WO2017053409A1

WO2017053409A1 - Pulmonary delivery of progestogen

Info

Publication number: WO2017053409A1
Application number: PCT/US2016/052858
Authority: WO
Inventors: Chang Lee; Tao Tom Du
Original assignee: Prairie Pharmaceuticals LLC
Priority date: 2015-09-21
Filing date: 2016-09-21
Publication date: 2017-03-30
Also published as: EP3344338A1; MY197560A; JP2018534347A; JP6693009B2; EP3344338A4

Abstract

The present invention relates to a pharmaceutical formulation powder that contains 17α-hydroxyprogesterone caproate (17-OHPC) powder and the method of producing the formulation produces paritcles that are suitable as an inhalant. The formulations, methods and kits of powdered 17-OHPC as taught herein may be used to reduce cytokine interleukin-17 (IL-17 or IL-17A) levels in both broncheoalveolar lavage fluid (BALF) and blood/serum and involve the inhibition of p38 mitogen activating protein kinase (MAPK) activity. The 17-OHPC powder formulation may be used in a method to treat IL-17 cytokine and/or p38 MAPK mediated auto- immune and auto-inflammatory diseases. Such diseases may include glucocorticoid (GC) insensitive related diseases or conditions. In alternate embodiment, the formulation may include the combined use of budesonide (BUD) and/or fluticasone with 17-OPHC.

Description

PULMONARY DELIVERY OF PROGESTOGEN [0001 ] Related U. S. Application Data

[0002] This is a Continuation-ln-Part application of U.S. patent application No.

13/174,939, filed on Jul. 1 , 201 1 , now pending, which is a Continuation-ln-Part application of U.S. patent application Ser. No. 13/021 ,950 filed Feb. 7, 201 1 , and claims the benefit of PCT International Patent Application No. PCT/US1 1/23917, filed Feb. 7, 201 1 , and U.S. Provisional Patent Application No. 61/302,325, filed on Feb. 8, 2010, the entire disclosures of which are incorporated herein by reference. This Continuation-in-Part application claims benefit of priority to U.S. Provisional Patent Application No. 62/195,649 filed on Jul 22, 2015, the entire disclosures of which are incorporated herein by reference.

[0003] Field of the Invention

[0004] The present invention relates, inter alia, to inhalation formulations

comprising a progesterone such as 17-alpha-hydroxyprogesterone caproate (17- HPC or 17-OHPC); and methods and kits for administering a progestogen as a glucocorticoid sensitizer to restore corticosteroid sensitivity, in order to treat one or more glucocorticoid insensitivity related diseases or conditions.

[0005] The present invention includes the inhalation formulations and methods in the U.S. Patent Application No. 13/021 ,950. The present invention also relates to inhalation formulations and methods for reducing cytokine interleukin-17 (IL-17 or IL-17A) levels in both broncheoalveolar lavage fluid (BALF) and blood/serum involving the use of 17-OHPC. Inhalation formulations and methods containing 17-OHPC may also treat IL-17 cytokine-mediated auto-immune and auto- inflammatory diseases.

[0006] The present invention relates to the inhalation formulations, methods and kits in using 17-OHPC in inhibiting phosphorylation (activation) of p38 mitogen- activated protein kinase (MAPK or RK or Cytokinin specific binding protein) in the lungs. Inhalation of 17-OHPC may treat related diseases involving the inhibition of p38 MAPK-mediated phosphorylation.

[0007] The present invention relates to the inhalation formulations, methods and kits involving the inhalation of 17-OHPC in combination with other medicines such as the use of a glucocorticoid (GC), for example, budesonide (BUD) or fluticasone. This combinatorial treatment of 17-OHPC and a GC may be used to treat IL-17 cytokine-mediated auto-immune and auto-inflammatory diseases, and with related diseases involving inhibition of p38 MAPK-mediated

phosphorylation.

[0008] The present invention relates to the inhalation formulations, methods and kits involving the manufacture of 17-OHPC powder that has a particle size suitable for inhalation. The manufacture of 17-OHPC powder involves applying cavitational forces on formulations containing 17-OHPC through repeating cycles of high pressure homogenization followed by spray drying. Particle sizes are reduced to a Mass Median Diameter, or a median of the volume distribution, to 57 μηη or less.

[0009] The novel features which are characteristic of the invention, both as to structure and method of operation thereof, together with further objects and advantages thereof, will be understood from the following description, considered in connection with the accompanying drawings, in which the preferred

embodiment of the invention is illustrated by way of example. It is to be expressly understood, however, that the drawings or figures are for the purpose of illustration and description only, and they are not intended as a definition of the limits of the invention.

[00010] General Background and State of the Art

[00011] Pharmaceutical micronization. Achieving desirable dry powder

characteristics, such as granule size and purity, is critical for optimal performance of a pharmaceutical inhalant comprising of an active ingredient. Therefore, appropriate micronization of a drug or an active pharmaceutical ingredient (API) is an integral part of manufacturing. "Bottom-up" approaches such as

crystallization, spray drying, ionic complexation, and precipitation of dissolved active pharmaceuticals may be performed. Though simple and cost effective, a disadvantage of the "bottom-up" approach is the difficulty in controlling particle size and shape. Lonare A.A., et al., Int J Chem Eng App. 2013 Vol.4(5): 337-341 , Chikhalia V., et al., Eur J Pharm Sci. 2006 Jan;27(1 ):19-26.

[00012] An alternative method to obtain desired particle size and shape is the "top- down" approach. The "top down" approach involves the mechanical reduction of previously formed larger particles to the desired size. Supra Lonare A.A. et al. The mechanical reduction process relies on milling and/or grinding and includes techniques such as wet milling, dry milling, ball/pearl milling, spiral media milling, jet milling, high pressure homogenization (HPH), or any other form of impact milling known in the art. Supra Lonare A.A. et al.; Nakach M., et al., Int J Min Proc. Dec 2004. 74:S173-181 . As discussed further below, these techniques require high input energy, which may cause shear and heat, thus leading to potentially undesirable polymorphisms, amorphisation, denaturation, and loss of activity. Also, these methods may allow the particles to frequently contact portions of the milling equipment which may lead to equipment erosion and impurities within the particles. Nonetheless, milling and/or grinding have been the commonly employed techniques for the preparation of pharmaceuticals.

[00013] Milling technology. There are two basic technologies that are used for preparing pharmaceutical powders; bead/pearl milling and HPH. Keck CM. et al., Eur J Pharm Biopharm. 2006 Jan;62(1 ):3-16. More recently, combinative technologies have also been implemented that rely on a pre-treatment size reduction process, such as spray-drying or freeze drying, before the top-down process is performed. Moschwitzer J. P. Int J Pharm. 2013 Aug 30;453(1):142- 56.

[00014] Bead milling. Bead milling (also known as pearl milling or wet ball milling) is a process of preparing pharmaceutical suspensions by grinding in a chamber, for example a cylindrical chamber. The chamber is filled with a pharmaceutical drug along with a grinding/milling medium such as beads/balls made from ceramic, glass, plastic, stainless steel, or polystyrene derivatives, or zirconium salts. Movement of the milling medium for example by rotation of the cylindrical chamber causes shear forces during impaction of the milling medium with the pharmaceutical drug, and such shear forces causes fracture of the pharmaceutical drug. Nekkanti V., et al., The Delivery of Nanoparticles

ISBN:978:953-51 -0615-9; Khadka P., et al., Asi J Pharm Sci. 2014 Dec(9)6:304- 316. Particle sizes achieved by ball milling have been reported to be between 100 and 300 nm. Supra Moschwitzer J. P. However, "erosion from the milling material during the milling process is a common problem of this technology", thereby introducing impurities into the particles. Shegokar R., et al., Int J Pharm. 2010 Oct 31 ;399(1-2):129-39.

[00015] High pressure homogenization. High pressure homogenization is a

"particle size reduction [technique] that utilizes high-shear processing of an aqueous slurry of drug and stabilizing agents". Sharma P.H., et al., Eur. J.

Pharm. Med. Res. 2015, 2(2), 484-502. The HPH milling method includes three types of homogenization processes; Microfluidizer jet milling (IDD-P™™ technology) which is based on the jet stream principle, in water piston-gap homogenisers (Dissocubes® technology), and in water-reduced/non-aqueous media piston-gap homogenisers (Nanopure® technology). Junghanns J.A.H. et al. Int J Nanomedicine. 2008 Sep; 3(3): 295-310; Supra Shegokar R. et al.

[00016] Jet milling. Jet stream homogenizers, such as the Microfluidics Inc.

Microfluidizer®, rely on "frontal collision of two fluid streams in a Y-type or Z-type chamber under pressures up to 1700 bar" to generate small particles. Supra Shegokar R. et al. The collision between the two jet streams results in shear and cavitation forces which lead to particle size reduction.

