAJP and -decrease m R (Figure 9 an Figore 12 respectively). BRECl Si i-020¾ BRECI Sl 1-02QD, and Bree IS 114*201 dsnonsiratec! a nxoderaie s ift In aerosol properties. While BREC15I -038B did not exhibit a significant aerosol shift as the one observed for BREC 151 1 -024 and BREC 153 1 -020.M, a small shift was detected (Figure 1 1).

[00163] In conclusion, the results obtained in these studies dernonsir e that ( I) general potency and purity of ^'bulk- powder is unchanged afte 4 weeks at 30^¾€ and 65% RB; (2) spray dried milled ASA suspended in hexane (BREC15 H-038A) and spray dried^' oiled ASA suspended in hexane with lecithin. (BREC 151.1 -038B) showed stability over the period, of weeks; and (3) spray dried milled ASA suspended in hexane (BRECl 511-038 A) and spray dried milled ASA suspended in feexane with lecithin (BRECl 51 1 -03SB) do not exhibit any change (or exhibit slight changes) in the aerosol performance after weeks. On the contrary, Jet milled and in-li e mixed, products changed after 4 weeks.

[00164} As shown in Figure 10, BREC 1511 -03 S A displayed, the folio wing character! sties at 0 time point; MM AD: 3,92 + ø.13 pm; geometric: standard deyiation. (GSD): 1 ,67 0,02 p e emitted fraction (EF): 63.6 xb 1.2.7%; tine particle fraction (FPF) <S μτα: 58,8 3.3%; and fine particle dose (FPD): 11.6 ± 1.1 mg. After 4 weeks at 30°C and 65% RF3_f BRECl 511-038 A had he fbiiowing characteristics: MMAB; 3,90 0.08 um GSD: j.,64.·£: 0.02 pm; EF; 75..1. ±^■ 3.2%; EPF <5 jim: 58.2 * 2,2%; and FFD: 12, 1 ± 0.8 mg. As evident, none of the measured parameters changed by more than 10% during me period of 4 weeks. (§0165| As shown I». Figure 11, B EGl 511-038B displayed the following characteristics at 0 time point M AD; 3,36 0.09 μπι; geometric standard deviation. (GSD): 1.67 ½ 0.02 μ«ι; emitted fraction (EF): 55.2■ 3.2 %; fine particle fraction (FPF) <5 μ-m; 70.1 ± 3,0 ^'% and fine particle dose (FPD): 12,9 ± i.S tag. After 4 weeks at 30°C and 65% RH, BREClSi I-Q38B bad the following characteristics; MMAD: 3.36 0.09 μΓπ; GSD: 1.7.3 ± 0,03 μηι EF; 73.8 ± 2,3 %; FPF: 69.4.÷ 23 %; and FPD; 16.9 ± 1,5 mg,

j0O166| I certain embodiments_., the. dry particles of the present composition hav an MMAD hich, varies less than about 10%, Less than about §¾, o less than about 1 %, after the composition is stored at 30^ftC at 65% relative ^'humidity for about 4 weeks.

{UQ J 6?| Collectively,, these findings indicate the superiority of spray dried milled. AS A suspended in 100% he ane compared to other AS A formulations described in the present disclosure.

|Θ0168 | Next, particle size distribution analysis was performed to characterize the formulation before and after the 2 week storage period at 50 75 RH,. Average D(6.1), P(0,5) and 0(0.9), D(3, 2, and B(4,3) values for BRBCI511-024, BRECISI 1 -03SA , and BREC 511 -0388 are shown M Table 1.1,

|0O169} As illustrated, in Table 11 and Figure 20, all 3 formulations showed an iacrease ¾ particle size after the 2-week storage period. H owever, BREO 151 1 -038A exhibited th least variation between week 0 and week 2, while BREC-1311-024 and B EC-1 II 1-038B e hihited similar levels of variation m partic l e size distribution before and after the 2- eek storage period. While the particle size of milted ASA spray dried with lecithin was slightly smaller compared to ASA alone, the change in particle size from week 0 to week 2 was greater fo BREC-151 Ϊ 4)3 SB then BREC-151 1-038A.

100170} The aerodynamic particle ske distributions o BEEO51 !«024_} BREC1511-038A, and BREO 51 1-03 SB at week 0 and" week..2 were compared determining mass median aerodynamic diameter (MMAD), geometric standard deviation (GSD), emitted fraction (EF), and fin particle fraction (FPF) <S micron. Figures 21-23 illustrate deposition profile -of each aspirin ienmdation before and after the 2-week period in the next-generation impactor following aerosoiization, where y a i™ deposited, fr ction (% recov red dose)). ΙραΐΤΪ] While BREC151 3 -024 (Plgure 21) a¾<i B EC-lSi i-03EB (Figure 23) displayed large shifts HI aerosol properties after 2 eeks, BftECl 3 1-0:38 A showed the smallest change among the 3 formulations (Figure 22). The observed change was eharacteri¾ed b increase in emitted fraction as well a increase in MMAD and corresponding decrease in fine particle fraction (Figure 22), Thus, taking into account the amount of change, spray dried mi l led AS A suspended i n 100% hexane exhibits improved properties compared to other ASA formulations tested (at 2 weeks and 50°C / 75% ^'RE These results are in acc rdance with the outstanding stability characteristics of BR.EC-15.1 1 -03 SB at 4 weeks described in Example 6.

16017 } Thus, under various temperature, time, and humidit conditions, milled ASA suspended in hexane and spray dried, as well as milled ASA suspended k faexane and spray dried with lecithin, exhibits high stability.

