Long-acting intra-articular dosage forms containing fluticasone propionate and their use

Abstract

This specification discloses a dosage form of fluticasone propionate for intra-articular administration to patients with osteoarthritis of the joints.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 510,309, filed on 26 June 2023, which is incorporated herein by reference in its entirety. [Background technology]

[0002] This disclosure relates to a long-acting intra-articular injection of a sustained-release form of fluticasone propionate, and its therapeutic uses, including for managing the symptoms of osteoarthritis. Description of related technologies

[0003] Osteoarthritis of the knee (OA) is the leading cause of lower limb disability worldwide. Treatment guidelines aim at symptom management. Intra-articular (IA) corticosteroid injections, such as triamcinolone acetonide (TCA), are conditionally recommended for symptom management (Non-Patent Literature 1). However, currently available corticosteroids are not optimal due to their limited duration of effectiveness and the risk of systemic side effects (Non-Patent Literature 2). It is expected that longer IA dwell times would extend the duration of effectiveness and reduce the frequency of injections, thereby increasing clinical benefit. However, to date, only one sustained-release corticosteroid (Zilretta®) is approved.

[0004] The local safety of IA corticosteroids remains a subject of debate. Data published in 2017 suggested that chronic exposure to TCA administered every 12 weeks for two years was associated with increased cartilage loss (Non-Patent Literature 3). A more recent study evaluating the safety of IA cortisone or hyaluronic acid (HA) over seven years concluded that IA corticosteroids were not associated with an increased risk of knee osteoarthritis progression compared to HA (Non-Patent Literature 4). [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Kolasinski et al., Arthritis & Rheumatology, pp. 220-223, 72(2), 2019 [Non-Patent Document 2] Juni et al., Cochrane Database Syst. Rev., 10, 2015 [Non-Patent Document 3] McAlindon et al, J.Am.Med.Asoc., pp. 1967-1975, 317(19), 2017 [Non-Patent Document 4] Buchi et al., Arthritis Rheum., 72(Suppl 10), 2020 [Summary of the Invention] [Problems to be Solved by the Invention]

[0006] There is a need for corticosteroid therapy with fewer systemic side effects such as changes in glucose and suppression of cortisol, and a longer duration of local efficacy. [Means for Solving the Problems]

[0007] The fluticasone propionate microparticles of the present disclosure enable local controlled release that optimizes the pharmacokinetics (PK) of FP. The controlled release is achieved by coating FP crystals with a defined shape and dimensions with a thin film of hardened polyvinyl alcohol (PVA). The combination of FP crystals and the thin PVA film allows for fine-tuning of the release rate of FP via diffusion. The structure and release mechanism of the PVA-coated FP crystals are described in more detail in U.S. Patent No. 9,987,233.

[0008] Non-clinical studies evaluating the pharmacokinetic (PK) and local safety of IA injections of long-acting coated fluticasone propionate microparticles (also known herein as "EP-104IAR"), including cartilage health, have been previously disclosed (Malone et al. Osteoarthritis and Cartilageopen, 3(4), 2021). These data showed that the long local residence time of EP-104IAR did not affect cartilage health. Safety and PK data obtained in a Phase I trial involving 32 patients with knee OA (24 of whom received the drug) were consistent with the non-clinical findings and supported the continued development of EP-104IAR.

[0009] This specification discloses the top-line results of a Phase II trial evaluating the efficacy of EP-104IAR in 318 patients with knee osteoarthritis (OA). Primary and secondary endpoints were met, as described in more detail herein. These results support the objectives of EP-104IAR: to maximize IA residence time while limiting systemic exposure, and to extend the duration of efficacy with reduced systemic side effects such as glucose changes and cortisol suppression.

[0010] Therefore, one embodiment provides a dosage form comprising fluticasone propionate, which, after a single intra-articular injection into a subject, delivers a maximum plasma concentration of fluticasone propionate in the subject of approximately 5-600 pg / g / mL, or in the range of 30-200 pg / mL (C max ) and within a range of approximately 2 hours to 2 days max The fluticasone propionate is provided in the form of multiple microparticles, each microparticle containing a crystalline core of fluticasone propionate coated with a polyvinyl alcohol film.