[00017] Jet mills use highly pressurized air to grind pharmaceuticals. At times, the term "fluid" jet mill is used to refer to a jet milling process with the fluid being high pressurized air. Supra Khadka P. et al. The energy of the fluid grinds the pharmaceutical into powder. Advantages of jet milling include that jet milling can be a dry process, can result in the preparation of micron-sized particles with a narrow size distribution, may have an absence of contamination, and may be suitable for heat sensitive pharmaceuticals. Id. Alternative jet milling procedures employ the use of water, for example water jet milling. Water jet milling creates cavitation zones which "disintegrate particles by dynamic impact of liquid on particle surface without a direct contact with milling bodies and inner surfaces". Dvorsky R., et al., Adv Pow Tech. 201 1 (22):639-643. Unfortunately, jet milling requires "a relatively high number of cycles (50-100 passes)" which are necessary to obtain sufficient particle size reduction". Supra Shegokar R. et al.

[00018] Piston-gap homogenizers. Piston-gap homogenizers, such as the

DissoCubes® (SkyePharma PLC), rely on forcing an aqueous solution under high pressure through a thin gap, for example, a 5-20 pm gap. Supra Dvorsky R. As the aqueous solution passes through the gap, there is an increase in dynamic pressure which is simultaneously compensated by a reduction in static pressure, thus causing the solution to boil. Upon exiting of the solution from the gap, the bubbles from boiling collapse under normal atmospheric pressure, and undergo cavitation. Id. The cavitation forces of HPH are responsible for inducing particle size reduction.

[00019] Nanopure® technology by PharmaSol GMBH, Berlin, now Abbott

Laboratories, is a piston-gap homogenization process that uses dispersion medium with a low vapor pressure (i.e. oils, PEG, water-reduced or non-aqueous media) and optionally homogenization at low temperature. Supra Shegokar et al., Supra Junghanns J.A.H., et al. Thus, this process may be used for temperature labile and hydrolysis sensitive pharmaceuticals.

020] Control parameters. Control parameters for achieving desirable size, shape, density, dispensability, agglomeration, aerodynamic properties, and stability during a given milling procedure not only include choosing the type of milling equipment, but may also include a precise understanding of temperature, pressure, duration of milling, and number of milling cycles performed. All of which have an influence on the powder granulometry of a particular

pharmaceutical. Furthermore, a person having ordinary skill in the art knows that a method of particle processing and size reduction of any active pharmaceutical ingredient (API) cannot easily be predicted to produce a particle of proper structure and effectiveness. With regards to using different milling processes, "[different equipments have their pros and cons, but experience is required to select the right one...[m]aterial characterization of the drug substance needs to be associated with the micronisation technique to have a clear pictures of the size, shape and crystallinity of the powder." Larran J.M., et al., Pharm Man Pack Sou, Spring 2005. Vehring R. teaches that particle size reduction is a complex engineering process that is "difficult to design using an empirical approach alone because of the many processes and formulation variables that need to be tuned correctly to achieve the desired result". Vehring R., Pharm Res. 2008(25)5:999- 1012. [00021] HPH milling cycles and particle size reduction. Size reduction using HPH depends on the power density of the homogenizer, the temperature, number of homogenization cycles, and pressure which has a relatively small effect on decreasing the size of a pharmaceutical but a significant effect on particle size distribution. Supra Keck CM. et al., Supra Nekkanti V. et al. With respect to cycles, the fluid passing through the HPH gap occurs within several milliseconds, which is not sufficient time to comminute pharmaceutical crystals into a uniform size. Hence, it is necessary to perform "five, ten, or more cycles depending on the hardness of [the] drug and desired particle size". Junyaprasert V.B. et al., Asian J Pharm Sci. 2015(10)1 :13-23.

[00022] For example, milling cycles to obtain span values in the approximate

range of 1.4 to 2.0 for fluticasone propionate, salmeterol xinafoate, and titropium bromide are 20, 7, and 21 cycles, respectively. See Gil et al., U.S. patent application no. 13/642,397. There has also been teaching that milling over 20 cycles may be damaging to particles, such as in the case of microfluidisation of PEG-PLGA. Sani S.N. et al. J Microencap, 2009 Sep;26(6):556-561. PEG- PLGA particle size reduction is limited to 5 milling passes (i.e. cycles), and specifically up to 20 passes. Beyond 20 cycles causes agglomeration and variable size distribution of particles, and is "evidence that over - processing and excessive shear stress placed upon nanoparticles is likely to be detrimental upon the size distribution and morphology of the [nano] particles". Id.

[00023] Therefore, it is well known by one with ordinary skill in the art that

experimentation with regards to the optimal number of homogenization cycles varies for each composition, and substantial testing is required for achieving a desirable size of an API. Thus, the number of milling cycles required for the desired preparation of pharmaceutical formulations cannot simply be

extrapolated from one teaching to the preparation and formulation of other APIs.

[00024] Furthermore, continuously increasing HPH cycle numbers was believed to not further reduce particle size. Keck CM. et al. teaches that the reduction of particle size is due to breaking of particles/crystals at weak points (i.e.

imperfections), and thus the remaining crystals become more perfect with a reduction of particle size. With every subsequent milling cycle, there are less weak points in a particle that are available to further reduce its size. "[T]he particles will not further diminute, even when additional homogenization cycles are applied." Supra Keck CM. et al. Keck CM. et al. shows that the maximum reduction of the mean diameter for azodicarbonamide is asymptotically achieved after five homogenization cycles, with higher cycles only reducing the width of any remaining large crystals. Id.

[00025] Furthermore, "particle size reduction effectiveness of [milling] depends more on the physico-chemical properties of the processed drug", and therefore, each milling process used to micronize any API requires empirical evaluation. Supra Moschwitzer J.P. Additionally, experimentation of formulation

performance is also required for scale-up production, as there is "no framed algorithm which can help the formulators predict the large scale performance of a product based on its small scale behavior." Srivalli K.M.R. et al. Saudi Pharm J, May 2014. Therefore, every API requires experimental evaluation and material characterization to determine the most optimal milling procedure and associated operational parameters.

[00026] Sources of impurities. A possible source of contamination and introduction of impurities and undesirable components into pharmaceutical preparations prepared by HPH is from direct contact with milling parts leading to abrasion and wearing of HPH equipment. For example, wear and tear of the tip of the homogenization valve may lead to reduction of process efficiency. Therefore, ceramic tips may be used in modern homogenizers as a means to decrease contamination and maintain process efficiency. Also, the cavitation process of particle size reduction minimizes direct contact between a drug and milling parts, reducing the potential of contamination to acceptable limits. For example, Krause et al. reported that a nanosuspension of the drug RMKK98 prepared by HPH contained less than 1 ppm of iron after 20 cycles at 1500 bar, which falls well below the 10 ppm acceptable limit. Krause K.P., et al. Int J Pharm. 2000 Mar 10;196(2):169-72.

[00027] Crystallinity and amorphous state. In an ideal crystal, the atoms are

arranged in a symmetrical structure resulting in a stable system with distinct physical properties. The crystalline arrangement of an API allows for increased chemical and physical stability. On the contrary, amorphous solids have a noncrystalline molecular order. The lack of a crystalline lattice increases the surface area and in turn increases exposure to the environment which may increase the apparent solubility. However, due to the increased surface area, "hygroscopicity, air oxidation, adsorption on excipients, and/or instrumentation and blending effects are more problematic with amorphous drugs." Bauer J. F. J Valid Tech; Aug 2009, 15(3)63-68. Thus, maintaining a crystalline structure of an API during the manufacture process is warranted when an increased stability and shelf-life is desired.

[00028] The milling process may induce undesirable structural changes in the pharmaceutical ingredient and result in structural variability and impurities. It is well known that milling methods, such as dry milling and ball milling, induce active pharmaceutical ingredients to lose their crystalline form to an anhydrous or amorphous form of the active ingredient. US Pat. Application 13/642,397, Gil et al. "Milling can reduce the crystallinity of a drug and create areas of disorder or amorphous regions; [and] total change to the amorphous state is possible".

Supra Bauer J.F. For example, progesterone is known to exist in two

polymorphic forms; form 1 (a-form) and form 2 (β-form). Araya-Sibaja A.M., et al., Pharm Dev Technol. 2014 Nov;19(7):779-88. The stress of mechanical grinding of progesterone form 2 induces its polymorphic transformation into progesterone form 1. Therefore, since milling may influence the crystallinity and amorphous state of a pharmaceutical drug, experimentation is necessary to identify milling parameters that produce a desirable polyphorm.

