High dose inhaled indomethacin dry powder with dual deposition for pulmonary and oral delivery

Abstract

The disclosure provides a high-dose dry powder inhaler formulation of a carrier-based formulation. Specifically, larger drug particles serve as the carrier for the smaller micronized drug particles such that an inhaled dose is combined with an oral dose. The coarse drug particles act as a carrier and allow improved powder flow and aerosol performance while also providing a potential secondary route of absorption of indomethacin; oral.

Description

Attorney Docket No. 093331-1520585 8530 SMY-WOHIGH DOSE INHALED INDOMETHACIN DRY POWDER WITH DUAL DEPOSITION FOR PULMONARY AND ORAL DELIVERYCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 699,290, filed on September 26, 2024, and titled “HIGH DOSE INHALED INDOMETHACIN DRY POWDER WITH DUAL DEPOSITION FOR PULMONARY AND ORAL DELIVERY,” the content of which is herein incorporated by reference in its entirety for all purposes.BACKGROUND

[0002] Indomethacin is a nonsteroidal anti-inflammatory drug (NSAID) used in the treatment of acute pain such as that associated with arthritis. Indomethacin is most commonly administered orally, subcutaneously, or by suppository. While the suppository route is not preferred by patients, the subcutaneous route is not amenable to at-home treatment, and the oral route often leads to GI side effects and treatment discontinuation. Given that the effectiveness of treatment by indomethacin for a wide range of pain conditions is limited by side effects and slow onset of action, the development of an alternative route of administration is imperative. Among the most promising is the delivery of indomethacin by inhalation which may have the advantage of rapid onset in treating acute pain due to rapid and extensive absorption of small molecular weight relatively hydrophobic compounds.

[0003] Inhalation has been used as a route of administration of therapeutics for centuries. Modem devices can be classified by three categories; nebulizers, pressurized metered dose inhalers (pMDIs), and dry powder inhalers (DPIs). Modern dry powder inhalers were first introduced in the late 1960’s and have since become an important option for drug development. Some advantages of dry powder inhalers over other routes of inhalation include breath-actuation as well as formulation stability. Formulations for DPIs are usually ordered mixtures consisting of larger carrier particles and small micronized drug particles with a typically low drug content (<5%). However, some high dose systems have been developed and DPIs may be useful in the delivery of low potency therapies for systemic diseases like pain and headache.

[0004] Inhaled indomethacin has previously been investigated for effects in asthmatic patients Generally inhaled indomethacin has been well tolerated and no adverse effects observed. Positive effects of inhaled indomethacin were observed including reduction in asthma exacerbations in corticosteroid in steroid-dependent asthma. The inhaled dose in this previous study was not reported although 25 mg was loaded into a nebulizer and administered twice daily indicating lungAttorney Docket No. 093331-1520858 8530 SMY-WO delivered doses were likely in the low milligram range. Previously we also studied inhaled indomethacin formulations. We loaded indomethacin using polyelectrolyte complexation into microparticles (approximately 20% drug loading). Around 15 mg of powder was aerosolized from a commercially available device resulting in approximately 30% respirable fractions. Although acceptable aerosol performance was observed with these composite particles, only a few milligrams of drug were found to be respirable. In all of the previous reports for inhaled indomethacin none have demonstrated doses more than a few milligrams. Doses for treatment of headache pain in humans are likely to be substantially higher than these previous attempts in developing an inhaled indomethacin.

[0005] Of particular interest is hemicrania continua (HC). HC is an indomethacin-responsive headache disorder and is classified as a trigeminal autonomic cephalalgia (TAC). Since HC responds to indomethacin, as opposed to other NSAIDs, the intra-muscular administration of indomethacin (INDOTEST) has been suggested as a diagnostic test. Subsequently, HC is often treated by the three times a day dosing of indomethacin between 25 - 500 mg / day.

[0006] Development of inhaled indomethacin via DPI would provide benefit to patients by potentially speeding onset of action, lowering dose, and preventing or decreasing GI side effects. This advantage may be substantial for patients facing lifelong high dose treatment and where there are no other treatment options. However, a major challenge for an inhaled indomethacin therapy is the high dose requirement. Specifically, a target indomethacin therapeutic plasma range of 0.5-3 microg / mL has been suggested for the treatment of pain associated with headache. Assuming typical absorption for a low molecular weight lipophilic drug, this equates to a lung delivered dose of between 3 mg - 18 mg. Thus, a high drug loading formulation is required. Fortunately, indomethacin does not suffer from poor taste when dosed orally and therefore a high drug loading formulation is feasible.

[0007] In view of the foregoing, what is needed in the art are new high dose dry powder indomethacin formulations. The present disclosure satisfies this need and offers other advantages as well.SUMMARY OF DISCLOSURE

[0008] This disclosure provides a composition or formulation of indomethacin drug particles, methods of use, and preparation thereof. In certain aspects, the composition comprises indomethacin coarse drug particles, which delivers an oral dose and fine drug particles, which deliver an inhaled dose. This technology achieves sufficient dosing of indomethacin for rapid onset (inhaled fraction) and duration (oral fraction) through a mixture of coarse and fineAttorney Docket No. 093331-1520858 8530 SMY-WO indomethacin particles delivered via an inhaler. The dose requirements are quite high for the treatment of a special headache called hemicrania continua (or indomethacin responsive headache) and other headache conditions including migraine. Treatment of other indications are also disclosed.

[0009] Advantageously, by using a novel method of formulation, using coarse drug (indomethacin) as the carrier system for the respirable indomethacin particles, a respirable dose and inhaled dose to target hemicrania continua has been achieved. This has the benefit of delivering indomethacin orally for slower absorption from the gastrointestinal tract providing sustained levels, while delivering a rapid inhaled dose as well.

[0010] In certain aspects, the disclosure provides coarse drug particles as a carrier for fine drug particles in an inhaler. Advantageously, coarse drug particles are combined with fine / micronized drug particles for inhalation.

[0011] In one embodiment, the disclosure provides a formulation comprising micronized drug particles adhered to larger, coarse drug particles.

[0012] In certain aspects, the micronized drug particles comprise the same drug as the coarse drug particles.

[0013] In certain aspects, the micronized drug particles comprise a different drug than the coarse drug particles.

[0014] In certain aspects, the drug is a NS AID.

[0015] In certain aspects, the NSAID is selected from the group of ibuprofen, naproxen, celecoxib, diclofenac, indomethacin, ketoprofen, meloxicam, etodolac, meclofenamic acid, nabumetone, or fenoprofen.

[0016] In certain aspects, the NSAID is indomethacin.

[0017] In certain aspects, the micronized indomethacin: coarse indomethacin has a ratio of a 1:20 blend.

[0018] In certain aspects, the micronized indomethacin: coarse indomethacin has a ratio of a 1:5 blend.