[0011] Unless otherwise specified, "C max The term "t" refers to the maximum plasma concentration of a drug achieved after administration to a subject. max The term "Cmax" refers to the time at which Cmax was observed.

[0012] References to the value “approximately” as used herein include (and are described) embodiments that focus on the value itself. In certain embodiments, the term “approximately” includes the indicated amount ± 20%. In other embodiments, the term “approximately” includes the indicated amount ± 10%. In certain other embodiments, the term “approximately” includes the indicated amount and a range of -20% to +25% of the indicated amount.

[0013] As used herein, “patient” or “subject” being treated by means of various embodiments may mean either a human or a non-human animal such as a primate, mammal, or vertebrate.

[0014] In a more specific embodiment, the dosage form contains approximately 11 mg to 30 mg of fluticasone propionate. In an even more specific embodiment, the dosage form contains approximately 25 mg of fluticasone propionate.

[0015] In other, more specific embodiments, the dosage form provides plasma concentrations of fluticasone propionate ranging from about 1 to 150 pg / mL, or from about 30 to 120 pg / mL, over a period of at least 24 weeks.

[0016] In other, more specific embodiments, the dosage form provides a half-life of fluticasone propionate of at least 12, 16, 18, 20, 22, 24, 28, 32, 36, or 40 weeks.

[0017] In other, more specific embodiments, the dosage form provides a half-life of fluticasone propionate of at least 26 weeks.

[0018] In still other more specific embodiments, the dosage form provides an average serum concentration of cortisol of about 250 nmol / L or more in a subject over a period of at least 24 weeks. In other more specific embodiments, the dosage form provides an average serum concentration of cortisol of about 250 nmol / L or more in a subject over a period of at least 12 weeks, or at least 16 weeks, or at least 18 weeks, or at least 20 weeks, or at least 22 weeks, or at least 24 weeks, or at least 28 weeks, or at least 32 weeks, or at least 36 weeks, or at least 40 weeks.

[0019] In various embodiments, the subject has moderate OA pain with a WOMAC pain score in the range of 3.5 to 6.5, and the dosage form reduces the subject's WOMAC pain score. In other embodiments, the subject has OA with a WOMAC pain score in the range of 3.5 to 9.5, and the dosage form reduces the subject's WOMAC pain score.

[0020] In various embodiments, the size distribution of the plurality of microparticles in the dosage form is such that (i) 90% (D 90 ) of the total mass is 250 microns or less, (ii) 50% (D 50 ) has an average size in the range of 120 to 160 microns, and (iii) 10% (D 10 ) of the total mass is less than 65 microns.

[0021] In various embodiments, the plurality of microparticles in the dosage form have the following size distribution: (i) D 10 of the microparticles in the dosage form is at least 65 microns, (ii) D 50 of the microparticles in the dosage form is in the range of 120 microns to 160 microns, and (iii) D 90 of the microparticles in the dosage form is 250 microns or less, provided that D 10 is less than D 50 , and D 90 is greater than D 50 . BRIEF DESCRIPTION OF THE DRAWINGS