[00029] Inhalant particle size. The optimal size of a particle suitable for inhalation is between approximately 1-5 pm. Siew A. Pharm Technol. 2014(38):2. For example, salbutamol aerosols with a mass median aerodynamic diameter (MMAD) of 2.8 pm produced superior bronchodilation, while the optimal particle size for a β₂ antagonist was shown to be approximately 3 pm. Labiris et. al., Br J Clin Pharmacol. 2003 Dec; 56(6): 588-599. Particles greater than 10 pm are deposited in the oropharyngeal region and settle on the larynx, and are subsequently swallowed having a minimal to no therapeutic effect. Id. Particles with a size of 5-10 pm are mainly deposited in the oropharayngeal region, while particles of 1-5 pm in diameter are deposited in the small airways and alveoli. Id. Particles with an MMAD of less than 0.5 pm deposit via diffusion, however, particles of the size of 0.5 pm may fail to deposit and be exhaled. Id. The desirable size range of pharmaceutical particles intended for therapeutic use by inhalation is between 1-5 pm. Particle sizes between 5-15 pm are suggested for nasal delivery, with a recommendation of 9 pm in order to avoid lung inhalation of drugs intended for nasal delivery. Djupesland P.G. Drug Deliv TransI Res. 2013 Feb;3(1 ):42-62.

[00030] Inhalant Span Value. The span value of the power (or polydisperity) must also be accounted for in preparing an effective inhalant. The span value is the width of the distribution of the particle size as defined below. Too broad of a span value may result in impaction or retention within the inhaler, thereby reducing the effective dosage necessary for treatment. Chew et al. J Pharm. Pharmaceut. Sci., 2002 5(2) 162-168. An ideal span value is 2.5 or less. US Pat. Application 13/642,397, Gil et al..

[00031] Achieving a desirable particle size suitable for inhalation while maintaining crystallinity, purity, and activity requires experimentation and validation for every API. There has been no method to prepare an inhalant containing 17-OHPC of proper particle size, span, structure, and purity. [00032] SUMMARY OF THE INVENTION

[00033] The present invention is directed to inhalant formulations and methods for restoring corticosteroid sensitivity or reversing the glucocorticoid insensitivity or enhancing glucocorticoid sensitivity.

[00034] Other embodiments of the present invention are directed to inhalation formulations comprising a progestogen such as 17alpha-hydroxyprogesterone caproate for pulmonary delivery.

[00035] Yet other embodiments of this invention are directed to inhalation

formulations comprising a progestogen such as 17alpha-hydroxyprogesterone caproate and budesonide for pulmonary delivery.

[00036] Yet other embodiments of this invention are directed to inhalation

formulations comprising a progestogen such as 17alpha-hydroxyprogesterone caproate and fluticasone for pulmonary delivery.

[00037] It is understood that the embodiments above are provided as

representative embodiments of the present invention, and in no way are to be constructed as limiting the scope of the present invention.

[00038] BRIEF DESCRIPTION OF THE DRAWINGS

[00039] FIG. 1 is an exemplary comparison of particle size distribution profiles of

17-OHPC versus high pressure homogenization cycles.

[00040] FIG. 2 shows exemplary particle size distribution values of 17-OHPC after increasing HPH cycles.

[00041] FIG. 3 is a graphical representation of Dv50 particle size distribution values of 17-OHPC after milling in water and after spray drying. [00042] FIG. 4 is an exemplary comparison of particle size distribution profiles of 17-OHPC powder obtained after HPH in water and after spray drying.

[00043] FIG. 5. shows an exemplary particle size distribution values of 17-OHPC after HPH in water and after spray drying.

[00044] FIG. 6 is a graphical representation of the FIG. 5 results.

[00045] FIG. 7 is an exemplary comparison of XPRD profiles between bulk material and 17-OHPC powder after spray drying.

[00046] FIG. 8 is an exemplary High Pressure Liquid Chromatography (HPLC) data showing the impurity profile of bulk and spray dried 17-OHPC.

[00047] FIG. 9 is an exemplary area percentage of impurities of bulk and spray dried 17-OHPC as determined from HPLC data.

[00048] FIG. 10 depicts exemplary results showing a good correlation between 17- OHPC particle size and fine-particle dose (FPD).

[00049] FIG. 1 1 depicts additional exemplary results showing good correlation between 17-OHPC particle size and fine-particle dose (FPD).

[00050] DEFINITIONS

[00051] As used herein, the term "glucocorticoid insensitivity" is intended to

include, but is not limited to, corticosteroid resistance, corticosteroid dependence, corticosteroid refractory responses, corticosteroid intolerance, and other types of corticosteroid ineffectiveness. It has been recognized that several distinct molecular mechanisms contribute to decreased anti-inflammatory effects of glucocorticoids. Different inflammatory diseases may share similar molecular mechanisms, and a single disease may have a heterogeneity of mechanisms. [00052] "Corticosteroid resistance" to the anti-inflammatory effects of

corticosteroids is defined as no clinical improvement after treatment with high- dose glucocorticoid.

[00053] "Corticosteroid dependence" is defined as a condition that initially

responds to corticosteroids but relapses quickly upon drug withdrawal or dose tapering.

[00054] "Corticosteroid refractory response" is defined as a condition that does not respond to an adequate induction dose of corticosteroids. It includes relatively or totally refractory responses to glucocorticoid therapy, and often needs to be controlled by add-on treatment.

[00055] Other types of "corticosteroid ineffectiveness" includes the need for a very high dose treatment, "difficult to treat" and "do not respond well" or severe cases, and impaired in vitro and in vivo responsiveness.

[00056] "Corticosteroid intolerance" is defined as toxicity of the therapy and/or risks for developing corticosteroid-related adverse events such as opportunistic infections and bone loss.

[00057] "Glucocorticoid sensitizer" is defined as a pharmaceutical agent and

product that has a function in restoring corticosteroid sensitivity, enhancing glucocorticoid sensitivity, reversing the glucocorticoid insensitivity, and protecting against loss of glucocorticoid sensitivity, and used for treating, preventing, or ameliorating one or more of the symptoms of diseases or disorders associated with glucocorticoid insensitivity (e.g., corticosteroid dependent or corticoid resistant or unresponsive or intolerant to corticosteroids). Therapeutic effects of the use of a glucocorticoid sensitizer include any, but are not limited to, steroid- sparing in corticosteroid-dependent patients, better responsiveness or tolerance to corticosteroids, achieving efficacy by using a lower dose of corticosteroid, preventing individuals at risk for developing refractory responses or resistance or exacerbations in response to antigen exposures, infections, exercise, or irritants, achieving optimal immune functions, easier responses for the subject or patient when steroid administration is tapered or withdrawn, or after prolonged administration of corticosteroids, decreased risks for developing corticosteroid- related adverse events such as opportunistic infections, bone loss, pathologic fracture, diabetes, cataract, and combinations thereof.

[00058] As used herein, the term "progesterone" or "P4" refers to the chemical compound with systematic name pregn-4-ene-3,20-dione, Chemical Abstracts Services (CAS) number 57-83-0.

[00059] As used herein, the term "17 a-hydroxyprogesterone caproate" or "17- OHPC" refers to the chemical compound with systematic name 17-[(1- Oxohexyl)oxy]-pregn-4-ene-3,20-dione, CAS Registry Number 630-56-8.

[00060] Unless otherwise noted, the term "lnterleukin-17" or "IL-17" as used

herein, refers to the cytokine protein "IL-17A". Wherein "IL-17A" refers to the protein of any IL-17A protein sequence known in the art.

[00061] As used herein, the term "p38" refers to any of the p38 isoforms known in the art, namely, ρ38α (MAPK14), ρ38β (MAPK1 1 ), ρ38γ (MAPK12/ERK6), or ρ38δ (MAPK13/SAPK4), unless otherwise specifically noted. [00062] As used herein, the term "R-group" refers to any combination of carbon, hydrogen, oxygen, nitrogen, and/or halogen atoms attached to the C-17 position on the cholesterol hydrocarbon ring framework.

[00063] As used herein, the term "patient" refers to a human receiving or

registered to receive medical care or treatment.

[00064] As used herein, the term "severe asthma" or "corticosteroid resistant asthma" or "therapy resistant asthma" refers to asthma symptoms and exacerbations that are unresponsive or respond suboptimally to inhaled or systemic corticosteroids resulting in a reduction in effectiveness of corticosteroids in controlling asthma. Bhavsar P. et. al. states that suboptimal response in corticosteroid resistant asthma is "defined as <15% of baseline forced expiatory volume in 1 s (FEV-i ) after taking prednisolone (30-40 mg/day) over 14 days while demonstrating marked bronchodilator response to inhaled β₂ agonists" as compared to patients with corticosteroid responsive asthma who demonstrate "a >25% improvement in FEVi after prednisolone treatment". Bhavsar P. et al., 2008 Sep;63(9):784-90. Corticosteroid resistant asthma patients also show "a reduction in suppressive effect of dexamethasone on the proliferative response of or release of neutrophil activating factor from peripheral blood mononuclear cells (PMBCs) has been observed". Id. Also, severe asthamtics have increased levels of active p38 than non-severe asthma patients. Id. Furthermore,

"decreased glucocorticoid responsiveness is found in patients with severe asthma and asthmatics who smoke, as well as in all patients with COPD and cystic fibrosis". Barnes P.J., J Steroid Biochem Mol Biol. 2010 May 31 ;120(2- 3):76-85. Mild intermittent asthma may be controlled by β₂ agonists alone while moderate to severe asthma may necessitate the use of high-dose inhaled or oral corticosteroids. Stirling R.G., et. al., Allergy 2001 :56:825-840.