[0017 ] 1 one embodiment, ASA is suspended in hexane prior to spray dryin . In another efflbodir ien j ASA is suspended in heptane prior to spray drying, in furthe embodiment, ASA is siispended in heptane or hexane isomer, la yet another embodiment ASA is suspended in heptane or hexane derivative p ior to spray drying,

Example I

[00174] In Examples 1-5, di inventors set out to manufacture and generaliy characterize batches of aspiri n formulation were manufactured using e ither a jet milled or solution based (wet polishing) approach, and were generally characterized,

[00175] Aspirin (ASA) was jet milled to <5 prn and suspended at 2 wt% i a particular solvent Briefly, ASA solutions were prepared by adding aspirin to the appropriate solvent follo wed by Stirling until a homogeneous solution, was obtained. A BUCHI spra dryer model B~ 290 Advanced was used in alt experiments. High performance cyclones were used to collect the dried product. The spray-drying urn t was operated in open cycle, with the aspirator blowing ni trogen at 100% of capacity , corresponding to a flow rate of the dry nitrogen of approximately 40 kg per hour. Before feeding the stock solution, the spra dryer was stabilized with the particular solvent During the stabilization period, the solvent flow rate was adjusted in order to give the target ontlet temperature. A fter stabilisation of the outlet temperature , the feed of the

^3 s ray dryer was committed from the solvent to me product sol ution (inlet tempetature was then readj osted to maintain the outlet temperature in the target value)_* A t he end of the stock sohiiton, the feed was once more commuted to solvent, in order to rinse die feed line and cany out controlled shutdown.

[ΘΘ 76] la this specific Example, jet milled ASA was suspended at 2 wt% in exane, and then spray dried in the presence or absence of lecithin. The properties of me ASA formulation were evaluated, f 08177J In some cases, an exc.ip.ient is provided to dry powder formulation in order to coat the active pharmaceutical ingredient* thus "masking" it Masking can be useful when the unm dified active pharmaceutical is irritating or otherwise unpleasant to the recipient

[00178 Exampl s of suitable phospholipid excipiems include, without limitation,,

phosphatidylcholines, os hatidylei ^^^_^

sphingomyelin, or other eetatnides, as well as phospholipid containing oils such as lecithin oils. As mentioned above, in this example the inventors tested the effects of lecithin addition to hexane ASA .suspension.

{^■00179 J Genera i manufacturing and ield characteristics of jet-mi lied control (BR EG 151 1 -024 (100% jet-milled ASA), spray dried from hexane 1 0% ASA (BEECiS ! 1-03SA), and spray dried from hexane 99.9/0,1. ASA/Leciihin (BREC151 1 ~038B) are depicted in Table 2.

Table 1 General characteristics of BRIC 1511-024 ΒΕΒ€15ίι*#38Α, and BREClSll-

100180} As se r) in. Table 2, particle si e distribution analysts showed^' that Dl 0 was higher for spray dried fonnulations than for the initial jet milled product. Furthermore, D50 arid D90 were higher for BREC1511-038A (100% ASA in - hexarie, without lecithin} compared to BRBC151 1~ 038B (spray dried .from hexane 9:9.9/0 J ASA/Leeiihin),

{00181} Next, the particle si¾e and particle morphology were evaluated in further detail. Particle size distribution .analysis was performed using Malvern Particle size analyzer (Figure 1 A). As shown in Figure 1 A, the collected spray dried particle size was larger than the initial milled product Without being bound to particular theory, it is expected that this is likely related to slight agglomeration or fusion of -particles during the spray drying process.

Furthemjom, it Is known that cyclone efficiency decreases with smaller particle size, which can result in slight bias of collected particles,

JOOi 82} Crystal morphology plays an important role in drag processing and delivery. Here, particle morphology of jet rallied control B .EC 1311-024, 100% ASA B ECl 51 Ϊ -038 A₅. and 99.9/0.1 AS A/Lecithin BREC 151 1 -038B was determined by scanning electron microscopy (Figure IB), Briefly, -field emission scanning electron. microscopy (FE~SEM, FBI, Sitio»_s USA) was used to examine th morphology and surface appearance of various ASA particles. The samples were attached to specimen stubs wit two-sided adhesive tape and Pt~coated with a sputter eoater (B.AL-TEC, SCO 005. Germany) at 30 mA for 150 s. The coated mtcrocapsal s- ver · e&amiiied nsiti ^'Saieft SEM at 10 fcV with a 1.5 una resoitition according to a previously .reported method (Rosenberg e at, 1985).

[001831 As illustrated in figure IB, lecithin formulation exhibits a slight difference in particle morphology., Thus, according to the results obtained here, a more su tab particle morphology, is obtained using hexane ASA fomiulafion without lecithin, than with lecithin. 0018 ] Thus, this Example shows that in. ASA formulations, where hexane is used as a solvent, mi l ASA spray dried with lecithin leads to slightly smaller particle size as compa ed to 100% ASA in hexane.