[0022] [Figure 1] This graph compares the change from baseline in WOMAC pain in EP-104IAR and vehicle over a 24-week period. [Figure 2] The graph shows the change from baseline in WOMAC functionality of the EP-104IAR and the vehicle over a 24-week period. [Figure 3] The graph shows a comparison of the AUC of EP-104IAR and vehicle-based WOMAC pain over a 24-week period. [Figure 4] The graph shows a comparison of the percentage of strict OMERACT-OARSI responders for EP-104IAR and vehicles over a 24-week period. [Figure 5] This graph compares the change from baseline in WOMAC pain for EP-104IAR and vehicle-based moderate WOMAC pain over a 24-week period. [Figure 6] The graph shows a comparison of the proportion of severe responders with WOMAC moderate pain (OMERACT-OARSI) in EP-104IAR and vehicles over a 24-week period. [Figure 7a] The graph shows a comparison of the proportion of patients with moderate WOMAC pain (WOMAC pain ≤ 1) at baseline in the EP-104IAR and vehicle groups over a 24-week period. [Figure 7b] The graph shows a comparison of the proportion of patients with moderate WOMAC pain (WOMAC pain ≤ 2) at baseline in the EP-104IAR and vehicle groups over a 24-week period. [Figure 8] The geometric mean plasma concentration curve of FP over a 24-week period is shown. [Figure 9] This graph shows the mean serum cortisol concentration over a 24-week period. [Figure 10a] This graph shows serum glucose levels in a diabetic population over a 24-week period. [Figure 10b] This graph shows serum glucose levels for the entire patient population over a 24-week period. [Figure 11]This graph compares the plasma FP concentrations of Phase I and Phase II products over 24 weeks following intra-articular injection in OA subjects. [Modes for carrying out the invention]

[0023] As described in further detail herein, this disclosure provides a long-acting dosage form of fluticasone propionate (FP) for IA injection. Based on clinical trial results, the dosage form provides a long-lasting and stable release of FP, as evidenced by plasma FP levels being below levels that could result in clinically significant cortisol suppression. Patients with moderate OA pain experienced sustained pain relief.

[0024] Clinical trial protocol In this Phase II randomized, double-blind, vehicle-controlled, parallel-group trial (NCT04120402), eligible subjects with eligible knee OA pain were randomized in approximately a 1:1 ratio to receive either a single IA dose of EP-104IAR 25 mg or a vehicle, and followed for 24 weeks. The study enrolled men and women aged 40 years or older diagnosed with primary knee OA (according to the ACR clinical and radiological criteria), with Kellgren-Lawrence grade 2-3 and OA symptoms lasting for at least 6 months.

[0025] Potential participants completed a two-week washout / baseline period from which baseline and eligible pain were determined. Eligible knee pain was defined as a weekly pain subscale score of 4.0 to 9.0 (out of 10) on the Western Ontario and McMaster University Osteoarthritis Index (WOMAC®), with no change exceeding 3 points. Subjects with bilateral knee OA needed a WOMAC pain score of 6.0 or less (out of 10) on the non-index knee.

[0026] Subjects received a single dose of either EP-104IAR or the vehicle, and weekly WOMAC pain and monthly WOMAC total index measurements were recorded using the provided ePRO device. Safety was assessed by adverse events, vital signs, laboratory evaluations (including serum cortisol and ACTH stimulation tests), and physical examination / knee examination. Blood samples for FP measurement were collected at each visit.

[0027] Relief medication (up to 3g of acetaminophen per day) was approved. Participants were instructed to record their usage on a device and refrain from using it for 12 hours prior to completing the WOMAC questionnaire.

[0028] The primary efficacy endpoint was the difference in the change from baseline between EP-104IAR and vehicle-based WOMAC pain at week 12. The analysis was performed using a repeated-measures mixed-effects model (MMRM) in the intention-to-treat (ITT) population.

[0029] The primary secondary endpoints were analyzed using a similar method employing a step-down hierarchical test procedure to avoid the issue of multiplicity. Secondary endpoints included: (1) subscale differences in WOMAC function at week 12, (2) differences in WOMAC area under the pain-time curve up to week 12, (3) WOMAC pain at week 24, and (4) differences between treatment groups in strict OMERACT-OARSI responders (Pham, et al., 2004) at week 12.

[0030] This study consisted of 318 treatment subjects (n=163 EP-104 IAR, n=155 vehicles), with a median age of 64 years, 58% female, and 99% Caucasian. 304 subjects completed the study. 14 subjects withdrew before the 12-week visit (mostly due to "subject withdrawal").