[0019] In certain aspects, the micronized indomethacin: coarse indomethacin has a ratio of a 1: 1 blend.

[0020] In certain aspects, the size of the micronized drug particles are from about 0.5 pm to about 15 pm.Attorney Docket No. 093331-1520858 8530 SMY-WO

[0021] In certain aspects, the size of the coarse drug particles are from about 1 pm to about 70 pm.

[0022] In one embodiment, the disclosure provides a method for treating a patient in need thereof, the method comprising administering a formulation comprising micronized drug particles adhered to larger, coarse drug particles.

[0023] In certain aspects, the administration is by inhalation.

[0024] In certain aspects, a portion or fraction of the formulation is deposited in the oropharyngeal cavity and swallowed.

[0025] In certain aspects, the patient suffers from an indication selected from the group consisting of migraine, asthma, COPD, Parkinson’s disease and hemicrania continua.

[0026] In certain aspects, the patient suffers from hemicrania continua.

[0027] In certain aspects, the administered dose achieves a therapeutic plasma range of about 0.5 pg / mL to about 3 pg / mL for the treatment of pain.

[0028] In certain aspects, the formulation has a unit dose of about 1.0 mg to about 100 mg.

[0029] In certain aspects, the micronized particle dose is about 3 mg to about 18 mg.

[0030] These and other aspects, embodiments and objects, will become more apparent when read with the following detailed description and figures.BRIEF DESCRIPTION OF THE DRAWINGS

[0031] FIG. 1A-C illustrate particle size distribution of A) micronized indomethacin; B) 1:5 (w / w) micronized indomethacimlactose; and C) 1 :5 (w / w) micronized indomethacin: coarse indomethacin.

[0032] FIG. 2A-E illustrate scanning electron microscopy images. A) Coarse indomethacin. B) 1 :5 (w / w) micronized:coarse indomethacin blend. C) Lactose with 0.4% (w / w) magnesium stearate. D) 1 :5 (w / w) micronized indomethacimlactose blend. E) Micronized indomethacin.

[0033] FIG. 3 A-B illustrate A) Powder X-Ray Diffraction (PXRD) with blends described are formulated as (w / w); and B) Differential Scanning Calorimetry (DSC), blends described are formulated as (w / w).

[0034] FIG. 4A-C illustrate RODOS dispersion of indomethacin formulations. A) dlO; B) d50; and C) d90. Blends described are formulated as (w / w).Attorney Docket No. 093331-1520858 8530 SMY-WO

[0035] FIG. 5 A-B illustrate fine particle fraction of pure micronized indomethacin at increasing fill weights. A) Total aerosol performance; and B) Aerosol performance on stages 3-8.

[0036] FIG. 6 illustrate aerosol performance of 1 : 1 (w / w) micronized indomethacin: coarse indomethacin formulation.

[0037] FIG. 7 illustrates fine particle dose as a function of percent fines (w / w) for indomethacin- only formulations. Blends described are formulated as (w / w).

[0038] FIG. 8 illustrates an embodiment of the present disclosure.DETAILED DESCRIPTION

[0039] In one embodiment, the present disclosure provides a formulation comprising micronized drug particles adhered to larger, coarse drug particles. In certain aspects, the drug is an NSAID.

[0040] In certain aspects, the NSAID is a member selected from the group of ibuprofen, naproxen, celecoxib, diclofenac, indomethacin, ketoprofen, meloxicam, etodolac, meclofenamic acid, nabumetone, fenoprofen and mixtures thereof.

[0041] In certain aspects, the NSAID is indomethacin, having an empirical formula of C19H16CINO4, a CAS Number: 53-86-1 and a molecular weight of 357.79 g / mol.

[0042] Indomethicin works by inhibiting cyclooxygenase (COX) enzymes, which enzymes are responsible for producing prostaglandins. Prostaglandins cause inflammation, pain, and fever. By blocking the production of prostaglandins, indomethacin reduces these symptoms.

[0043] Indomethacin is available in several different forms for administration to a subject. These therapeutic dosage forms include, but not limited to, oral capsules, oral suspensions, suppositories and intravenous (IV) injections. A dry powder or micronized form for inhalation into the lungs is another therapeutic form.

[0044] Delivery of indomethacin via the lung represents an opportunity to circumvent the prostaglandin (PG) independent mucosal injury associated with the oral administration of NS AIDs, as it eliminates the direct GI exposures to these drugs. Furthermore, the pulmonary drug delivery route usually decreases the dose requirements by ten to twenty -fold, especially for drugs acting locally on the lungs.

[0045] In certain aspects, the present disclosure provides a micronized formulation of an NSAID obtained via jet-milling. Jet milling transforms the NSAID from a powder with a very poor Flow Property rating into one with a Flow Property rating of almost good flow. Advantages of micronization of the NSAID include the ability to be inhaled in the respiratory tract and airways,Attorney Docket No. 093331-1520858 8530 SMY-WO usage in an undiluted, pure form, enabling higher doses and less frequent administration. In certain aspects, the flow of a micronized NSAID is improved compared to that of the bulk powder.

[0046] In certain aspects, the formulation comprising micronized drug particles adhered to larger, coarse drug particles, such as indomethacin micronized drug particles adhered to larger, coarse indomethacin particles.

[0047] In certain aspects, the micronized indomethacin: coarse indomethacin ratio is a 1 : 1-20 blend, such as a 1 : 15 blend, 1 : 10 blend, 1 :5 blend or 1 : 1 blend. The blend can be a ratio of 1 :20, 1 : 19, 1 : 18, 1 : 17, 1 : 16, 1 :15, 1 : 14, 1 : 13, 1 : 12, 1 : 10, 1 :9, 1 :8, 1 :7, 1 :6, 1 :5, 1:4, 1 :3, 1 :2, 1 : 1 or 1 :0.5.

[0048] In certain aspects, the micronized drug particles are sized to about 0.5 pm to about 15 pm. In certain instances, the d90 is less than or about 10 pm, less than or about 9 pm, less than or about 8 pm, or less than or about 7 pm, 7.1 pm, 7.2 pm, 7.3 pm, 7.4 pm or 7.5 pm. In certain instances, the d50 is less than or about 5 pm, less than or about 4 pm, less than or about 3 pm, or less than or about 2.9 pm, less than or about 2.8 pm, less than or about 2.7 pm, less than or about 2.6 pm, less than or about 2.5 pm or less than or about 2.4 pm. In certain instances, the dlO is less than or about 2 pm, less than or about 1 pm, less than or about 0.9 pm, or less or about 0.8 pm. In one instance, micronized indomethacin has a dlO of about 0.8 pm, a d50 of about 2.7 pm and a d90 of about 7.3 pm.