Example 2 Spray Dryin of Milled Suspensi ns hi Et au l the Preseuee or Abseuee of Lecith sB or SPC 00185} Given its high solubility and its approval for inhalation use, ethanol (EtOH) has been described to be the most .suited solvent to dissolve aspirin, in this experiment, the goal was t characterize the formications obtained through spray drying of EtQH-based solutions (obtained b wet polishiug;}. Additionally, previous studies ha ve shown that coating of the drug particles with a surfactant, in particular a surfactant such- s dipalmitoyl phosphatidylcholine (DPPC) or distearoyl phosphatidylcholine (DSPC) reprodiicibly improves delivery of the drug from the dry powder inhaler device (Morales et al. Titer Peliv. 2(5);623-4.1 (20.1 I). 0O.186^'| in addition to the control formulation (spray dried EtOH based aspirin, BREC-02i)l), EtOH based form.ulaii.ons containing distearoyl phosphatidylcholine (DSPC) ( EEC-020 ) o iecitihin (8REC-020L) were evaluated. Table 3 contains general features of the manufacturing process for each formulation. As evident by % yield, similar yields wer obtained for all formulations. ^'However, as evident by D50 aud D90., formulations containing DSPC or lecithin displayed greater particle size compared to pure (100%) ASA fin EtOH).

100187] Further particle size analysis (using Malvern laser diffraction Mastersizer 2000) confirmed^' that addition of lecithin or DSPC to EtOH based formulation increases particle size (Figure 2A). Additionally, particle morphology analysis (by scanning electron microscopy) revealed a difference in particle morphology in both lecithin and DSPC formulations compared pure aspirin (Figure 2B), where the nano-crystalline domains were found in DSPC. 1 ίΗί 188J These results indicate thai aspirin for»i«ktid»s- obtained by spray drying iro * EiOE based, solutions containing pyre ASA exhibit smaller panicle si¾e and no change m morphology compared with the aspirin .formulations obtained by spray drying from EtOH based solutions containing surfactants, such as DSFC or lecithin.

Table 3. Spray Drying of EtOH Based Solutions

Example 3 Spray Prying Process with ticleatkifi Agent

[00189] The rate of crystallisation can. be ac i ved vi two ways ; either by the increase in the steady-State concentration of nuclei in the polymer matrix, or by the increase of crystal growth. Generally,; an increase i mscleafion density can be readily accomplished, by adding endearing agents, where an introduction of foreign particles can serve as a nucleatio agent (Ashton. Acton, Advances in Bioenginsering Research and Application; 20 3 Edition). Such n deatio agents include, ^'but are not limited to starch, sucrose, or lactose.

[0019®} in this Example, the investors used lactose as a nucleatiou agent in order to improve crystallisation, Jet milled lactose was suspended hi 0.2 wt% in an EtOH solution containing ASA. and then spray dried.

[00191] General rnanufactxire, yield, and particle size characteristics of spray dried EtOH based aspirin (BREC-0201, used for the comparison in this example), and spra dried. EtOH based ASA containing lactose (BREC-Q20D) are shown in Table 4,

Table 4, Sp ay Drying with a iideatiora Agent

[00192] As shown in Figure 3A and Table 4, addition of lactose as a. nucleatioo agent resulted in similar particle size as neat ASA. when sprayed at less aggressive atomizatio conditions,. Thus, in this instance, the addition of nnei cat on agent does uot intliienee partiele size. D 1 (0.6) and D50 (2,0) were e ual f both formulations, while D90 differed slightly (see Table 4). However, introduction of lactose alters fjarttele irior feoio¾f by i«troduci»g small siir&ce crystal dom ins (Figure 3B).-

Example 4 - pra Dry ng with an Anti-Solvent

\ 00! 93] In the present Exasnple, the investors evaluated th outcome of adding an anri-soiverrt reagent to the spray drying process.. The rationale for this experiment was based on the act that decrease in the ini tial solubilit (due to the presence of anti-solvent) increases the driving force for crystallisation. However , comparison of ASA sprayed Born pure EtOH (BREC~0201) with, the formulation containing ami-solvent (¾0) (BREC-151 i-020M) revealed similar particle istr bution between the two formulations (see Table 5).

! 00194] Further analysis of particle si¾e disuibntions showed similar particle size distribution (Figure 4 A). Compared to pure ethauol process (BREC- 151 1-0201), B EC-lSl I-020M appeared to have different., heterogeneous particle morphology, characterized by rod-lik and spherical par tides -(Figure 4B),

Table 5. Spray Drying with an Anii-Soiveiit

Example S Effect of AtotMi¾atio« oit Particle Size

| 019S| Additional parameter that can influence particle size is the gas to liquid (G L) ratio. Generally, decreasing G/L ratio results in larger particles, in th present Example, the inventors tested 3 possibilities regarding the G/L ratio of spray dried from EiOH 100% ASA (BREC1511- 0201), The 3 possibilities included hlgb G/L ratio (BRECiSi 1-0201), m dle G/L ratio

(BREC15U-020A), and low G/L ratio (BREC151.1-020H). The general ieatares of each compound are depicted in Table 6,

Table 6. Effect of Atomizatioti on Particle Size

j00l96| Detailed evaluation of particle siz showed that both increasing and decreasing the G/L ratio leads to a decrease ¾ particle si¾e (Figure 5A). One of the commofl values used for laser diffraction results is the span, where the span is used to quantify distribution width; (1⁾90 - Dl.0) / I3S0, Here, lower span was obse ve at both low and high G/L ratios (Figure 5 A). Better yield was obtained at lower G/L ratio,. Additionally, G L changes led to particle morphology alterations (Figure SB).

Example 6 Accelerated Stability Study | Ο197] In the next series of studies (Examples 6 and 7), the balk stab lit * particle siae stability, and aerosol stability of ASA formulations described in ^'Examples 1 ~5 were evaluated.