[00065] As used herein, the term "inhalation" refers to inhaling or breathing as a route of administration of a pharmaceutical composition through respiratory passages, wherein delivery of said pharmaceutical composition may preferably be, for example, via an aerosol spray, a powder mixture, gas, or vapor in a pressurized pack or nebulizer or in an inhaler.

[00066] As used herein, the term "fine particle dose" (FPD) refers to the dose of aerosolized particles with an aerodynamic diameter of less than five microns. Fine particle fraction (FPF) is defined as the ratio of FPD to the total recovered dose.

[00067] As used herein, the term "high pressure homogenization" refers to any milling technique/technology that employs cavitation forces for reducing particle size, including any piston-gap homogenizers. Examples of HPH technology include, but are not limited to, jet stream homogenizers, microfluidizers, and piston-gap homogenizers. Examples of HPH technologies include, but are not to, IDD-P™™, Nanopure®, Microfluidizer®, and DissoCubes®.

[00068] As used herein, the terms Dv10, Dv50, and Dv90 refer to the standard percentile readings of particle size analysis performed by an optical measuring unit such as, but not limited to, a Malvern Mastersizer 2000S. Dv50 refers to the size in microns at which 50% of the sample is smaller and 50% is larger. This value is known as the Mass Median Diameter (MMD) or the median of the volume distribution. The v in the expression shows that this refers to the volume distribution. Dv10 is the size of particle below which 10% of the sample exists. Dv90 is the size of the particle below which 90% of the sample exists. As used herein, the term span refers to a measurement of width distribution and is calculated using the formula (Dv90 - Dv10) / Dv50. The narrower the

distribution, the smaller the span value. Malvern Instruments Ltd. Mastersizer 2000 user manual (2007).

[00069] DETAILED DESCRIPTION OF THE INVENTION

[00070] A particularly preferred route of delivery for administering effective amounts of the progesterone compounds or compositions containing therapeutically effective concentrations of the compounds is via an inhalation route of administration. When an inhalation route of administration is used, delivery may preferably be, for example, via an aerosol spray or powder mixture in a pressurized pack or a nebulizer or in an inhaler.

[00071] Inhalation formulations may be used for the treatment of glucocorticoid- insensitivity related diseases or disorders, or conditions as previously provided in the U.S. patent application no. 13/174,939. Inhalation formulations may also be used for treating IL-17 cytokine-mediated auto-immune and auto-inflammatory diseases. For example, IL-17 has been linked to numerous inflammatory and auto-inflammatory diseases such as autoimmune and type-1 diabetes (Emamaullee J.A. et al., Diabetes 2009, 58:1302-131 1 , and Kudo et al., Nat. Med. 2012, 4;18(4):547-54), end-stage kidney disease (Kim Y.G. et al., Am. J. Nephrol. 2012, 36:472-477), obliterative bronchiolitis post-lung transplant (Suzuki H. et al., J. Immunol. 2013, 191 :4431 -4439), asthma (Busse W.W. et al., Am J respire Crit Care Med 2013, 188 (1 1 ): 1294-1302), encephalomyelitis (Knier B. et al., J. Autoim. 2015, 56:34-44), pulmonary fibrosis (Frangois A. et al., J. of Autoimmun. 2015, 56: 1 -1 1 ), liver fibrosis (Amara S. et al., Mol. Immunol., 2015, 64: 26-35), chronic obstructive pulmonary disease (Caramori G. et al., Intl. J. of COPD 2014, 9:397-412), preeclapsia (Cornelius D.C. et al., Pregnancy Hypertens. 2015, 5 (1 ): 17), parenchymal lung fibrosis (Martinu T. et al., J. Heart and Lung Transpl., 34:4, 2015, 175-6), atherosclerosis (Gong F. et al., Cell Immunol. 2015 Sep;297(1 ):33-9), rheumatoid arthritis (Konya C. et al., Cytokine. 2015 Oct;75(2):207-15), systemic lupus erythematosus (Id.), psoriasis (Id.), lupus nephritis (Qiao G. et al., Clin. Immunol. 2015, 157(2): 166-174), inflammatory bowel disease (Fujino S. et al., Gut 2003; 52:65-70), Crohn's disease (Hueber W. et al.,Sci TransI Med. 2010 Oct 6:2(52):52ra72), multiple sclerosis (Gold R. et al., Am. J. Pathol. 2008; 172(1 ): 8-10), Duchenne muscular dystrophy (De Pasquale L. et al., Neurology. 201278(17):1309-14), and psychiatric disorders such as schizophrenia and depression (Potvin S. et al., Psychiatry 2008;63(8):801-8, and Roy T. et al., J Affect Disord. 142 Suppl: S8- 21 ).

072] Exemplary 17-OHPC Powder Formulations. As described herein, when an inhalation route of administration is used, delivery may preferably be accomplished, for example, via an aerosol spray or powder mixture in a pressurized pack or a nebulizer or in an inhaler. [00073] it is preferred that pharmaceutically acceptable compositions for inhalation delivery include dry powders comprising an active ingredient (for instance, 17- OHPC) present in a dry bulking powder suitable for dry powder inhalation or suspensions suitable for nebuiization, and aerosol propellants suitable for use in a metered dose inhaler.

[00074] One particularly preferred exemplary formulation is a 17-OHPC powder formulation for dry powder inhalation. Moreover, it is preferred that the 17-OHPC powder formulation for administration by inhalation comprises the 17-OHPC active substance and a pharmaceutically acceptable excipient (e.g., lactose, Respitose ML001 , and Lactohaie LH300). !t is also preferred, according to one embodiment of the present invention, that the composition has the form of a physical mixture (for instance, a powder blend) and comprises from about five (5) to about fifty (50) weight percent of the excipient, and wherein the active substance (17-OHPC) has a particle size distribution profile of from about one nanometer to about ten (10) microns (pm), and wherein the excipient has a particle size distribution of from about fifteen (15) to about five-hundred (500) microns. It is to be understood, in accordance with other embodiments of the present invention, that the compositions of the present invention can alternatively have other particle size distribution profiles as needed or desired, wherein said compositions are suitable and effective for administration to a subject, for instance, administration by inhalation,

[00075J Pulmonary local delivery of 17-OHPC and progesterone to a subject (for instance, a human) is preferably accomplished by inhalation through the mouth. Surprisingly, it has been found in accordance with the present invention that respiratory (i.e., inhalation or pulmonary) delivery of the 17-OHPC active ingredient is safe, in contrary to the previous conventional belief thai 17-OHPC and progesterone are harmful if they are inhaled. This surprising and unexpected finding, in accordance with the present invention, represents a significant discovery.

[00078] Moreover, another surprising and unexpected finding, in accordance with the present invention, is that particle size reduction of 17-OHPC to a particle size distribution that ranges from about one nanometer to about ten (10) microns is optimal for a therapeutically effective powder composition (e.g., powder blend). According to certain preferred aspects of the invention, particle size reduction of 17-OHPC, for instance, preferably substantially hydrophobic 17-OHPC, can be achieved by milling in water, either with a surfactant or without a surfactant, wherein the particle size reduction of 17-OHPC is achieved -without changing its basic crystalline structure and without generating any measurable additional impurity or impurities.