[0049] In certain aspects, the coarse drug particles can be sized from about 1 pm to about 70 pm, such as 5 pm, 10 pm, 15 pm, 20 pm, 25 pm, 30 pm, 35 pm, 40 pm, 45 pm, 50 pm, 55 pm, 60 pm, 65 pm, or 70 pm. In certain instances, the d90 is less than or about 45 pm, less than or about 44 pm, less than or 43 pm, or less than or about 42.9 pm, 42.8 pm, 42.7 pm, 42.6 pm or 42.5 pm. In certain instances, the d50 is less than or about 17 pm, less than or about 16 pm, less than or about 15 pm, or less or about 15.9 pm, less than or about 15.8 pm, less than or about 15.7 pm, less than or about 15.6 pm, less than or about 15.5 pm or less than or about 15.4 pm. In certain instances, the dlO is less than or about 4 pm, less than or about 3 pm, less than or about 2.9 pm, or less or about 2.8 pm, less than or about 2.7 pm, or less or about 2.6 pm. In one instance, the dlO is about 2.6 pm, the d50 is about 15.7 pm, and the d90 is about 42.5 pm.

[0050] In certain aspects, the micronized indomethacin: coarse indomethacin ratio of 1 :5 w / w has a d90 between about less than or about 41 pm, less than or about 40 pm, less than or about 39 pm, less than or about 38 pm, or less than or about 37 pm. In certain aspects, the micronized indomethacin: coarse indomethacin ratio of 1 : 1 w / w has a d90 less than or about 25 pm, less than or about 24 pm, less than or about 23 pm, less than or about 22.9 pm, or less than or about 22.8 pm.Attorney Docket No. 093331-1520858 8530 SMY-WO

[0051] The coarse indomethacin can have a tap density of about 0.1 g / mL to about 1.0 g / mL, such as about 0.1 g / mL to about 0.9 g / mL, about 0.2 g / mL to about 0.9 g / mL, about 0.3 g / mL to about 0.9 g / mL, about 0.3 g / mL to about 0.5 g / mL, about 0.3 g / mL to about 0.4 g / mL, or greater than about 0.2 g / mL, greater than about 0.3 g / mL, or about 0.3 to about 0.4 g / mL. Alternatively, tap density may be about 0.4 g / mL.

[0052] The milled indomethacin can have a tap density of about 0.1 g / mL to about 0.5 g / mL, such as about 0.1 g / mL to about 0.4 g / mL, about 0.2 g / mL to about 0.3 g / mL, or greater than about 0.1 g / mL, greater than about 0.2 g / mL, or about 0.15 to about 0.25 g / mL. Alternatively, tap density may be about 0.2 g / mL.

[0053] In some aspects, the formulation has a unit dose of about 1.0 mg to about 100 mg such as 1 mg, 5 mg, 10 mg, such as 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg.

[0054] In certain instances, the formulation does not contain a carrier. In other instances, the formulation contains a carrier. A carrier can be a sugar, a sugar alcohol, or a combination.

[0055] In one instance, the sugar carrier is lactose, such as a-lactose monohydrate. The lactose particles can be from 1 pm to about 150 pm. In certain instances, Lactohale® from DFE Pharma can be used, such as Lactohale® 200, 206, 210, 220, 230 or 300. In certain instances, magnesium stearate be included to improve performance where a small amount of magnesium stearate coats the surface to “lubricate” the drug-carrier interface.

[0056] In certain instances, the sugar alcohol is mannitol. As a non-reducing sugar alcohol, mannitol is less hygroscopic than lactose. Other sugar-based carriers include non-reducing sugars such as trehalose and sugar alcohols such as dextrose, erythritol, sorbitol, and xylitol.

[0057] In certain aspects, the formulation is administered by inhalation, such as by a dry powder inhaler (DPI) or a metered dose inhaler (MDI).

[0058] In certain aspects, the disclosed compositions are formulated to be suitable for inhalation, in which the composition is inhaled or sprayed into the lungs. Typically, the composition is administered in such a manner that it is distributed evenly throughout the airways. The composition may be in the form of a powder, or other suitable form for pulmonary administration. These compositions are administered to the lungs, for example, in a powder or aerosol form through appropriate devices known in the art. The amount of the composition administered can be controlled by providing a valve to deliver a metered amount, as in a metered dose inhaler (MDI) that delivers a fixed dose in a spray with each actuation of the device. In this way, an appropriateAttorney Docket No. 093331-1520858 8530 SMY-WO dose (e.g., a therapeutically effective amount) of the composition can be delivered reliably from a device that contains multiple doses.

[0059] The formulation employed for delivery will typically be designed to work with a particular mode of administration, such as a dry powder formulation.

[0060] In certain embodiments, the composition is formulated with at least one pharmaceutically acceptable acid to reduce the pH or a pharmaceutical acceptable base to increase the pH. For example, the pH of a NS AID may be reduced. The acid may be citric acid or hydrochloric acid with the resulting composition having a pH of about 1 to about 7, or less than about 6, or less than about 5, or less than about 3 or less than about 2. In certain aspects, the buffering capacity of the pH-adjusted composition is either low or not buffered.

[0061] In certain aspects, the micronized drug particles comprise the same drug as the coarse drug particles, or the micronized drug particles comprise a different drug than the coarse drug particles. The drugs disclosed herein can be the micronized drug, the coarse drug or both the micronized drug and the coarse drug in any combination.

[0062] In certain aspects, the composition comprises an antimicrobial agent.

[0063] In certain aspects, the composition comprises one or more antibacterial agents such as penicillins, cephalosporins, carbacephems, cephamycins, carbapenems, monobactams, aminoglycosides, glycopeptides, quinolones, tetracyclines, macrolides, and fluoroquinolones.

[0064] In certain aspects, the composition comprises one or more anti-fungal agents such as terbinafine hydrochloride, nystatin, amphotericin B, griseofulvin, ketoconazole, miconazole nitrate, flucytosine, fluconazole, itraconazole, clotrimazole, benzoic acid, and selenium sulfide.

[0065] In certain aspects, the composition comprises one or more anti-viral agents such as amantadine hydrochloride, rimantadin, acyclovir, famciclovir, foscarnet, ganciclovir sodium, idoxuridine, ribavirin, sorivudine, trifluoridine, valacyclovir, vidarabin, didanosine, stavudine, zalcitabine, zidovudine, interferon alpha, and edoxudine.

[0066] In certain aspects, the composition comprises one or more anti -parasitic agents such as pirethrins / piperonyl butoxide, permethrin, iodoquinol, metronidazole, diethylcarbamazine citrate, piperazine, pyrantel pamoate, mebendazole, thiabendazole, praziquantel, albendazole, proguanil, quinidine gluconate injection, quinine sulfate, chloroquine phosphate, mefloquine hydrochloride, primaquine phosphate, atovaquone, co-trimoxazole (sulfamethoxazole / trimethoprim), and pentamidine isethionate.Attorney Docket No. 093331-1520858 8530 SMY-WO

[0067] In certain aspects, the composition comprises one or more anti-inflammatory agents such as hydrocortisone, triamcinolone, nabumetone, indomethicin, naproxen, anti-inflammatory cytokines, and cytokine antagonists.