[0031] Clinical trial results In this study, a single dose of EP-104IAR 25 mg resulted in statistically significant pain relief at week 12 compared to the vehicle control, thus achieving the primary endpoint. Furthermore, three key secondary endpoints showed statistically significant differences at week 12 for WOMAC function, WOMAC area under the pain-time curve, and composite pain and functional OMERACT-OARSI response. In addition, the persistence of the response was statistically significant, with statistically significant differences in WOMAC pain subscale scores observed between EP-104IAR and the vehicle up to week 14.

[0032] EP-104IAR 25 mg was safe, generally well-tolerated, and resulted in low but sustained plasma levels throughout the entire 24-week study period. The safety and efficacy of EP-104IAR will be further evaluated in a Phase III trial.

[0033] As shown in Figure 1, the primary endpoint was achieved. In particular, EP-104IAR showed a statistically significant difference compared to vehicle in WOMAC pain at week 12 (least squares mean change from baseline: -2.89 vs. -2.23, p=0.004). Figure 1 further shows significant, sustained, and meaningful pain relief up to 14 weeks.

[0034] Three secondary endpoints were also met. Firstly, the EP-104IAR demonstrated a statistically significant improvement in WOMAC function at week 12, with a difference in the change from baseline between the EP-104IAR and the vehicle (least squares mean change from baseline: -2.59 vs. -2.04, p=0.014). See Figure 2.

[0035] Furthermore, as shown in Figure 3, EP-104IAR showed a statistically significant reduction in the area under the WOMAC pain-time curve up to week 12 (EP-104IAR at week 12: -239 vs. -167, p<0.001). Figure 3 further shows that EP-104IAR provided better mean pain relief than placebo up to week 24. Thus, EP-104IAR resulted in a statistically significant improvement in the difference in change from baseline between EP-104IAR and the vehicle in WOMAC function at week 24 (least squares mean change from baseline: -462 vs. -352, p=0.012).

[0036] In contrast to 87 subjects (56%) in the EP-104IAR group who met the strict OMERACT-OARSI responder definition (assessed by either pain or function) after 12 weeks of medication, only 61 subjects (43%) in the vehicle group met this definition (p=0.028).

[0037] The OMERACT-OARSI strict responder alternative depends solely on pain. Under this definition, a strict responder is a patient who has experienced a clinically significant impact on their pain response. Equally important as pain treatment is achieving the level of pain relief that is most comfortable for the patient. A strict pain responder is defined as having a 50% or greater improvement in the WOMAC pain score from baseline and an absolute change of at least 2 points on the WOMAC scale. Patients must achieve both of these to be considered a strict responder. As shown in Figure 4, strict responders experienced a significant improvement in pain.

[0038] The majority of patients (68% of the study population, n=214) had moderate OA pain, defined as patients with a WOMAC pain score of 3.5–6.5. Therefore, in these patients with moderate OA pain, the EP-104IAR demonstrated a statistically significant improvement in the difference in change from baseline between the EP-104IAR and the vehicle for WOMAC pain at all weeks up to week 17 (least squares mean change from baseline: -2.34 vs. -1.77, p=0.026). See Figure 5.

[0039] Figure 6 shows that strict responders (pain alone) of the OMERACT-OARSI in patients with moderate OA pain (approximately two-thirds of all patients) experienced clinically meaningful pain improvement over 22 weeks.

[0040] Figures 7a and 7b show that a significant proportion (approximately 40%) of patients with moderate OA pain maintained a WOMAC pain score of less than 1 or less than 2, respectively, for 22–24 weeks. This indicates that nearly complete pain relief can be achieved over a sustained period.

[0041] As summarized in Table 1, the majority of adverse events (AEs) that occurred as a result of treatment were mild to moderate in severity. The most common AEs (occurring in more than 5% of subjects in either treatment group) were arthralgia, COVID-19, nasopharyngitis, influenza, and influenza-like illness. In the safety analysis population, two AEs in two subjects led to discontinuation of treatment: spinal injury and arthralgia (worsening of left (non-indexed) knee pain). [Table 1]

[0042] Pharmacokinetic results Plasma concentrations of fluticasone propionate were measured at various intervals for 24 weeks, and the measured plasma concentrations (pg / mL) are summarized in Table 2 below. [Table 2]

[0043] Delivery dose: average 26.3 mg, SD 2.9 mg, median 27.2 mg, IQR 25.2–28.2 mg, range 11.5–30.0 mg.