[00077] In addition, it has also been surprisingly discovered, in accordance with the present invention, that one or more pharmaceutically acceptable surfactants may be used in achieving optimal particle size reduction, i.e., the reduction in API particie size, for instance, 17-OHPC particle size reduction. One preferred surfactant is Tween 80, which can preferably be used at a concentration of from about five (5) to about fifteen (15) percent. In addition to Tween 80, other examples of pharmaceutically acceptable surfactants that may be used in accordance with the present invention include, but are not limited to, e.g., monogiycerides, di-glycerides, poiysorbate 80, sorbitol-fatty acid esters, and giyceroi-!actie acid esters. Additional examples of surfactants include, but are not limited to, polyoxyethylene (hereinafter abbreviated as POE-branched alkyl ethers such as POE-octy!dodecyi alcohol and POE-2-decyifetradecyl alcohol, POE-a!ky! ethers such as POE-o!ey! alcohol ether and POE-cetyl alcohol ether, sorbitan esters such as sorbitan monooieate, sorbitan monoisostearate and sorbitan monolaurate, POE-sorbitan esters such as POE-sorbitan monooieate, POE-sorhitan monoisostearate and POE-sorbitan monolaurate, fatty acid esters of giycerol such as glyceryl monooieate, glyceryl monostearate and glyceryl monomyristate, POE-fatty acid esters of glycerol such as POE-giyceryl monooieate, POE-glyceryl monostearate and POE-giyceryl monomyristate, PQE- dihydrocholesterol ester, POE-hardened castor oii, POE-hardened castor oii fatty acid esters such as POE-hardened castor oil isostearate, POE-alkylaryl ethers such as POE~octylphenol ether, giycerol esters such as glycerol monoisostearate and glycerol monomyristate, POE-g!yceroi ethers such as POE-glycerol monoisostearate and POE-glycerol monomyristate, poiyglyceroi fatty acid esters such as diglyceryl monostearate, decaglyceryl decastearate, decag!ycery! decaisostearate and diglyceryl diisostearate and other nonionic surfactants; potassium salts, sodium salts, diethanolamine salts, triethanolamine salts, amino acid salts and other salts of higher fatty acids such as myristic acid, stearic acid, palmitic acid, behenic acid, isostearic acid and oleic acid, the above alkali salts of ether carboxylic acids, salts of N-acyiamino acids, N-acylsalconates, higher a!ky!su!fonates and other anionic surfactants; a!ky!amine salts, polyamine, aminoalcohol fatty acids, organic silicone resin, alkyi quaternary ammonium salts and other cationic surfactants; and lecithin, betaine derivatives and other amphoteric surfactants. St is to be understood that other surfactants may also be used.

[00078] in preferred embodiments of the present invention, 17-OHPC

compositions include dry powders that comprise the 17-OHPC present in a dry bulking powder suitable for dry powder inhalation; or suspensions comprising 17- OHPC suitable for nebulization, or alternatively, aerosol propellant formulations suitable for use with a metered dose inhaler. It is preferred to achieve a fine- particle dose (FPD) of 17-OHPC in the range of approximately about fifteen (15) to about nine-hundred ninety (990) micrograms (pg), wherein FPD is defined as the dose of the aerosolized drug particles with an aerodynamic diameter less than about five (5) microns.

[00079] In preferred embodiments of the present invention, and referring to FIGS, 10 and 1 1 the composition for inhalation delivery exhibits a desired correlation such that a relatively small particle size distribution (for instance, less than about 3.8 microns) correlates with a desired fine-particle dose (FPD) of 17-OHPC, e.g., FPD in the range of between about fifteen (15) to about six-hundred (800) micrograms (pg). Moreover, it is preferred that the compositions of the present invention are characterized by a blend homogeneity having a relative standard deviation (RSD) less than about five percent, and it is also preferred that the compositions for inhalation delivery have a fine particle fraction (FPF) of about thirty percent or greater, it is also to be understood that blend homogeneity can be determined by any suitable method, for instance, by high-performance liquid chromatography (HPLC).

[00080] Exemplary Techniques for Bulk Material Characterization. For purposes of characterizing bulk material used, for instance, in a powder formulation, e.g., a 17-OHPC powder formulation, any suitable technique or method can be used in accordance with the present invention for characterizing the bulk material.

Characterization of the bulk material can be performed, for instance, using bulk powder density analyzers; X-Ray Powder Diffraction (XRPD): water vapor sorption; or dynamic vapor sorption (DVS) techniques.

[00081 j XRPD is an established and very reliable technique for determining

crystalline structure.

[00082] Dynamic vapor sorption (DVS) is a gravimetric technique that measures how quickly and how much of a solvent is absorbed by a sample, such as a dry powder absorbing water. DVS accomplishes this by varying the vapor concentration surrounding the sample and measuring the change in mass which this produces,

[00083] Exemplary Techniques for Characterizing Particle Size and Distribution.

[00084] In accordance with the present invention, any suitable technique or

method can be used for characterizing particle size and particle size distribution, for instance, the particle size distribution of an active pharmaceutical ingredient (API) in a powder formulation. Exempiary methods include, for instance, the use of one or more of surface area analysis, pore size analysis, continuous-imaging particle analysis, powder characterization, diffraction laser particle size analysis; pattern recognition techniques; and imaging particle analysis, just to name a few examples, imaging particle analysis systems, for instance, with laser-scatter triggering, can accurately calculate concentrations of particles in relatively concentrated samples. For sparse samples, methods using a laser-scatter trigger signal can be used to image and measure particles in a sparse sample.

[0Θ085] Pattern recognition techniques can also be used to identify and

differentiate different particle types contained in a heterogeneous solution.

Pattern recognition techniques may involve, for instance, imaging microscopic particles in real-time as they flow in a solution, segregating each individual particle as a separate image, and then applying pattern recognition techniques to differentiate the individual particle types.

[00088] Laser diffraction instrumentation may also be used for characterizing

particle size and particle size distribution. Particle size and particle size distribution can be determined from a detected diffraction pattern using an appropriate scattering model.

[00087] In determining and characterizing particle size, e.g., particle size of an API (active pharmaceutical ingredient), the particle size parameters Dv(10), Dv(50) and Dv(90) may be used. Particle size measurements are preferably expressed in terms of Dv(10), Dv(50), and Dv(90), wherein Dv{10) refers to the particle size below which 10% of the volume of material exists; Dv(50) refers to the particle size below which 50% of the volume of materia! exists; and Dv(90) refers to the particle size below which 90% of the volume of materia! exists, 088] Other Routes of Delivery. Other routes of deliver may be used for administering effective amounts of the progesterone compounds or compositions containing therapeutically effective concentrations of the compounds. For instance, the present invention also contemplates formulations for systemic delivery, including for instance parenteral, oral, or intravenous delivery, or for local or topical application, for the treatment of giucocorticoid-insensitivity related diseases or disorders, or conditions, including, but not limited to, glucocorticoid resistant conditions (e.g., glucocorticoid resistant asthma, refractory rheumatoid arthritis, refractory inflammatory bowel disease, chronic obstructive pulmonary disease and acute respiratory distress syndrome, interstitial pulmonary fibrosis, and cystic fibrosis); glucocorticoid refractory conditions (e.g., refractory ulcerative colitis, children with severe Crohn disease, corticosteroid refractory asthma, desquamative interstitial pneumonia refractory to corticosteroid, refractory inflammatory myopathies, refractory myasthenia gravis, refractory pemphigus vulgaris, methotrexate-refractory RA patients, refractory nephrotic syndrome, refractory multiple sclerosis, refractory sprue-like disease, steroid-resistant sarcoidosis, refractory mucosal lesions of pemphigus vulgaris, refractory Schnitzler syndrome, resistant dermatitis of the head and neck, severe refractory atopic dermatitis, refractory idiopathic thrombocytopenia purpura, refractory orbital myositis, refractory or recurrent lymphomas, critically ill patients with sepsis or acute respiratory distress syndrome (ARDS) and relative adrenal insufficiency); glucocorticoid dependent conditions (e.g., rosacea, polymyalgia rheumatic, giant cell arteritis, polymyositis, dermatomyositis, Kawasaki syndrome, Guillain Barre syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, Stiff man syndrome, corticosteroid dependent systemic lupus erythematosus, corticosteroid dependent multiple sclerosis, symptomatic corticosteroid dependent asthma, primary Sjogren's syndrome, systemic vasculitis, polymyositis, organ transplants, and graft-versus- host disease); and other inflammatory diseases, autoimmune diseases, hyperproiiferative diseases, and other such disease when giucocoriicoid- insensiiivity is implicated. Exemplary of these diseases are lupus, osteoarthritis, rhinosinusitis, polyarteritis nodosa, Wegener's granulomatosis, giant cell arteritis, allergic rhinitis, urticaria, hereditary angioedema, tendonitis, bursitis, autoimmune chronic active hepatitis, cirrhosis, transplant rejection, psoriasis, dermatitis, malignancies (e.g., leukemia, myelomas, lymphomas), acute adrenal