[0068] The compositions or formulations of the disclosure are administered with the aid of an inhalation device (“inhaler”), which can be a MDI, DPI, or other device capable of conveying the formulation into the lower airways. The frequency of administration will depend on the clearance rate of the drug and / or additional therapeutic agent from the subject’s lungs. In some embodiments, a formulation is administered no more than 8, 7, 6, 5, 4, 3, 2, or once per day, or no more than once every 1, 2, 3, 4, 5, 6, or 7 days. The therapeutically effective amount will depend on the condition to be treated, the severity of the condition, the general health and state of the subject, and the drug.

[0069] In certain aspects, during administration, a portion of the formulation is deposited in the oropharyngeal cavity and swallowed.

[0070] In certain instances, the dose is delivered via inhalation using a dry powder inhaler (DPI).

[0071] In certain aspects, the patient suffers from an indication selected from the group of migraine, asthma, COPD, Parkinson’s disease and hemicrania continua.

[0072] In certain aspects, the patient suffers from hemicrania continua.MATERIALS AND METHODSMaterials

[0073] For studies using micronized indomethacin, indomethacin was jet milled according to conditions previously used for a wide range of API’s. Grinding gas pressure was set at 3.7 bar and injector gas pressure was set at 4.1 bar. The material was passed through the micronizer one time. The terms micronized and milled are used interchange-ably in this paper. The inhalation-grade lactose, Lactohale 206, was obtained from DFE Pharma (KI ever Strasse 187, Goch, Germany). Magnesium stearate, vegetable source, was purchased from Macron Chemicals (Radnor, PA).MethodsFormulation preparation

[0074] Micronized indomethacin was used as-is for the pure drug-in-capsule formulation.Particle size is described in Table 1.Attorney Docket No. 093331-1520858 8530 SMY-WOLactose carrier formulation

[0075] For the lactose carrier formulation, a 1 :5 (w / w) micronized indomethacimlactose with 0.4% magnesium stearate blend was prepared. A batch size of 130 g was pre-blended using a V- blender for 5 minutes at 15 rpm. The pre-blend was blended using a Leistritz Nano-16 extruder American Leistritz Extruder Corp., Somerville, NJ) using parameters previously described by our lab. A twin-screw volumetric feeder (Brabender Technologies, Ontario, Canada) was used to control the feed rate at 4 g / min. The screw profile consisted of conveying elements and one GFM mixing element. The screw speed was set at 100 rpm.

[0076] To assess blending as a function of processing time, the powder output from the extruder was sampled (n = 3) and the powder was fed back into the extruder for additional mixing cycles (4 runs through the extruder were assessed). Each run was performed at a feed rate of 5.16 g / min.Coarse drug carrier formulation

[0077] The coarse drug carrier formulation was prepared as a 1 :5 (w / w) micronized indomethacin: coarse indomethacin blend or 1 : 1 (w / w) micronized indomethacin: coarse indomethacin blend. The formulation was blended using a V-blender for 30 minutes at 34 rpm. The blends were prepared at 1 :5 (w / w) fine to coarse indomethacin and 1 : 1 (w / w) fine:coarse indomethacin as a means to help identify the ratio that would lead to proper therapeutic dosing.Blend uniformityLactose carrier formulation - UV-VIS assay

[0078] An ultraviolet absorbance assay was used to measure blend uniformity for the lactose carrier formulation. A 1 mg / mL indomethacin stock solution was prepared in 100% methanol. The stock was diluted using 90% methanol down to approximately 2 pg / mL and a range of 250 pg / mL to 2 pg / mL was used as the standard curve. Samples were prepared by measuring 10 mg of powder in 10 mL 90% methanol diluent, then centrifuged at 14,000 rpm for 30 minutes. A Tecan® Infinite® 200 PRO multimode microplate reader (Tecan Systems, Inc. San Jose, CA, USA) was used with Greiner plates. Ultraviolet measurements were performed at 320 nm.Coarse drug carrier formulation - Particle Size Dispersion (PSD)

[0079] For the coarse drug carrier formulation, blend uniformity was measured using a particle size distribution assay to estimate the uniformity of fines distributed throughout the powder. Laser diffraction (HELOS, Sympatec, Germany) was used with RODOS powder dispersion. A pressure drop of 3 bar was used with the rotor speed set at 50%. Optical concentration measurementsAttorney Docket No. 093331-1520858 8530 SMY-WO between 5% and 25% were included in analysis. The particle diameter is considered the mean Xn diameter values, with n% of the particles having a diameter < X.Aerosol performance

[0080] In vitro aerosol performance was measured using a next generation impactor (NGI) (MSP Corporation, MN, USA). The NGI was attached sequentially to a volumetric digital flow meter (TSI 4000 Series, TSI Performance Measurement Tools, Shoreview, MN, USA), a two-way solenoid valve timer box, and a high-capacity vacuum pump (HCP5, Copley Scientific Limited, Nottingham, UK). A medium resistance Plastiape (Berry Global, Osnago, Italy) RS01 dry powder inhaler was used with size 3 inhalation grade HPMC Vcaps capsules donated from Capsugel Inc. (Morristown, New Jersey, USA). To prepare the equipment, 10 mL of 90% methanol was added to the pre-separator and the stages were coated with a 5 mL solution of 1% (v / v) of glycerin in ethanol which was evaporated. The flow rate was determined to be approximately 60 L / min creating a 4 kPa pressure drop across the device with a total volume of 4 L. A SRH77A thermohygrometer by Cooper- Atkins Instrument Corporation (Middlefield, CT, USA) was used to monitor temperature and relative humidity. The capsule, device, and mouthpiece were each washed with 15 mL of 90% methanol. The induction port was washed with 10 mL of 90% ethanol, and the pre-separator was washed with a total of 30 mL 90% ethanol. The stages of the NGI were washed with different volumes of 90% methanol depending on the formulation being tested.Samples were assayed using the UV method described in Lactose carrier formulation - UV-VIS assay. Samples containing lactose were centrifuged at 14,000 rpm for 30 minutes prior to measurement.Blend characterizationParticle Size Distribution

[0081] Particle size distribution was measured as discussed in Course drug carrier formulation - Particle Size Dispersion (PSD).Flow Properties

[0082] The Angle of Repose (AOR) was measured for the coarse and fine indomethacin powders using a Flodex system. Approximately 30 g of powder was weighed and added to the funnel. The powder was allowed to flow through the funnel and onto the stage forming a cone. The height of the cone was measured and the angle of repose was determined.Attorney Docket No. 093331-1520858 8530 SMY-WO