[0044] C max Geometric mean of 90.1 pg / mL, CV of 126.1%, IQR of 38-189 pg / mL, maximum of 602 pg / mL.

[0045] t max : Median over 22.25 hours, IQR for 2 hours to 2 days

[0046] Half-life is estimated to be 36.78 weeks.

[0047] Therefore, the EP-104IAR dosage form can be released for longer periods of more than 24 weeks with a broad systemic safety margin. Figure 8 shows the geometric mean plasma concentration curve over 24 weeks, which is far below the mean plasma concentration of Flovent, a daily inhaled aerosol of fluticasone propionate. In particular, the mean peak plasma concentration (C) of FP is significantly lower. max ) is administered on day 2 (t max The concentration was 89.3 pg / mL. Following this initial peak, plasma concentrations decreased slowly and steadily over time, remaining at low but detectable levels until the end of the study. Safety Profile

[0048] Serum cortisol was a key safety indicator and was monitored throughout the study. As shown in Figure 9, mean cortisol levels in EP-104 subjects decreased to approximately 250 nmol / L on day 2, but returned to near normal levels (pre-FP administration levels) by two weeks post-administration. It is significant that serum cortisol levels (except on day 2) remained comparable to placebo throughout the monitoring period, despite the fact that fluticasone propionate was present in the plasma for 24 weeks.

[0049] In the ACTH stimulation trials, it was demonstrated that no subjects experienced ACTH trial failure accompanied by signs and / or symptoms of adrenal insufficiency after administration of EP-104IAR. There were no clinically significant differences in any clinical laboratory assessments between the treatment groups.

[0050] Therefore, the dosage forms of the present disclosure can provide mean serum cortisol levels of 250 nmol / L or higher, which is above the lower limit of normal. In some embodiments, this safety profile allows for repeated or bilateral administration, i.e., treatment of both knees at once, for 70% of OA patients with bilateral disease, rather than treating only one knee and leaving the patient with painful discomfort in the untreated knee.

[0051] Serum glucose is also an important marker in the pathogenesis of osteoarthritis (OA). It is understood that steroids not only suppress cortisol levels but can also affect hepatic glycogen levels by increasing glucose release.

[0052] Such glucose abnormalities can make the treatment unsafe for patients with diabetes. Figure 10a shows the mean serum glucose levels of diabetic patients who participated in this study, with 13 in the active treatment group and 13 in the placebo group. Although baseline serum glucose levels were higher in diabetic patients, as expected in the diabetic patient population, the median change from baseline in glucose on day 3 in subjects treated with EP-104IAR was similar to that of subjects without a history of NIDDM (-0.10 mmol / L and 0.00 mmol / L, respectively). This study demonstrates that the dosage form of this disclosure may provide a durable, effective, and systemically safe therapeutic agent compatible with glucose-controlling diabetes treatment for 30% of OA patients who also have diabetes.

[0053] Figure 10b shows the mean serum glucose for the entire study population. As shown, the dosage form did not affect serum glucose levels.

[0054] Preparation of EP-104IAR The Phase II product manufacturing process comprises two main steps: the production of the bulk drug substance and the subsequent production of EP-104IAR powder. A commercially available active pharmaceutical ingredient (API), FP, was recrystallized, wet-milled, and sieved to obtain a uniform and larger crystal size suitable for subsequent application of a polyvinyl alcohol (PVA) polymer coating. The larger crystals, i.e., the bulk drug substance, were then coated, cured, irradiated, and aseptically filled into vials to form EP-104IAR powder ("Phase II product").

[0055] The resulting dosage form contains multiple microparticles containing fluticasone propionate, each microparticle containing a crystalline core of fluticasone propionate coated with a polyvinyl alcohol film. As described below, the particle size distribution of the microparticles affects the release characteristics of the dosage form.