insufficiency, rheumatic fever, granulomatous disease, immune

proliferation/apotosis, hypothalamic-pituitary-adrenal (HPA) axis suppression and regulation, hypercortisolemia, modulation of the Th1/Th2 cytokine balance, chronic kidney disease, spinal cord injury, cerebral edema, thrombocytopenia, Little's syndrome, Addison's disease, autoimmune hemolytic anemia, uveitis, pemphigus vulgaris, nasal polyps, sepsis, infections (e.g., bacterial, viral, rickettsial, parasitic), type H diabetes, obesity, metabolic syndrome, depression, schizophrenia, mood disorders, Cushing's syndrome, anxiety, sleep disorders, memory and learning enhancement, or g!ucocorticoid-induced giaucoma, atopic dermatitis, drug hypersensitivity reactions, serum sickness, bullous dermatitis herpetiformis, contact dermatitis, exfoliative erythroderma, mycosis fungoides, pemphigus, nonsuppurative thyroiditis, sympathetic ophthalmia, uveitis and ocular inflammatory conditions unresponsive to topical steroids, allergic bronchopulmonary aspergillosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate chemotherapy, hypersensitivity pneumonitis, idiopathic bronchiolitis obliterans with organizing pneumonia, idiopathic eosinophilic pneumonias, idiopathic pulmonary fibrosis, Pneumocystis carinii pneumonia (PCP) associated with hypoxemia occurring in an H!V(+) individual who is also under treatment with appropriate anti-PCP antibiotics, a diuresis or remission of proteinuria in nephritic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus, ankylosing spondylitis, polymyalgia rheumatic, psoriatic arthritis, relapsing polychondritis, trichinosis with neurologic or myocardial involvement, and tuberculous meningitis. 089] Generally, in accordance with the present invention, the methods described herein for the treatment of glucocorticoid-insensitivity related diseases or disorders, or conditions comprise administering a pharmaceutical composition comprising a steroid hormone. Typically, the lipophilic gonadal steroid hormone is a progestogen. The progestogen may be a naturally occurring progestogen or a synthetic progestogen (i.e., a progestin). Progestogens that can be used in accordance with the present invention are grouped into the following categories: progesterone, retroprogesterone, progesterone derivative, 17-OHPC progesterone derivatives (both pregnanes and norpregnanes), 19- norprogesterone derivatives, 19~nortestosterone derivatives (both estranges and gonanes), and spironolactone derivatives. Generally, the progestogen for use in accordance with the present invention is selected from the group consisting of progesterone and their derivatives or active metabolites. Specific examples of progestogens that may be used in trie methods and kits of the present invention include, but are not limited to, 17-OHPC, natural progesterone, dydrogesterone, medrogestone, medroxyprogesterone, megestroi acetate, chlormadinone acetate, cyproterone acetate, gestonorone caproate, nomegestrol acetate, demegestone, promegestone, nestorone, trimegestone, norethisterone acetate, norethisterone, lynestrenoi, ethynodiol diacetate, norgestrel, levonorgestrel, desogestrel, etonogestrel (3-ketodesogestrel), gestodene, norgestimate, noreigestromin (17-deacetyi norgestimate), dienogest, drospirenone, norethynodrel, 19-nortestosferone, dienogest, cyproterone acetate, tibolone, 19- norprogesterone, and drospirenone,

[0Θ09Θ] Other agents that can be used in accordance with the methods and kits of the present invention include, for example, any pharmaceuticaliy-acceptabie progestogen derivatives, i.e., derivatives of 17-OHPC, natural progesterone, dydrogesterone, medrogestone, medroxyprogesterone, megestroi,

chlormadinone, cyproterone, gestonorone caproate, nomegestrol acetate, demegestone, promegestone, nestorone, trimegestone, norethisterone, norethisterone, lynestrenoi, ethynodiol diacetate, norgestrel, levonorgestrel, desogestrel, etonogestrel (3-ketoclesogestrei), gestodene, norgestimate, noreigestromin (17-deacety! norgesiimate), dienogest, drospirenone, norethynodrei, 19-nortestosterone, dienogest, cyproterone, tiboione, 19- norprogesterone, and drospirenone. Each progestogen can be derivatized as the corresponding salts, esters, enol ethers or esters, acids, bases, soivates, hydrates or prodrugs prior to formulation, as described herein. Representative pbarrnaceutieaily-aeceptable salts inciude, but are not limited to, amine salts, such as but not limited to, cbloroprocaine, choline, ammonia; diethanolamme and other hydroxyalkylamines, ethylenediamine, Nmethylglucamine, procaine, diethyiamine and other a!ky!amines, piperazine and

tris(hydroxymethyi)aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc, aluminum, and other metal salts, such as but not limited to sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, salts of mineral acids, such as but not limited to hydrochlorides and sulfates; and salts of organic acids, such as but not limited to acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates, valerates and fu ma rates. For example, the organic acid of acetates is often used such as megestro! acetate, chiormadinone acetate, cyproterone acetate, gestonorone caproate, nomegestrol acetate, and cyproterone acetate. 091] Additional representative agents that can be used in accordance with the methods and kits of the present invention include, for example, any progestogen active metabolite including, but not limited to, active metabolites of 17-OHPC, natural progesterone, dydrogesterone, medrogestone, medroxyprogesterone, megestroi acetate, chiormadinone acetate, cyproterone acetate, gestonorone caproate, nomegesiroi acetate, demegestone, promegestone, nestorone, trimegestone, norethisterone acetate, norethisterone, lynestrenoL ethynodiol diacetaie, norgestreL levonorgestrel, desogestre!, etonogestrel (3-keto- desogestre!), gestodene, norgestimate, noreigestromin (17-deacetyl

norgestimate), dienogest, drospirenone, norethynodrei,19-nortestosterone, cyproterone acetate, tibolone, 19-norprogesterone, and drospirenone. For example, active metabolites of progesterone include allopregnanoione and 5a!phapregnan-3,20-dione the active metabolite. Active metabolites of 17-OHPC include M13 monohydroxy-; 12, monohydroxy-; M19, monohydroxy-; 7, dihydroxy-; and M16, monohydroxy-. 092] In various embodiments, another group of steroid hormone,

glucocorticoids, for use in accordance with the present invention is preferably selected from the group consisting of naturally produced steroid hormones, or synthetic compounds, that inhibit the process of inflammation. Specific examples of glucocorticoids include, but are not limited to, hydrocortisone (Cortisol), cortisone acetate, dexamethasone (hereinafter, "Dexamethasone"), prednisone, prednisolone, methyipreclnisolone, betamethasone, triamcinolone,

beclometasone, Paramethasone, fluticasone, fludrocortisone acetate, deoxycorticosterone acetate (DOCA), Fluprednisolone, fluticasone propionate, budesonide, beclomethasone dipropionate, flunisolide and triamcinolone acetonide. [00093] In practicing the methods of the present invention, effective amounts of the compounds or compositions containing therapeutically effective

concentrations of the compounds, are preferably formulated for systemic delivery, including parenteral, oral, or intravenous delivery, or for local or topical application. For example, the pharmaceutical composition may be administered by subcutaneous, intravenous, intraperitoneal, intraarterial or intramuscular injection; rectal!y; by transdermal^ delivery; intravaginai delivery; or buccally; or by oral delivery. When administered by subcutaneous or intramuscular injection, the steroid hormone is suitably formulated as a depot formulation to allow for sustained release of the steroid hormone over an extended period of time. When administered by topical administration, including intravaginai delivery, delivery may suitably be, for example, via a solution, suspension, emulsions or the like and are preferably formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages, dermal patches or any other formulations suitable for the route.

[00094J With respect to the frequency of administration, any frequency which achieves the desired result (i.e., steroid-sparing in corticosteroid-dependent patients, better responsiveness or tolerance to corticosteroids, achieving efficacy by using a lower dose of corticosteroid, preventing individuals at risk for developing refractory responses or resistance or exacerbations in response to antigen exposures, infections, exercise, or irritants, achieving optimal immune- functions, easier responses for the subject when steroid administration is tapered or withdrawn, or after prolonged administration of corticosteroids, decreased risks for developing corticosteroid-re!ated adverse events such as opportunistic infections and bone ioss, and combinations thereof, may be used. The frequency of administration will preferably be determined, at least in part, by the steroid hormone{s) and/or dosage form selected. In various embodiments, the pharmaceutical composition is preferably administered at an interval exceeding daily or once per week. For example, the pharmaceutical composition may be administered once every other week, once monthly, once every two months, or once every three months, in various other embodiments, the pharmaceutical composition is administered once weekly, or at an interval of less than one week (e.g., daily or every other day). For example, when the steroid hormone is 17- OHPC, administration may suitably be via daily, once-weekly or once every two- week, or once-monthly or once every 3-month injections. Those ordinary skill in the art will understand that the route of administration and frequency of administration for the pharmaceutical compositions used in the methods and kits of the present invention wili depend on a variety of factors including, for exampie, the particular steroid hormone(s) used, the formulation in which it is delivered, the tissue being treated, the age and gender of the individual treated, in vivo or in vitro test data, and the professional judgment of the particular patient's needs. The dosing frequency ranges set forth herein are exemplary only and are not intended to limit the scope or practice of formulations provided herein. 095] A person of ordinary skill in the art wili also appreciate that appropriate dosing of the steroid hormone will depend on the steroid hormone(s) selected, the route of administration and dosage form, the frequency of administration, the disease(s) to be treated, the metabolic stability and length of action of that compound, the species, age, body weight, general health, and diet of the subject, rate of excretion, drug combination, and seventy of the particular condition. The effective amount of a steroid hormone provided herein can be determined by one of ordinary skill in the art, and includes exemplary dosage amounts for a mammal of from about 0,001 to 100 mg/kg of body weight of active compound given orally per day. For example, to achieve the endometrium and antigonadotropic effects (i.e., dose for ovulation inhibition), 0.15 mg/day p.o. for levonorgestrel or desogestrel is preferably desired while the required amount is much higher, 5-10 mg/day for medroxyprogesterone acetate or 200-300 mg/day for progesterone.