[0083] Bulk density and tapped density were measured using a tapped density tester using a 50 mL graduated cylinder and an appropriate volume of powder. The Bulk Density, Compressibility Index (CI), and Hausner Ratio (HR) were calculated according to USP method <616>.Powder X-ray Diffraction (PXRD)

[0084] A Rigaku Miniflex 600 instrument (Rigaku Americas, The Woodlands, Texas, USA) equipped with a Cu-Ka radiation source generated at 40 kV and 15 mA was used to perform PXRD. Samples were scanned as a stepwise measurement with a step size of 0.03° over a 29 range of 4° to 45°.Differential Scanning Calorimetry (DSC)

[0085] A DSC Q20 (TA Instruments, New Castle, DE) was used to perform differential scanning calorimetry (DSC). Samples were scanned from 25°C to 200°C at a rate of 10°C / min using approximately 6 mg per sample.Scanning Electron Microscopy (SEM)

[0086] Scanning electron microscopy was performed with gold sputter-coated samples on an FEI Quanta 650 instrument.Statistics

[0087] Statistics was implemented using GraphPad Prism software. Analysis was performed using t-tests to determine p-values.RESULTSBlend preparation and uniformity

[0088] Indomethacinlactose (1 :5 w / w) blend and indomethacin: coarse indomethacin (1 :5 and 1 : 1 w / w) blends were prepared and blend uniformity was measured (Table 2). The indomethacimlactose blend measured 95.61% with a relative standard deviation (RSD) of 7.6%. The indomethacin: coarse indomethacin blends, because each component was the same chemically, were alternatively measured using particle size distribution analysis to assess uniformity of the coarse fraction and the fine fraction in the blend. The 1 :5 (w / w) fine indomethacin: coarse indomethacin blend had a dlO of 1.25 pm and an RSD of 3.0%, and a d90 of 37.85 pm with an RSD of 1.8%. The low RSD’s indicated high uniformity. The 1 : 1 (w / w) fine indomethacin: coarse indomethacin blend also showed good uniformity, with a dlO of 0.86 pm and a d90 of 22.81 pm with an RSD of 3.5%. The low value for dlO (1.25 pm for the 1 :5 coarse drug carrier formulation) indicates a large portion of the particles in the formulation are potentially respirable.Attorney Docket No. 093331-1520858 8530 SMY-WO

[0089] Table 2 Blend uniformity for lactose and coarse carrier formulations. Sample size n=3.Powder characterizationParticle size and morphology (Particle Size Distribution (PSD), Scanning Electron Microscopy (SEM))

[0090] Particle size distributions (FIG. 1 and Table 1) showed a single peak for micronized indomethacin, and a bimodal distribution for the indomethacimlactose formulation and the fine indomethacin: coarse indomethacin formulation. Regarding the carrier particles, lactose was demonstrated to be larger in size (d90 of 116.1 pm) as compared to coarse indomethacin (d90 of 42.5 pm). Scanning electron microscopy revealed a difference in the particle morphology (FIG. 2). Lactose carrier particles were, as expected, tomahawk-like structures, while coarse indomethacin were plate-like structures. Upon the addition of micronized indomethacin, both blends showed significant coating of the micronized indomethacin on the respective carrier (Figures 2A and 2B, Figure 2C and 2D respectively).

[0091] Table 1 Particle size distribution of indomethacin formulations.Powder physicochemical properties (PXRD and DSC)

[0092] The physicochemical properties of the powder blends were assessed using PXRD and DSC (FIG. 3 A-B). PXRD showed no change to the crystalline structure in the indomethacimlactose blend upon blending with fine indomethacin. DSC confirmed this finding, displaying the gamma crystalline form of indomethacin for all blends, while showing an additionalAttorney Docket No. 093331-1520858 8530 SMY-WO lactose peak for the lactose blend. It has previously been reported that amorphous indomethacin undergoes rapid surface crystallization which would account for any surface amorphous content introduced by air jet milling.Powder flow properties

[0093] Powder flow was measured in triplicate using the angle of repose (AOR) for coarse and fine indomethacin. The AOR for milled indomethacin was 46.73 ±3.00, which is designated as poor flow, must agitate or vibrate. The AOR for coarse indomethacin was slightly better at 38.99±0.58 with a designation of fair flow, aid not needed.

[0094] The bulk density and tapped density of coarse and milled indomethacin were measured according to USP <616>. The results are shown in Table 3.

[0095] Table 3 Bulk density and tapped density measurements for coarse and milled indomethacin (n=3, mean ± standard deviation).Powder interparticulate properties

[0096] A RODOS dispersion study was performed at 0.5, 1, 2, 3, and 4 bar to establish the changes in particle size as a function of dispersion pressure that introduces the powder to the laser diffraction instrument. The results can be seen in FIG. 4. 1:5 (w / w) fine indomethacimlactose, coarse indomethacin, and 1 :5 (w / w) fine indomethacin: coarse indomethacin all show a downward slope, indicating that full deagglomeration has not been achieved at the tested dispersion pressures. Alternatively, 1 : 1 (w / w) fine indomethacin: coarse indomethacin and milled indomethacin both show flat profiles, indicating beyond a certain point, deaggregation is independent of the shear force applied. These formulations therefore show lower interparticulate forces that often correlate with improved aerosol performance.

[0097] Rodos dispersion curves of the indomethacin and lactose formulations reveal interesting dispersion pressure dependencies of particle redispersion. The milled indomethacin powders displayed relatively constant particle sizes regardless of dispersion pressure. In contrast, both lactose blends and the coarse indomethacin powder particle sizes showed significant inverseAttorney Docket No. 093331-1520858 8530 SMY-WO proportionality with dispersion pressures indicating that these powders require significantly more energy to disperse indomethacin as an aerosol. Blends of fine and coarse indomethacin show intermediate dispersion dependency on dispersion pressures with the 1: 1 blend, resembling the pure micronized material. Aerosol performance

[0098] A summary of the aerosol performance of each formulation and capsule loading is presented in Table 4. A lactose blend formulation showed poor performance with only 0.3 mg out of the loaded 5 mg being classified in the fine particle range (and subsequent fine particle fraction of only around 7%). In contrast, pure micronized and blends of micronized indomethacin with coarse indomethacin resulted in fine particle doses greater than 1 mg for a 5 mg loading. Expectedly, in the indomethacin only formulations, as the amount of micronized drug was increased the fine particle dose also increased. Generally, the emitted fractions of the 1 : 1 (w / w) micronized:coarse blends were higher than the pure micronized powders (for highest fill, p=0.02)

[0099] Table 4: Summary of aerosol performance of indomethacin formulations

[0100] FIG. 5 shows the influence of drug mass loaded into capsules on the resulting stage deposition using the Next Generation Impactor for the pure micronized indomethacin powder. For this powder, as loading was increased, the fine particle fraction decreased (although the overall fine particle dose increased, see for example Table 4). This was driven by the increased drug

[0101] Aerosol deposition of the 1 : 1 micronized to coarse indomethacin formulation is shown in FIG. 6. Similar to pure micronized indomethacin, as the powder loading was increased, the fine particle fraction decreased, although the differences were not as pronounced. Despite the general decreases in efficiency as quantified by FPF, the fine particle doses for the highest powderAttorney Docket No. 093331-1520858 8530 SMY-WO loadings of the pure micronized drug (65 mg) and the 1 : 1 (w / w) blends (50 mg) were found to have fine particle doses above 3 mg.