(§0198} Bulk: powder aHquo s were prepared under dry condi tions and placed in amber glass ]ar₅ after which they were sealed with de-sioeant in Mylar bags. The bulk stability study was designed to incorporate a 4 week analysis of samples at M C and 65% relative humidity (RH). f 00199 j The following nine fbrrnojations were prepared according to the protocol described it* Example 1; 100% jet-milled ASA (BREC151. l-¾24)₅ BRECI511-03SA (spray dried from hexaae 100% ASA), spray dried, torn hexane 99.970-1 SA/Leeitlna (B BC151 1-03IB , spray dried from ErOH 100% ASA (ΒΚΕ€~β20ί), spray dried from EtOH $9.9/0,1^' ASA/ Eecitbk

(B ClS i 1-02Q ), spray dried.. toi EtOH 99,4/<X6ASA DSPC (B EC15n*020L)_;> spray dried from EtOH 95/5 AS A/Lactose (BREC 1511-020D), spray dried from EtOH 45/55 BtQH/¾0 (BREC 51 MJ20M), and spray dried from EtOH 100% ASA Low G./L (BREC-151 I -02GH).

{OO280j RP~HPEC assay showed that there was no significant loss of potency or increase in degredents over the period of 4 weeks (Table 7), Also* under the 65% relative humidity conditions, none of the 9 formulations contained any measureabie water, nor was there an uptake detected

[60201 J Next, particle size stability over the period of 4 weeks were evaluated for

formulations generated ftDtn each distinct approach: milling (Figure 6), EtOH solutions (Figore ?}, and EtOH solutions/in line mixin (Figure 8). Particie size analysis at each step (0 wk, 1 k 2 wk; and 4 wk) was carried, out using Malvern, particle size analyzer, f 00:2021 The profile of particles obtain ed at tirne 0 ( 3 °C and 6$% relative hiuusdity (RH)) for spray dried milled. ASA suspended in 100% hexane (BREC-15.1 E038A) was tlw following: D(vO. l) ^» 0.9 ηι; D (vO.S) =2,3 pm; D (v0.9) -4.5 μηι; D [3,2] =1. pm; and Β[4 ~ 2.5 μηι (Figure 6). The profile of particles obtained at 4 weeks (30°C and 65% relative humidity (RH)} for spray dried milled ASA suspended i 100% hexane (BREO-15 M-Q3S ) was the following; D(vO. l) - 0.9 ,um; D (v&S) -23 μήι: D (vO.9) - .6 pni; D p₅2] -1.7 μχ ; arid D[43J - 2.6 pnt (Figure 6),

190203) The profile of particles obtained at titne 0 (30^aC an ^ 65% relative liaraidity (EH)) for spray dried milled ASA suspended in hexaae wiiii lecithin (BREC- 1511 -038B) was the following; D(v0,l) - 0.9 μηκ D (vO.S) *2.0 μηι; D (vO.9) -3.9 μ,η D p.2] -1.6 μηι; and D[4,3] - 2.2 pro (Figure 6), The profile of particles obtained at 4 weeks (3Q-C and 65% .relative hmnMIt (MI)} for spray dried milted ASA. suspended in liexaoe with lecithin (BREC-1511-03S.B) was the following: D(v0J) - 1.0 pm; D (v0.5) -2.4 pm; D (vO.9) -4.6 pra; D [3,2] -1.7 pra; a»d 0 4_}3] ~ 2.6 pin (Figure 6). 0020 | Taken together, particl size stability studies provide that spray dried milled ASA suspended m 100% hexane, as well as spray dried milled ASA suspended m hexaiie with lecithin, displays stabilit over the prolonged period (about at 39^s€ and 65% relative feumtdtty (RE), where the particle size distribution changed less than 10% over time.

jO02O j Of the 9 formulations tested., spray dried milled ASA from 100% hexane (BREC- 1511 -03 S A) exhibited the greatest particle size stability over 4 weeks of analysis, not onl fa comparison to powders generated from EtOH (BREC-1511 -0201, BREC- 1511 -020K, BREC- 151 I -020L, BREC- 1511 -020D, and BREC-151 1-020H (Figures? and 8» and in line mixing solutions (BREC I S 1 1-020M, Figure 8), but also in comparison to other powders obtained from milling approach, including jet milled ASA (BREC-1511*024, Figure 6) and jet milled ASA suspended in hexane with lecithin (Figure 6). The profile of pattici.es obtained at time 0 (30°C nd 65% relative hnniidity (RH)) using 100% hexane s a sal veer (BREC-.1.511-038 A) was the following; D(y0.i) μηι = 0.9; D (vO.5) prn=2.3; , D ( .9) μνα =4.5; 0 [3,2] μηι ^«1.6; and

D[4_S3] μη - 2.5 pm (Figure 6). As shown in figore 6, BREC-151 I -038 A exhibited excellent stability over the period of four weeks, where the particle size distribution changed less than 10% over: time.

Assay (ASA)

[00207] Collectively, detailed analysis of particle size stability described in this Example indicates that spra dried milled AS A suspended in 100% hexaae displays excellent stability over the prolonged period at 30°€^: and 65% relative bomi ity (RH)_< Moreover, particle size grew for all samples except BRECl 51 1-038 A (BREC1511-038A ^::: milled ASA suspended in bexarve and spray dried).