[00098] A preferably desired dose of budesonide for the treatment of asthma may be one to four inhalations of 90 pg to 400 pg once or twice daily. Another preferred budesonide dose may be between 0.25 mg to 1 mg total daily dose given once or twice daily in divided doses. A much lower or higher dose of budesonide may be selected when formulated and administered in combination with a progestogen, such as 17-OHPC. The dosing ranges set forth herein are exempiary only and are not intended to Iimit the scope or practice of formulations provided herein.

[00097] A preferably desired dose of fluticasone for the treatment of asthma may^¬ be one to four inhalations of 50 pg to 500 pg, and up to 2000 pg, once or twice daily. Another preferred fluticasone dose may be up to 880 pg given once or twice daily to patients that have previously been treated with corticosteroids. Another preferred fluticasone dose may be between 100 pg to 500 pg given once or twice daily to patients that have previously been treated with bronchiodllators. Another preferred fluticasone dose may be up to 1000 pg given once or twice daily to patients that have previously been treated with oral corticosteroids. Another preferred fluticasone dose may be between 50 pg to 1000 pg given once or twice daily to pediatric patients. Pediatric dosages may vary dependent on a patient's health history and previous treatment with broncbiodilators, inhaled corticosteroids, and/or oral corticosteroids. A much lower or higher dose of fluticasone may be selected when formulated and administered in combination with a progestogen, such as 17-OHPC. The dosing ranges set forth herein are exemplary only and are not intended to limit the scope or practice of formulations provided herein. 098] A person of ordinary skill in the art will also appreciate that appropriate dosing of the steroid hormone depends on gender as progestogen is a sex hormone. Progesterone is primarily secreted by the granulosa ceils and the corpus !uieum in the ovary. During pregnancy, a major source of progesterone also comes from the placenta. Males produce progesterone in the adrenal gland and testes, as this is a precursor of testosterone. In women, progesterone levels are relatively low during the preovulatory phase of the menstrual cycle, rise after ovulation, and are elevated during the luteal phase. Progesterone levels tend to be <2 ng/ml prior to ovulation, and >5 ng/ml after ovulation, if pregnancy occurs, progesterone levels are initially maintained at luteal levels. With the onset of the luteal-placental shift in progesterone support of the pregnancy, levels start to rise further and may reach 100-200 ng/m! at team. The reference range for progesterone levels in adult men is 0.13-0.97 ng/ml. Adult males have ievels similar to those in women during the foiiicuiar phase of the menstrual cycle as well as the ievei in postmenopausal women. Clearly, women regularly experience a 17-fold change in serum progesterone concentration during the menstrual cycle, or more than 100-fold increase in pregnancy. Thus, tolerance or maximum dose or minimal effective dose of progestogen treatment would be higher in women than in males. For example, when the steroid hormone is 17-OHPC and a common dosage used is 150-500 mg weekly injection for its uses in women- health related indications. Given some important effects of progesterone on restoring corticosteroid sensitivity are assumed to be mediated non-genomicaily through different molecular biological modes of action (i.e., functions not related to progestational activity), this may result in some pharmacodynamic variability. A much lower or higher dose of progestogen (e.g. 17-OHPC) may be selected as well as a different dosage level for male subjects. The dosing ranges set forth herein are exemplary only and are not intended to limit the scope or practice of formulations provided herein. 099] Exemplary Dosage Forms and Dosage Administrations. Preferably, the pharmaceutical compositions of the present invention contain: i) a physiologically acceptable carrier, diluent, or excipient, or a combination thereof; and ii) one or more steroid hormone(s) as described herein. The compositions can be formulated for single dosage administration or for multiple dosages. Dosage forms or compositions containing steroid hormone(s), for instance, in the range of about 0,005% to about 100%, with the balance of the dosage form or

composition made up of one or more non-toxic carriers and/or pharmaceuticaily acceptable excipients, can be prepared.

[000100] For example, an exemplary pharmaceutical composition in accordance with the present invention may contain one or more diluents, one or more carriers, one or more binders, one or more coatings, one or more lubricants, one or more solvents, one or more buffers, one or more preservatives, one or more flavoring agents, one or more dyes, and/or one or more absorption enhancers, and/or one or more biodegradable polymers.

[000101] The particular excipient(s) included in the pharmaceutical composition will depend on the particular steroid hormone(s) and dosage form selected, and the skilled artisan will be able to readily select appropriate excipients once the steroid hormone(s) and the dosage form therefore have been chosen.

[000102] For example, for oral administration, a pharmaceutically acceptable nontoxic composition in accordance with the present invention can preferably be formed by the incorporation of any of one or more normally employed excipients, such as, for example, pharmaceutical grades of mannitol, lactose, Respitose ML001 , Lactohale LH300, starch, magnesium stearate, talcum, cellulose derivatives, sodium crosscarmeilose, glucose, sucrose, magnesium carbonate or sodium saccharin. Such compositions preferably include, for instance, solutions, suspensions, tablets, capsules, powders and sustained release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, po!yanhydrides, poiyglyco!ic acid, polyorthoesters, polylactic acid and others.

[000103] Another example of a pharmaceutically acceptable non-toxic composition in accordance with the present invention, includes an injectable formulation. An injectable formulation can be prepared in conventional forms, for instance, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as an emulsion. Suitable excipSents inciude, for example, water, saline, dextrose, glycerol, mannitoi, 1 ,3~butanediol, Ringer's solution, an isotonic sodium chloride solution or ethanol. According to another example, an injectable suspension can be prepared using one or more appropriate iiquid carriers, suspending agents and the like. Certain

pharmaceutical compositions for injection can be presented in unit dosage form, e.g., in ampules or in muiti dose containers. Certain pharmaceutical compositions for injection include, for example, suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain one are more pharmaceutically acceptable excipient agents such as, for instance, one or more suspending, stabilizing and/or dispersing agents. Certain solvents suitable for use in pharmaceutical compositions for injection inciude, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes.

[000104] In addition to administration of a progestogen hormone, the formulations (e.g., inhalation formulations) and methods of the present invention may further comprise administration of one or more additional therapeutic agents aimed at the treatment of glucocorticoid insensitivity related diseases or disorders, or conditions, as discussed herein. Examples of additional therapeutic agents include, for example, glucocorticoid (e.g., hydrocortisone, cortisone acetate, dexamethasone, prednisone, prednisolone, methyiprednisoione, betamethasone, triamcinolone, bec!ometasone, Paramethasone, fluticasone, fludrocortisone acetate, deoxycorticosterone acetate, F!upredniso!one, fluticasone propionate, budesonide, beclomethasone dipropionate, flunisoiide and triamcinolone acetonide, an androgen (e.g., dehydroepiandrosterone (DHEA)), an estrogen (e.g., estradiol), immunosuppressive or immunomodulators agents (e.g., cyclosporine, methotrexate, gold, 8-mercaptopurine, biologic products such as infliximab, etanercept, and adaiimumab, intravenous immunoglobulin and Mepolizumab), and caicineurin inhibitors (e.g., cyclosporin, tacrolimus), p38 MAP kinase inhibitors, JNK inhibitors (decrease AP1 ), Vitamin D, SVHF inhibitors, Histone deacetyiate-2 activators, Theophylline, Phosphoinositide-3-kinase-5 inhibitors, ieukotriene modifiers, long-acting beta agonists, antioxidants, iNOS inhibitors, muscarinic receptor antagonist, bronchodilators, anticholinergic agents, narrow spectrum kinase inhibitors, and P-glycoprotein inhibitors, and combinations thereof, 0105j The other therapeutic agents, when employed in combination with the agents described herein, can be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art. The amount of an agent used with non-oral routes is preferably determined based upon corresponding serum concentration level of an oral dosage or containing a quantity of the active compound in an amount sufficient to alleviate the symptoms of the treated subject. In the formulations and methods provided herein, such other pharmaceutical agent(s) can be

administered prior to, simultaneously with, or following the administration of the compounds provided herein.

[000106] Therapeutic effects of the use of a glucocorticoid sensitizer include any, but not limited to, dosing-sparing of concurrent treatment drugs above, better responsive or tolerant to concurrent treatment drugs, achieving efficacy by using lower dose of concurrent treatment drugs, preventing individuals at risk for developing refractory responses or resistance of concurrent treatment drugs, achieving optimal immune-functions, easier responses after tapering or withdrawal of concurrent treatment drugs, or prolonged administration of concurrent treatment drugs, decreased risks for developing drug-related adverse events clue to concurrent treatment drugs, and combinations thereof.