[0102] Despite the general decreases in efficiency as quantified by FPF, the fine particle doses of the pure micronized drug and the 1 : 1 blends were found to have FPDs above 3 mg (see discussion below) as shown in FIG. 7.DISCUSSION

[0103] In addition to a lactose carrier formulation, the aerosol performance of two other indomethacin formulations was compared. First, micronized indomethacin without carrier was studied and was observed to have superior performance. Additionally, a novel formulation method was developed using coarse indomethacin particles as the fine particle carrier. This system also showed superior aerosol performance compared to the lactose carrier formulation. An additional benefit to the coarse drug carrier formulation includes the potential for a secondary route of administration, namely oral. Literature suggests a therapeutic range of 0.5-3 microgram / mL for indomethacin. Assuming the fine particle dose of indomethacin will be absorbed similar to the intravenous (IV) dose, past work shows that 25 mg indomethacin IV achieves peak plasma concentration of 4 microgram / mL. Therefore, if we target a 0.5-3 microgram / mL plasma concentration, an approximate inhaled fine particle dose will be approximately 3 mg - 18 mg. Since the 1 :5 (w / w) formulation achieved approximately 2 mg fine particle dose, we determined the optimal ratio to be 1 : 1 (w / w) to achieve a fine particle dose within the specified range. This drug-as-carrier system for an indomethacin DPI was therefore further studied. This system shows promise for alternative drug candidates sharing similar physicochemical properties that have a high dose requirement.Lactose blend formulations had poorer aerosol performance compared to indomethacin alone formulations.

[0104] Typical dry powder inhalation formulations have revolved around the concept of adhesive or interactive mixtures of the micronized drug with inert carrier particles. The general working principle with these carrier-based systems is that the inert carrier particle (most frequently lactose alpha monohydrate) facilitates improvements in powder flow and aerosol performance. This function relies upon the interactions between the drug and carrier particles being sufficient such that the drug adheres to the carrier particle to enable homogenous blending, but that is also sufficiently weak interaction such that the drug particles can be detached during inhalation to allow for lung deposition. Begat et al. described the concept of cohesive - adhesive balance of different model dry powder inhaler systems, showing that different API’s had different interactionsAttorney Docket No. 093331-1520858 8530 SMY-WO with lactose. In the studies presented here, we show that indomethacin - lactose interactions appear to be greater than indomethacin - indomethacin interactions as indicated by both powder interparticulate studies (Rodos dispersion) and the lower fine particle doses achieved with lactose formulations during aerosol performance testing. Specifically, for the 5 mg micronized indomethacin formulations, the lactose formulation fine particle doses averaged only 0.48 mg compared to 1.3 mg and 1.2 mg for the coarse drug and carrier free indomethacin formulations, respectively. The Rodos dispersion studies show the micronized indomethacin material had less dispersion pressure dependency than carrier-based (either lactose or coarse indomethacin). Collectively, these aerosol performance and powder dispersion studies indicate that indomethacin- lactose carrier formulations are more difficult to disperse, though it is not clear that is a result of differences in adhesion of the indomethacin with lactose and the cohesion between indomethacin particles.Indomethacin-only formulations achieve target respirable doses

[0105] Indomethacin has been studied for the treatment of pain for decades and the pharmacodynamic relationship between plasma concentrations and efficacy has been well established. Specifically, a target indomethacin therapeutic plasma range of 0.5-3 microg / mL has been determined for the treatment of pain associated with headache. In these studies, we used this as a guide for developing target doses for inhaled indomethacin. Because indomethacin is relatively lipophilic and small in molecular weight it is assumed that pulmonary absorption would be rapid and extensive similar to that of parenteral administration. Previous studies of intravenously administered indomethacin showed that 25 mg indomethacin achieves a peak plasma concentration of 4 micrograms / ml. Therefore, targeting a 0.5-3 microgram / mL plasma concentration for the rapidly absorbed pulmonary fraction of inhaled indomethacin we estimated that a fine particle dose of between 3 mg - 18 mg would be required for the acute treatment of head-ache pain. Thus, in these studies we investigated the influence of the mass of micronized indomethacin and the effects of the ratio of coarse to fine indomethacin on the ability to achieve FPDs on the order 3-18 mg. We found that as the total fill was increased of formulations with high proportions of micronized indomethacin, decreased fine particle fractions were observed (FIG. 5). The ratios used in this study were 1 : 1 and 1 :5 fine to coarse indomethacin.

[0106] However, for the formulations with higher content of coarse indomethacin (i.e., 1 :5 (w / w) blends) aerosol performance increased with increased fill albeit with increased variability for FPF (FIG. 7). The variability of the lead formulations in our studies (i.e., the 1 : 1 micronized to coarse indomethacin), as detailed in Table 4 was found to be at an acceptable level and within typical limits for inhaled products. For example, the optimal formulation to achieve adequateAttorney Docket No. 093331-1520858 8530 SMY-WO dosing (as described above) was the 1 : 1 micronized to coarse formulation with a high loaded mass. The variability of the emitted dose, as measured by the % coefficient of variation, was less than 6%. The variability of the fine particle dose was 7.7%, and the variability of the coarse particle fraction as outlined in Table 5 was 6%. Compared to lactose formulation (i.e., %CV on the order of 18%, Figure 5) these demonstrated low variability and promising for future development.Coarse particle dose, when using indomethacin only formulations, is likely to provide adequate oral dose for additional oral absorption and prolonged plasma levels