Aerosol Performance [§02O8| Follo ing the particle size stability analysis, aerosol peribrmanee assay was carried out. Briefly, aerosol performance was determined w vifm using Plasfiape low resistance dry powder inhaler device (Osnago, Itel ). The aerodynamic particle size distributions of

BREC 1511-02 BREC 151 1-038A, BREC 1511-0388, BREC 151 I-020M, BREC ! 51 i -020D, BREC 15! 1.-02013, BRECl 511-0201, BREC1511-O20K, a id BREC 15 1-020L emitted rorfl tire dry .powder inhaler (DM) were measured with an eight stage next generation- pharmaceutical impactor (NGI). The NG! is a particle-classifying cascade irapactor for testing etered-dose, ^•dry-p wder, and similar inhaler devices. One uniq e feature of NGi is a micro-orifice- collector (MOC) that captures in a collection cup extremely small particles noraia!ly collected on the final filter in other inipactors. The particles captured in the MOC cup can be analyzed i the same -m nner as the particles collected in the other irapactor stage cups (Marple et at Journal of Aerosol Medicine, v, 1.6, (2003),. 00209j For each compound formulation, a single si¾s 3 HPMC capsule was filled with 37 mg o f formulated aspirin, and loaded into a RS01 low resistance device. Material was -actuated -at 60L/mia for 4 seconds. Three replicates were performed per lot. Particle §i¾e distributions at week 0 and week 4 were compared determining mass median aerodynamic diameter (MMAD), geometric standard deviation (GS.D), emitted, fraction (EE), fine particle taction (FPF) <S iniCrom, and ine particle dose (FFD)- "Fable and Table .9 provide a suminarv of .findings of ^•aerodynamic properties for each fonttulation, whereas Figure 9: (B REC 1511 -G24 Figure 10 (BREC 151 1-038AX Figure 11 (BREC 151 1 -038B), Figure 12 (BREC 151. I.~02Q }_: Figure 13 (B ECi51 1-020D) Fi re 14 (BMC 1511-020ΪΙ}, Figure 15 (BREC1511-0201), Figure 16 (BREC 1511-020K.), and Figure- 17 (BRECi 511~020L) show detailed particle size distribution at week 0 and week 4 based on NGi analysi . f 00110] Aerosol performance studies revealed that the only formulation that maintained tire same aerosol properties during the 4 weeks was spray dried milled ASA suspended in 100% hexane (BREC 1511 -038A), (Figure 10). On the contrary, BRECiSI 1-024, BRE 5.511-020M, and BREC1511 -020X displayed large shift in. properties-, with dramatic increase in MMAD and. decrease in FPF (Figure 9 and Figure 12 respectively). BRECl 51. I~O20l¾ BREC! 51 1.-020D, and. Brec 1511-0201 demonstrated a moderate shift n aerosol properties. While BREC151 1-038B did not exhibit a significant aerosol shift as the one observed for BRECl 511 -024 and BREC! 51 1 ~ O20M, a small sbift was tieverfhe!ess .defected (Figure I I). It is possible that the small shift is due to inherent variability, but this remains to^"be tested ^'Fortftienaore, an improved EF was identified, which, resulted higher FPD. lastly, BREC I51 1 -02OK (99,9/0. J ASA/Lecit«¾) was stable, however, overall performance was poor.

Table 8. Particle Size Stability at 4 weeks

[00221_.1 In conclusion, the results obtained in these studies demonstrate that (1 } general potency and purity of bulk powder is unchanged alter 4 weeks at 30°C and 65% RH; (2) particle size increases Ibr all fonni ations tested over the period of 4 weeks except ibr spray dried milled ASA suspended in 100% hexane (BREC15 I 1-03SA); (2) spray dried milted ASA suspended in 100% hexane (BREC 151 1-Q38A), and spray dried milled ASA -suspended^' in hexane- with lecithin (BREC151 Ϊ-038Β), showed stability over the period of 4 weeks; and (I) spray dried milled ASA suspended, in ^'100%: hexane (BREC!Sl 1-03SA) and spray dried milled ASA.

suspended in hexane with lecithin (BREC 151 1-038B) did not exhibit any change (or exhibited slight changes) in the aerosol performance after 4 weeks. On the contrary Jet milled and in-line mixed products changed dramatically after 4 weeks.

£00.212] As shown in Figure 10, BREC1511~038A displayed the following characteristics at 0 time poin AD: 3:92 ± GJ3 ; GSD: 1.67 ± 0.02; EF: 63.6 ± 12.7 %; . EPF <5 μηι: S8J ± 33%; and FPD: ! 1,6 ± 1.1 mg. After 4 weeks at 3( C and 65% RH, BREC 151 1-038A had the following characteristics; MMAD: 3.90 * 0.08 μω; GSD; L64 ± 0.02; EF; 75.1 ± 3.2%; FPF <5 μητ 5S2 ± 2.2 %; and EPD: 12,1 ± 0,8 mg. As evident, none of the measured parameters changed by more than 10% during the period of 4 weeks. (§0213} As^■ sh wn in Figure i l_t BREOl 511-038B displayed the following characteristics at 0 ^'Ht point: M AD: 336 ί 0.09 μηι; geometric standar deviation (GSD); E67 & 0,02; emitted fraction (EF): 55.2■± 3.2 %; fine particle fraction (FPF) <5 μ-m; 70.1 ± 3,0 %; and fine paiticle dose (FPD): 12,9 ± 1.5 tag. After 4 weeks at 30°C and 65% RH, BREC1511-Q38B had the following characteristics; MM AD: 3.36 ± 0.09 μπι GSD: 1.73 ¾ 0,03; EF; 73,8 ± 2.3 %; FPF: 69,4* 23 %; and FPD; 16,9 ±· 1,5 mg,

iOOlMj In certain embodiments_., the dry particles of the present composition hav m MMAD which varies less than about 10%, less tha about §¾, or less than about 1 , after the composit on is stored at 30*C at 65% relative ^'humidity for about 4 weeks,

Exaiwple 7 Accelerated Stability Study (2 week 50^&C7S% KM)

[00215} la this study, 3 different formulations of spray dried aspirin were evaluated:

BRBClSf 1*024 (100% jet-milled ASA), B EEC 1511 -03 $ A (spray dried from hexan 100% A$A), and BREC1531-0383 (spray dried from hexane 99.9 0,1 A$A Le t ft),

[0021-6] Briefly, bulk powder aliquots were prepared under dry conditions and placed in amber glass j r, after which they were sealed with aesiecant in Mylar hags. Each sample was. then incubated for 2 weeks at 50°C and 75% relative humidity (KB) eoudttiorts. Su seq en to the 2-week, incubation period, the following properties of each formulation- were examined: 1) particle morphology; 2) water content;- 3) potmcy/purity of the fbojiiilation; 4) particle size ■distribution; and .5) NGI -analysis (single replicate).