[000107] Increasing HPH cycles reduces 17-OHPC size. In a preferred embodiment of the invention, size reduction on 17-OHPC was performed via HPH. In the preferred embodiment of the invention, the suspension of 17-OHPC using water as an anti-solvent was prepared at approximately 5% w/w and 15% of the total mass of solids of Tween-80 was milled at a pressure of 1400 bar (hydraulic pressure at 90bar). Particle size distributions were measured using a Malvern Mastersizer 2000S. The particle size distribution profile for each HPH cycle is shown in FIG. 1 . Particle sizes are listed in FIG. 2 and are expressed as Dv10, Dv50, Dv90, and span wherein Dv10 refers to the particle size below which 10% of the volume of material exists; Dv50 refers to the particle size below which 50% of the volume of material exists; and Dv90 refers to the particle size below which 90% of the volume of material exists. These exemplary results demonstrate that there is a decrease of particle size with increasing cycle number from the bulk material to cycle five (Dv50 = 3.393 pm), with a first unexpected increase in Dv50 particle size at cycle six (3.834 pm). See FIG. 3. Dv50 particle size appears to reach a first asymptote between cycle eight to ten (with a Dv50 range between 3.021 pm and 2.684 μιη, respectively). After this first intermediate particle size range, there is a second unexpected increase in particle size from cycle 10 to cycle 12 (2.884 prn to 2.781 prn), A second intermediate Dv50 particle size reduction -was then observed -where the Dv50 values asymptote toward another particle size with range from cycle 12 to cycle 20 (2.78 πΊ to 2.3 μηι, respectively). The Dv50 also levels at ~2.3 pm at cycle 18 and cycle 20. Surprisingly, an additional size reduction is further achieved after cycle 25, wherein Dv50 particle size further reduces to 2.255 prn.

[000108] Size reduction and spray-drying. Spray drying is a method of rapidly drying a liquid slurry to a dry powder using gas. A liquid stream such as a solution, suspension, or emulsion of an API is sprayed into a chamber in the presence of hot gas. During the process the drug is dried and atomized, and is then separated from the drying gas by a cyclone or bag-filter. Gil. M. et al. Chem. Today 2010. 28(4)18-22.

[000109] Combination spray drying such as the H42 process combines spray drying with high pressure homogenization. In the H42 process, a drug is spray dried following the synthesis of a drug. The spray dried drug product is then passed through high pressure homogenization for further size reduction. Keck C, et al., Dosis 2008. 24(2)124-128.

[000110] 17-OHPC particle size reduction was achieved by HPH in water (2.5% w/w) without the presence of surfactant Tween-80. After particle size reduction, the particles were recovered from the suspension using a spray-drying process. Spray drying was used to optimize the wet milling process of particle size reduction; i.e., particle size reduction was achieved by HPH followed by spray drying. This approach enabled the crystalline structure of the particles to be maintained without the formation of significant levels of amorphous material.

[000111] API particle size distribution after HPH was compared between 17-OHPC in water before (wet) and after spray drying (powder). Particle size reduction was achieved by HPH in water (2.5% w/w) without surfactant Tween-20. The particle size distribution profile for 17-OHPC after HPH in water is shown in FIG 4. Particle sizes distribution values for wet and powder 17-OHPC are listed in FIG. 5 and expressed as Dv10, Dv50, and Dv90, and span, wherein Dv10 refers to the particle size below which 10% of the volume of material exists; Dv50 refers to the particle size below which 50% of the volume of material exists; and Dv90 refers to the particle size below which 90% of the volume of material exists. The particle size of wet 17-OHPC after 55 HPH cycles was higher than after 40 HPH cycles due to agglomeration. After particle size reduction, the particles were recovered from the suspension using a spray-drying process. Spray drying was used to optimize the wet milling process of particle size reduction; i.e., particle size reduction was achieved by HPH followed by spray drying. The spray drying process following HPH further reduced the size of 17-OHPC, in particular, 17- OHPC after 55 cycles. FIG 6 compares the wet and powder 17-OHPC Dv50 size distribution and shows that there was a further size reduction of particle size after spray drying.

[000112] The powder obtained after spray drying 17-OHPC processed through 25 HPH cycles was analyzed by XRPD. The obtained spray dried powder and the pre-spray dried 17-OHPC had similar XRPD profiles, signifying that the spray drying process did not change the crystalline structure of 17-OHPC. See FIG 7. Thus, this approach provides suitable control over the particle size distribution and enables maintenance of crystalline structure, without the formation of significant levels of amorphous material.

[000113] Referring to FIG 8, another exemplary powder blend formulation of 17- OHPC demonstrates that the obtained powders after spray drying have similar impurity profiles when compared to the formulated material prior to spray drying as analyzed by High Pressure Liquid Chromatography (HPLC). Impurities of 17- OHPC after 10, 25, 40, and 55 HPH cycles and after spray drying were similar to those of the bulk material, FIG 9. The resultant powders and the bulk material have similar area percentage of impurities, meaning that the HPH and spray drying process does not generate any extra impurities.

[000114] While the specification describes particular embodiments of the present invention, those of ordinary skill in the art can devise variations of the present invention without departing from the inventive concept.

Claims

CLAIMS We claim,

1 . A method of preparing a pharmaceutical formulation powder comprising 17alpha- hydroxyprogesterone caproate, said method comprising:

(a) preparing a bulk material of the pharmaceutical formulation powder comprising 17-alphahydroxyprogesterone caproate, wherein the bulk material is prepared for the milling using a number of cycles of high pressure homogenization; and

(b) milling the bulk material using a number of cycles of high pressure homogenization wherein the number of cycles is sufficient to reduce the bulk material to a fine particulate, wherein the fine particulate has a particle size that is lower than a first intermediate particle size and a second intermediate particle size, and wherein the fine particulate has a Dv50 of at least less than 57 pm and a span distribution value of less than 6.

2. The method of claim 1 wherein said high pressure homogenization is water jet milling.

3. The method of claim 1 wherein said fine particulate has a Dv50 particle size range between approximately 9 pm to 2 pm and a span distribution value between approximately 1 to 4.

4. The method of claim 1 wherein said bulk material further comprising an excipient suitable for inhalation.

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5. The method of claiml wherein said pharmaceutical formulation powder comprises a glucocorticoid.

6. The method of claim 1 wherein said number of cycles is at least 25.

7. The method of claim 6 wherein said number of cycles does not exceed 55 cycles.

8. A method of preparing a pharmaceutical formulation powder comprising 17alpha- hydroxyprogesterone caproate, said method comprising the following steps:

(a) preparing a bulk material of the pharmaceutical formulation powder comprising 17-alphahydroxyprogesterone caproate, wherein the bulk material is to be milled using a number of cycles of high pressure homogenization; and

(b) milling the bulk material using a range of cycles that is in the range of 25 to 55 cycles of high pressure homogenization wherein the range of cycles is sufficient to reduce the bulk material to a fine particulate suitable for inhalation wherein the fine particulate has Dv50 particle size less that 57 pm and a span distribution value of 6.

9. The method of claim 8, wherein said high pressure homogenization milling is water jet milling.

10. The method of claim 8 wherein said milling reduces said 17alpha- hydroxyprogesterone caproate to a Dv50 particle size between approximately 2 pm and 9 pm and a span distribution value between approximately 1 and 4.

1 1. The method of claim 8 wherein said bulk material further comprising an excipient suitable for inhalation.

2

12. The method of claim 8 wherein said pharmaceutical formulation powder comprises a glucocorticoid.

13. The method of claim 12 wherein said glucocorticoid is budesonide or fluticasone.

14. The method of claim 8 wherein the method includes a spray drying step.

15. The method of claim 14 wherein the spray drying step is after the milling step.

16. The method of claim 15 where said milling step comprises milling with a

surfactant.

17. A method of preparing a pharmaceutical formulation powder comprising 17alpha- hydroxyprogesterone caproate, said method comprising the following steps: a) preparing a bulk material of the pharmaceutical formulation powder

comprising 17-alphahydroxyprogesterone caproate, wherein the bulk material is to be milled using a number of cycles of high pressure homogenization water jet milling;

b) milling the bulk material using a number cycles of high pressure

homogenization water jet milling wherein the number of cycles is sufficient to reduce the bulk material to a fine particulate, wherein the fine particulate has a particle size that is lower than a first intermediate particle size and a second intermediate particle size, and wherein the fine particulate has a Dv50 of at least less than 57 pm and a span distribution value of less than 6, and the number of cycles is not excessive wherein the excessive number of cycles results in substantial agglomeration of the fine particulates; and

c) spray drying the fine particulate.

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18. The method of claim 17 wherein said bulk material further comprising an excipient suitable for inhalation.

19. The method of claim 17 wherein said pharmaceutical formulation powder further comprises a glucocorticoid.

20. The method of claim 19 wherein said glucocorticoid is budesonide or fluticasone.

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