[0107] Indomethacin given orally has high bioavailability. The prescribing information for indomethacin capsules, for example, indicates that the bioavailability is approximately 100% and that around 90% of the dose is absorbed within 4 hours of dosing. Despite this high bioavailability, the time to peak plasma concentrations is relatively delayed compared to the clinical need to treat acute headache. In the fasting state, Tmax occurs between 0.9 and 1.5 hours. Thus, the rapid absorption of micronized indomethacin from the airways has the potential to bridge the gap in therapeutic levels observed upon oral administration of indomethacin. The indomethacin-only formulations studied here not only provide the potential for rapid onset of lung-delivered drug, but also provide this oral dose. As shown in Table 5, the Coarse Particle Dose (CPD) for both the micronized-only and coarse-fine indomethacin formulations also provide a significant dose that will be deposited in the oropharyngeal cavity and swallowed. For the micronized indomethacin- only formulation this oral dose is estimated to be 14.64 mg for a 30 mg fill. (Table 5), while for the 1 : 1 coarse indomethacin blend this oral dose is 12.19 mg for a 20 mg fill (Table 5). Assuming the oral pharmacokinetics remain the same for these powders, adequate plasma levels should be attained at prolonged time periods after the initial phase of absorption from the pulmonary compartment has occurred.Attorney Docket No. 093331-1520858 8530 SMY-WO

[0108] Table 5 : Coarse particle fraction of indomethacin formulations determines as dose deposited in mouth and lungs (=emitted dose - dose deposited on stages 3-8).Coarse indomethacin demonstrates superior flow over milled indomethacin

[0109] Using the angle of repose, coarse indomethacin demonstrated superior flow properties over milled indomethacin (p =0.012). This indicates that the coarse:fme indomethacin blend would also have superior flow properties over the micronized indomethacin, suggesting a benefit for the novel formulation over the carrier-free formulation during processing.

[0110] Powder flow analyses of the micronized and coarse indomethacin powders revealed interesting observations that can be related to both powder filling and aerosol performance. Firstly, it can be seen from the angle of repose (AOR) data that coarse indomethacin has improved flow (Table 3). Significant differences were observed with the coarse AOR corresponding to a “fair” flowability while the micronized was classified in the “poor” category. For capsule filling operations using commercial filling equipment variability is correlated with AOR and Carr’s Index and Hausner Ratio’s. Thus, it can be expected that capsule fill variations would be minimized using the coarse indomethacin blends.CONCLUSIONS[OHl] A novel formulation was developed using a coarse drug carrier for the high dose dry powder inhaled indomethacin. This formulation consists of micronized drug particles adhered to larger, coarse drug particles. This micronized drug-coarse drug blend, in comparison to the standard micronized drug-lactose blend, allows inhaled dose and a secondary oral dose to be administered in addition to the inhaled dose. In terms of aerosol performance, carrier-free and coarse drug carrier formulations showed similar performance, indicating the addition of the coarse drug carrier did not compromise the superior aerosol performance relative to the micronized drug- lactose blend. However, improvements in the powder flow were observed for the coarse-drug blends. A 1 : 1 (w / w) formulation of micronized:coarse indomethacin was determined to be the optimal blend for depositing a relevant lung and oral dose for the treatment of hemicrania continua.

[0112] Inhaled therapeutics have been used beyond applications in asthma and COPD and include diseases such as rescue medication in Parkinson’s disease and rapidly acting insulin to name a few. For hemicrania continua we anticipate a high degree of patient acceptability with this modality of treatment. The rapid onset and prolonged action obtained through the dual routes of absorption would be especially attractive. As an analogy, intranasal zolmitriptan, a standard commercialized treatment for migraine, also has an observed biphasic pharmacokinetic profileAttorney Docket No. 093331-1520858 8530 SMY-WO(rapid onset within minutes from nasal absorption and second phase absorption through swallowed fraction) which is marketed as a significant clinical benefit for onset and duration of action. Lastly, the clinical experience of oral cavity administered indomethacin also provides evidence of suitability in terms of taste.The following citations are hereby incorporated by reference.REFERENCES[1] O’Brien M, McCauley J, Cohen E. Indomethacin. In: Florey K, editor. Analytical Profiles of Drug Substances [Internet], Academic Press; 1984 [cited 2022 Feb 6], p. 211-238. Available from: https: / / www.sciencedirect.eom / science / article / pii / S0099542808601926.[2] Boardman PL, Hart FD. Side-effects of indomethacin. Ann Rheum Dis. 1967;26: 127- 132.[3] Prakash S, Husain M, Sureka DS, et al. Is there need to search for alternatives to indomethacin for hemicrania continua? Case reports and a review. Journal of the Neurological Sciences. 2009;277: 187-190.[4] Nalamachu S, Wortmann R. Role of Indomethacin in Acute Pain and Inflammation Management: A Review of the Literature. Postgraduate Medicine. 2014;126:92-97.[5] Patton JS, Byron PR. Inhaling medicines: delivering drugs to the body through the lungs. Nat Rev Drug Discov. 2007;6:67-74.[6] Bell JH, Hartley PS, Cox JSG. Dry powder aerosols I: A new powder inhalation device. Journal of Pharmaceutical Sciences. 1971;60: 1559-1564.[7] Tamaoki J, Nakata J, Nishimura K, et al. Effect of inhaled indomethacin in asthmatic patients taking high doses of inhaled corticosteroids. J Allergy Clin Immunol. 2000;105: 1134- 1139.[8] Shimizu T, Mochizuki H, Shigeta M, et al. Effect of inhaled indomethacin on exercise- induced bronchoconstriction in children with asthma. Am J Respir Crit Care Med. 1997; 155 : 170— 173.[9] Onischuk AA, Tolstikova TG, Sorokina IV, et al. Anti-inflammatory Effect from Indomethacin Nanoparticles Inhaled by Male Mice. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2008;21 :231-244.

[0010] Ceschan NE, Bucala V, Mateos MV, et al. Carrier free indomethacin microparticles for dry powder inhalation. Int J Pharm. 2018;549: 169-178.Attorney Docket No. 093331-1520858 8530 SMY-WO

[0011] Dodick DW. Indomethacin-responsive headache syndromes. Current Science Inc. 2004;8: 19-26.

[0012] Prakash S, Patel P. Hemicrania continua: clinical review, diagnosis and management. J Pain Res. 2017;10: 1493-1509.

[0013] Cingolani E, Alqahtani S, Sadler RC, et al. In vitro investigation on the impact of airway mucus on drug dissolution and absorption at the air-epithelium interface in the lungs. European Journal of Pharmaceutics and Biopharmaceutics. 2019;141 :210-220.

[0014] Smyth HDC, Saleem I, Donovan M, et al. Pulmonary Delivery of Anti-Cancer Agents. Advanced Drug Formulation Design to Optimize Therapeutic Outcomes. CRC Press; 2008.

[0015] Sheikh Z, Ong HX, Pozzoli M, et al. Is there a role for inhaled anti-inflammatory drugs in cystic fibrosis treatment? Expert Opinion on Orphan Drugs. 2018;6:69-84.

[0016] Lucas S. The Pharmacology of Indomethacin. Headache: The Journal of Head and Face Pain. 2016;56:436-446.