Particle Morphology

0 J 7] Particle Biorphology was determined by scanning electron microscopy (Figure 18). As shown in Figure IS, some degree of particle fusion was observed in all 3 samples.

Poteney pnrifcy of the fbfrmnatlort

(002 ί 81 Aspirin is off ai in many pharmacopoeia which recommends a titrime trie method and HPLC for its analysis (British Pharmacopoeia, Vol. 1 < London: Her Majesty's Stationary Office; 2009, pp. 442 --5; The United States Phannacopoeia. Vol, 30. Rockville; U.S.

Pharroacopoeial Convention Inc.; 2008. p, 1 164; Patel et l, Indian I Phairn Sci 75(4): 13-41 (2013)). Using the r^ve sed^p se bigh-perlbfrriaBee liquid chromatograph (RP-HPLC) method, degradation studies were performed on each compound fona¾lation after the 2-week storage period. The chromstegi¾fii showing the peak parity of each compound fo isJulation by UV

(Figure 1 ) demonstrates die Jack of significant degradantii after 2 weeks, Ftir hemiofe, potency of each of the 3 compound formBlat oas s preserved after 2 weeks of incubation. (50°C 75% RB) (Table 10).

Table 10. No significant loss of potency is observed after 2 weeks at 50° 75 EM

^'Panicle_, size distribution j 002 I I Next, particle si¾e disnifeutioa osiri Mai vera panicle si e analyzer was peribrrtted to cliaracteri2e the Ibrmis!atiors before md after the 2 week period. Average 1 >, D(0.5) and 0(0.9), D 3_f 2], an X)[4,3] values for BRECI 511 -024 BEEC! S l 1 -038A , and BEBC 1511 -038 B are shown in. Table 1 1.

Table I L Fartiele Si¾e Distribution

(SO

| 1220J As illustrated in Table 1 1 and Figure 20. all 3 compound fom laiions showed, m increase in particle size after e 2-week storage period. While the particle size of milled AS A spray dried with lecithin wis slightly smaller compared to. ASA alone, the change ire particle size from week 0 to week 2 was greater for BREC-151 I-Q38B then BREC-! 511-038A. However, BREC-151 E038A exhibited, the least variation between week 0 and week 2, while BREC-1511 - 024 and BREC-1511-038 B exhibited simitar levels of variation in. particle size distribution before and after the 2- eek storage period. While the particle size of milled ASA spray dried wi th lecithin was slightly smaller compared, to ASA alone, the change in particle size frost week 0 to week 2 was greater for BREC-IS 1 I-038B then BREC-l 1 1-03 A, Thus, the study demonstrates that, addition of lecithin to the formulation of BREC-151 1-0388 does not improve aspirin particle stability_^ and that under the above described conditions (2 weeks at 50°C/75% RH), BREC~ i.511- 038A provides the greatest stability in terms of particle size distribution.

A erosol Performance

|i0221 J The aerodynamic particle size distrfbyliorts of B EC 151 ! -¾24, BEEC 1511 -038 A_} md BRBCI5J 1-0 SB were determined according to the following: lor each compound fomuilatioa, single capsule was filled with 3? rng of formulated aspirin, and loaded into a low resistance device. Material was actuated at 6&Umim for 4 econds. Particle size distributions at week 0 ari week 2 were compared detenmning mass median aerodynamic diameter (MMAD), geometric standard deviation (GSD), emitted fraction ^'(EF), and fine particle fraction (EPF) <5 rnierom. Figures 21-23 illustrate deposition profile of each aspirin formulation before and after the 2-week period in the next-generation rpaetor l¾!lowi«g aerosdliaatioii, where y axis™ de osited fraction (% recovered dose)).

[002221 While BRECI 51 1-024 (Figure 21) and ΒΚΕ€ 5ίΪ >38Β ( igBfe 23) displayed large Shifts in aerosol properties after 2 weeks, BREC 151 i.~038A showed the smallest change of the 3 formulations -(Figure 22). The.obse.rved· change was characterized by increase emitted fraction as well as increase in MM AD and eoixesponding decrease in fine particle .fraction (Figure 22), Thus, taking into account the amount of change, spray dried milled ASA suspended in 100% hexane exhibits improved properties compared to other ASA formulations tested (at 2 weeks and 5iF€ / 75% RH . These results are in accordance with, the outstanding stability characteristics of BREC- Ϊ.51 1 -03 B at 4- weeks described in Example 6.

Tabic 12, Stability of jet Milled Sam l (BREC-15i.l-024) - Particle -Si ffis bution (PSD)

Table 13_* Stability o et Milled Sampl (BREC-151.1-024} - Aerodynamic Particle Size Distribution (APS

Table 15. Stability of Spray Dried Sample (BREe-l5li-038Ai 100% ASA (liexase)) a ambient ternperatiire - Particle Size Distribution (PSD)

A; balk po wder stored in ambient !ab conditions with desiccatit Table 16, Stability of Spray D ied Sample (B:K£€»15il~038Ai iW% ASA (ffesane)) Aerodynamic Particle Size Distribution (APS )

A: bulk powder, stored in ambient la conditions with desieeant

|0O224j n^:::3_; 37j¾g, low resistance device, single actuation of 4L of air at 60L ifl (not USP method).

Example 8 Process Optimization

1061225] in the next se t of experiments, the optimisation of suspension spray dry ing process was conducted, with the goal of evaluating options for increasing throughput ofhexane

formulations by increasin -suspension flow rate and/or increasing, suspension concentrat on. 5 batches of spray-dried ASA suspension were manufactured on a PSD-1 scale spray dryer at batch sizes up to 300 g usin jet-milled^' A A from a third, party supplier. The following variables were evaluated: increased spra dr ying suspension feed rate and increased solids concentration in suspension. liese i clude the following femm!aiions: Spray Dried 1.00% Jet Milled A.SA (BREC-151 J -052A), Spray Dried 100 jef Milled ASA (High Ffow;}(BRBC~I5 i I-052B), Spra Dried 100% Jet Milled ASA (High Flow, High SoKds)(B!REC- 15 1-G52C), Spray Dried 100% Jet Milled ASA (High Flow, High Solids, High Tout}{BREC* 151 i -052D), and Spray Dried 99.9/0, J Jet Milled ASA/Leciihk (Hig Flo )( B EC-151 1 ~052E). The goal was to evaluate the feasibility of spray drying batches with higher solids (BRBC-l5i i-052€) aid flow rate (BREC- 151 | ~0S2B). Table 17 provides a suBinw y of manufacturing characteristics. As shown in Figure 24, all processing conditions produced particles of similar size and within- tire hl alable range. Furthermore... particle morphology was similar for ail five batches (Figure 25). f 122|i| Further chaf crerijatiori of powder derflons ra ed that ail samples have similar properties. No measurabl ainouat of residual hexaii or water was found in powder, Moreover, potency was within the expected range (Figure 26), Finally, time course of stabilit of each of the five batches described in this example at 5 days and 50°C was stiidied. The summary of these findings is depicted in Table 18, Each of the five batches exhibited excellent stability mider these conditions.

Table 11, Manufacturing Sunwnary

TaMe IS, Parlic!e Size StaMilty alter 54ms 50C)

High Flow)

purposes.

Table 20* Stability of Spray ^'Dried Sample (SREC-lSI ! }S2C: 100% ASA ^'ffexane) High Flow, High Solids) at 25 °C - Particle Sim D ributiea (PSD)

Table 21. Stability of Spray Dried Sample {BREC-1S!1 ⁾S2C: 100% ASA .(Hexaite); High low, Hi h Solids) at 30 ^,J ~ Particle Size BistribHti©« (PSD)

Table 22» Stabilit of Sp ay Dried Sample (HKEO-1511 :-052C; .100% ASA (Bexatte); High Flow, High Solids) at 0 *C - Particle Siie Distribution {PSD)

Tabl .23_* Stability of Spray Dried Sam le (6REC-I5.ll-4MS.2C. 100% ASA {Mexaiie , High Flow, High Solids) - Aerodynamic Particle Sfee Distribution (APSD)

stability chamber with desiccant C: hulk powder stored in 25*C stability chambe wit desiccant, D: bulk powder stored in 40°C stability chamber with tesiecant

Example 9

{00228] ASA was first jet milled, suspended at 5 wt% in hexane, and then spray dried, 'Specifically, AS A was jet milled. Batch size of spray dried material was approximately 10 kg. Yield was 42% arid 55% for the two tots. Solid contest was .high (about 15%).

Table 24

Example 1 ¾329f ASA was first jet milled, suspended: at 15 wt% in hexan or heptane, and then spray dried. Specifically_* ASA was jet milled. Batch size of spray dried materia! was approximatel 2 kg. Yield was 60% and 56% for the two lots. Solid content was hig (about Ϊ 5%),

P023ft| The foregoing description is provided to enafele a person skilled in the art to practice the various corrfigiiratians described herein. ^' hile the subject technology has been particularly described with reference to the various figures and cftfiiigatatioas, it should be: tmderstood mat these are for illustration purposes onl and should not be taken as limiting the scope of the subject technology. j-00231] There may he marry other ways to implsm&M the subject technology . Various ftractions and elements described nereis may be partitioned differentl from those shown without departing from the scope of the subject technology, Varions niodifications to these crmfigntatiotis will he readily apparent to those skilled In the art, and generic principles defined herein may be applied: to other configurations. Thm, many changes and modifications may be made to the siibfeet technology, by one having ordinary skill in the art, without departing from the scope of the subject technology^

[0023-3} It is iderstooi thai the specific order or hierarchy of steps hi the processes disclosed is an llmsimt rt of exemplary approaches_* Based upon design preferences, it is understood that the specifie order or hierarchy of steps in the processes may be rearranged. Some of the steps may^¬ be performed sirnnltaneonsly. The accompanying method claims present elements of the variotis steps in a sample order, and are not meant to be limited to the specific -order or hierarchy presented.,

[00233} it is to he understood thai, while the subjec technology has been described in eon|nnctioii with the detailed description, thereof, the foregoing deseriptisn is intended to illustrate and not limit the scope of the subject technology. The citation of any references herein is not an admission that snch references are prior art to the present disclosure.