[0017] Nagaoka H, Momo K, Hamano J, et al. Effects of an Indomethacin Oral Spray on Pain Due to Oral Mucositis in Cancer Patients Treated With Radiotherapy and Chemotherapy: A Double-Blind, Randomized, Placebo-Controlled Trial (JORTC-PAL04). Journal of Pain and Symptom Management. 2021;62:537-544.

[0018] Hebbink GA, Jaspers M, Peters HJW, et al. Recent developments in lactose blend formulations for carrier-based dry powder inhalation. Advanced Drug Delivery Reviews. 2022;189: 114527.

[0019] Brunaugh AD, Smyth HDC. Formulation techniques for high dose dry powders. International Journal of Pharmaceutics. 2018;547:489-498.

[0020] Spahn JE, Hefnawy A, Smyth HDC, et al. Development of a novel method for the continuous blending of carrier-based dry powders for inhalation using a co-rotating twin-screw extruder. International Journal of Pharmaceutics. 2022;623: 121914.

[0021] Clydesdale G, Roberts KJ, Telfer GB, et al. Modeling the Crystal Morphology of a- lactose Monohydrate. Journal of Pharmaceutical Sciences. 1997;86: 135-141.

[0022] Slavin PA, Sheen DB, Shepherd EEA, et al. Morphological evaluation of the y- polymorph of indomethacin. Journal of Crystal Growth. 2002;237-239:300-305.

[0023] Wu T, Yu L. Surface Crystallization of Indomethacin Below Tg. Pharm Res. 2006;23:2350-2355.Attorney Docket No. 093331-1520858 8530 SMY-WO

[0024] The United States Pharmacopeia. <1174>Powder Flow [Internet], 2016. Available from: https: / / www.usp.org / sites / default / files / usp / document / harmonization / gen- chapter / g05_pf_30_6_2004.pdf.

[0025] Grasmeijer F, Grasmeijer N, Hagedoorn P, et al. Recent advances in the fundamental understanding of adhesive mixtures for inhalation. Curr Pharm Des. 2015;21 :5900-5914.

[0026] Donovan MJ, Smyth HDC. Influence of size and surface roughness of large lactose carrier particles in dry powder inhaler formulations. International Journal of Pharmaceutics. 2010;402: 1-9.

[0027] Spahn JE, Zhang F, Smyth HDC. Mixing of dry powders for inhalation: A review. International Journal of Pharmaceutics. 2022;619: 121736.

[0028] Begat P, Morton DAV, Staniforth JN, et al. The Cohesive- Adhesive Balances in Dry Powder Inhaler Formulations I: Direct Quantification by Atomic Force Microscopy. Pharm Res. 2004;21 : 1591-1597.

[0029] Yeh KC. Pharmacokinetic overview of indomethacin and sustained-release indomethacin. The American Journal of Medicine. 1985;79:3-12.

[0030] Alvan G, Orme M, Bertilsson L, et al. Pharmacokinetics of indomethacin. Clin Pharmacol Ther. 1975;18:364-373.

[0031] Food and Drug Administration. INDOCIN (indomethacin) Capsules, for oral use [Internet], 2019. Available from: https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2019 / 016059sl001bl.pdf.

[0032] Turakka H, Airaksinen MM. Biopharmaceutical assessment of phenylbutazone and indomethacin preparations. Ann Clin Res. 1974;6:suppl 11 :34-43.

[0033] Tan SB, Newton JM. Powder flowability as an indication of capsule filling performance. International Journal of Pharmaceutics. 1990;61 : 145-155.

[0034] Uemura N, Onishi T, Mitaniyama A, et al. Bioequivalence and Rapid Absorption of Zolmitriptan Nasal Spray Compared with Oral Tablets in Healthy Japanese Subjects. Clin Drug Investig. 2005;25: 199-208.

Claims

Attorney Docket No. 093331-1520858 8530 SMY-WOWHAT IS CLAIMED IS:

1. A formulation comprising micronized drug particles adhered to larger, coarse drug particles.

2. The formulation of claim 1, wherein the micronized drug particles comprise the same drug as the coarse drug particles.

3. The formulation of claim 1, wherein the micronized drug particles comprise a different drug than the coarse drug particles.

4. The formulation of claim 2, wherein the drug is a NSAID.

5. The formulation of claim 4, wherein the NSAID is selected from the group consisting of ibuprofen, naproxen, celecoxib, diclofenac, indomethacin, ketoprofen, meloxicam, etodolac, meclofenamic acid, nabumetone, and fenoprofen.

6. The formulation of claim 4, wherein the NSAID is indomethacin.

7. The formulation of claim 6, wherein the micronized indomethacin: coarse indomethacin is a ratio 1 :20 blend.

8. The formulation of claim 6, wherein the micronized indomethacin: coarse indomethacin is a ratio 1:5 blend.

9. The formulation of claim 6, wherein the micronized indomethacin: coarse indomethacin is a ratio 1 : 1 blend.

10. The formulation of claim 1, wherein the formulation is configured for inhalation.

11. The formulation of claim 6, wherein the size of the micronized drug particles are from about 0.5 pm to about 15 pm.

12. The formulation of claim 6, wherein the size of the coarse drug particles are from about 1 pm to about 70 pm.

13. A method for treating a patient in need thereof, said method comprising administering a formulation comprising micronized drug particles adhered to larger, coarse drug particles.

14. The method of claim 13, wherein the administration is by inhalation.Attorney Docket No. 093331-1520858 8530 SMY-WO15. The method of claim 14, wherein a portion of the formulation is deposited in the oropharyngeal cavity and swallowed.

16. The method of claim 13, wherein the micronized drug particles comprise the same drug as the coarse drug particles.

17. The method of claim 16, wherein the drug is a NSAID.

18. The formulation of claim 17, wherein the NSAID is indomethacin.

19. The method of claim 13, wherein the patient suffers from an indication selected from the group consisting of migraine, asthma, COPD, Parkinson’s disease and hemicrania continua.

20. The method of claim 19, wherein the patient suffers from hemicrania continua.

21. The method of claim 17, wherein the dose achieves a therapeutic plasma range of about 0.5 pg / mL to about 3 pg / mL for the treatment of pain.

22. The method of claim 13, wherein the formulation has a unit dose of about 1.0 mg to about 100 mg.

23. The method of claim 22, wherein the micronized particle dose is about 3 mg to about 18 mg.

24. A method for treating a patient suffering from hemicrania continua, the method comprising: administering by inhalation a formulation comprising indomethacin micronized drug particles adhered to larger, coarse indomethacin particles, to thereby treat hemicrania continua.

25. The method of claim 24, wherein the micronized indomethacin: coarse indomethacin is a ratio of 1 :20 blend.

26. The method of claim 24, wherein the micronized indomethacin: coarse indomethacin is a ratio of 1 :5 blend.

27. The method of claim 24, wherein the micronized indomethacin: coarse indomethacin is a ratio of 1 : 1 blend.

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