[002-3 j Those skilled in the art will recognize, or he able to ascertain using no more than routine experirnentation, many equivalents to the specific embodimen ts of the invention described herein. Swch eqtnvaierrts are intended to be e»eorrspassed by the followin embodiments..

Claims

^'hat is claimed is-

L A pharmaceutical com osit on comprising dr particles that comprise aeetylsafieylic aci d, or a pharmaceutically acceptable salt thereof, wherein the dry particles lave a mass median aerodynamic diameter (MM AD) ranging from about 0.5 μι» to about 10 pm₅ wherein the MMAD of the dry particles changes less than about 10% after stored at 30^CC a 65% relative humidity for about 4 weeks compared to the M AD of the dr y panicles befor storage,

2. The ^'pharmaceutical composition of claim 1, wherein the dry particles have a D90 of about 5 pm, a 50 of about 3 μηι, and a Dl 0 of about ! urn, and wherein the D 0-, D50 and DIG c an e less tfeari about 10% after stored at 30°C at 65% relative humidity for about 4 weeks compared to the D90, D50 and DID before storage.

3÷ The pharmaceutical composition of claim L wherein said pharmaceutical com osition former comprises a pharmaceuttcaily acceptable excipient.

4. The pharmaceutical composition of claim I , wherein the percen tages deposited at Stages

5, 6 and 7 when tested in a Next Generation impactor do not var greater than ab ut 10% when tested at time,. T~4 weeks as compared with time, T- 0.

5., The pharmaceutical composition of claim L, wherein the MMAD ranges from about 0.5 urn to about 5 itsrt.

6. The pbanBaceutical composition of claim 1 , wherein th e MM AD ranges from about 2.0 μηι to about m.

7. The pharmaceutical composition of claim 1. wherein the MM AD changes l ess than ab ut 5% when stored at 30°C -at 65% relative humidity for about 4 weeks compared to the MMAD before storage,

8. The phan¾aceuiiea! composition of claim 1 , wherein aceiylsaiicyik acid is present at dose of about 40 mg or less.

') The pharmaceutical composition of ciaim 1, wherein aeetyisaMeylie acid is present in an amount greater than about 80% (w/w) of the dry particles.

10.· pharmaceutical composition^ comprising dry particles that comprise acetylsalieylic acid, or a pharmaceutically acceptable salt thereof, wherein said dry particles have a mass median aerodynamic diameter (MM AD) ranging from about 0.5 pm-to about 1 pro, and wherein the MMAD of the dry particles changes less than about 10% after stored at 50°C at 75% relative -humidity i¾t about 2 weeks Compared to the MMAD of the dry particles before storage,

11. The pharmaceutical composition of claim 10_} wherein the dry particles have a D 0 of •about .5 pm, a D50 of about 3 μοι, aid a Di O of about^' I urn, sad wherein 30 and DIO change less than, about 10% after stored at5Q C at 75% relative humidity for about 2 weeks compared to the D90, D50 and DIO before storage.

12:, The pharmaceutical composition of claim 10, wherein said pharmaceutical composition further comprises a pharmaceutically acceptable exeipient

13. The ^'pharmaceutical composition of claim 10, -wherein the percentages deposited at Stages 5, and 7 when tested in a Next Generation Irapactor do not vary greater than about 10% when tested at time, ^::~2 weeks as compared with time, T~ 0.

14. The pharmaceutical composition of claim 10, wherein the MMAD ranges from, about 0.5 μί» to about 5 pm.

15. The pharro ceutical composition .of claim .10, wherein the MMAD ranges from about 2.0 μπι to about; 4 pm.

1 . The pharmaceutical composition of claim 1 , wherein the MMAD ch nges less than about .5% when stored at 50^GC at 75% relative iiumiditv for about 2 weeks compared to the MM AD before storage.

17. A pharmaceutical composition comprising dry particles that comprise aeetylsalicylic acid, or a pharmaceutically acceptable salt: thereof wherein said dry particles nave a mass median aerodynamic diameter (MM AD), ranging front about 0.5 pm to about 10 pm, and wherein the MMAD of the dry particles changes less than about 10% when, stored^' at 50°C for about 5 days compared to the MMAD of the dry particles before storage.

18. A method Of treating thrombosis or reducing the risk of a thromboembolic event,

comprising administering to a subject in need thereof a therapeutically effective dose of aeetylsalicyiic acid, wherein said aeetylsalicylic acid is delivered by a dr powder inhaler that comprises the pharmaceutical composition of any one of cl aims 1 -17, wherein a single dose of the acetyisalieylic acid administered to said subject is about 40 rag or less.

W, A .method of treating thrombosis or reducing the ris of a- thromboembolic- event,

comprising administering to a subject die phamiaceutical composition of any one of claims 1 -1 7, wherein, a single dose of the aeetylsalicylic acid administered to said subject is about 40 mg o less,

, A .met od of making dry particles that comprise acetylsalicylic acid, or a

pharmaceutically acceptable salt thereof, the method comprising the steps of:

a) jet milling aceiyfealicylic acid, or a armaceutically acceptable salt thereof, to particles wit a size of o greater than about 5 Jim;

b) .suspending the particles comprising acetylsalicylic. acid, or a pharmaceutically acceptable salt thereof, in a solvent chosen { orn hexa«e he ane;, or a mixture thereof; and

c) spray <fcymg the suspension.

, The -method of claim 20, wherein the solvent is hexane.

, The method of clai 20, wherein in step .(b) acetylsalicylic acid, or a pharmaceutically acceptable salt thereof is suspended in the solvent at 2 wt%_>