[0056] U.S. Patent Publication 2022 / 0168665 discloses prior iterations that generate the bulk drug substance and coated particles ("Phase I Products") used in Phase I testing. Table 3 compares the particle size distributions of the Phase I Products and Phase II Products, where the Phase II Products represent one embodiment of the present disclosure. [Table 3]

[0057] The difference in size distribution between the Phase I and Phase II products is thought to have caused a significant difference in in vivo release, as is evident in Figure 11. As illustrated, in one embodiment described herein, the Phase II product showed stable (flat) and sustained plasma FP concentrations for at least 24 weeks, which constitutes the majority of the clinical trial. In contrast, the Phase I product showed a decrease in plasma FA concentrations without the stable (flat) period shown by the Phase II product.

[0058] When used in this specification, D 10The term refers to the particle size below which 10% by mass of the particles are sized in the particle size distribution of the particles. In some embodiments, the D of the particles in the dosage form 10 The particle size is at least 65 μm (i.e., 65 μm or larger). In some embodiments, the D of the fine particles in the dosage form 10 This range is 65μm to 90μm, or 65μm to 70μm, or 70μm to 75μm, or 75μm to 80μm, or 80μm to 85μm, or 85μm to 90μm.

[0059] In some embodiments, the particle size distribution of the fine particles in the dosage form is such that 10% by mass of the fine particles is less than about 65 μm (i.e., D 10 The particle size is such that it has a particle size of ~65 microns. In some embodiments, the particle size distribution of the fine particles in the dosage form is such that 10% by mass of the fine particles is less than about 70 μm (i.e., D 10 The particle size is such that it has a particle size of ~70 microns. In some embodiments, the particle size distribution of the fine particles in the dosage form is such that 10% by mass of the fine particles is less than about 75 μm (i.e., D 10 The particle size is such that it has a particle size of ~75 microns. In some embodiments, the particle size distribution of the fine particles in the dosage form is such that 10% by mass of the fine particles is less than about 80 μm (i.e., D 10 The particle size is such that it has a particle size of ~80 microns. In some embodiments, the particle size distribution of the fine particles in the dosage form is such that 10% by mass of the fine particles is less than about 85 μm (i.e., D 10 The particle size is such that it has a particle size of ~85 microns. In some embodiments, the particle size distribution of the fine particles in the dosage form is such that 10% by mass of the fine particles is less than about 90 μm (i.e., D 10 These have a particle size of approximately 90 microns.

[0060] When used in this specification, D 50 The term refers to the median particle size of the microparticles in the dosage form. That is, 50% by mass of the microparticles are sized below that particle size, and 50% by mass of the microparticles are sized above that particle size. In some embodiments, the D of the microparticles in the dosage form 50The diameter is at least 120 μm. In some embodiments, the D of the fine particles in the dosage form 50 The diameter is at least 120 μm. In some embodiments, the D of the fine particles in the dosage form 50 The size is 160 μm or less. In some embodiments, the D of the fine particles in the dosage form 50 The size of the particles is in the range of 120 μm to 160 μm, or 120 μm to 125 μm, or 125 μm to 130 μm, or 135 μm to 140 μm, or 140 μm to 145 μm, or 145 μm to 150 μm, or 150 μm to 155 μm, or 155 μm to 160 μm. In some embodiments, the size of the particles in the dosage form is D 50 It is at least 125 μm to 135 μm.

[0061] In some embodiments, the particle size distribution of the fine particles in the dosage form is such that the median particle size (D 50 The size of the particles in the dosage form is such that the median particle size (D 50 The size of the particles in the dosage form is such that the median particle size (D 50 The size of the particles in the dosage form is such that the median particle size (D 50 The size of the particles in the dosage form is such that the median particle size (D 50 The size of the particles in the dosage form is such that the median particle size (D 50 The size of the particles in the dosage form is such that the median particle size (D 50 The size of the particles is such that the median particle size (D 50 The size of the particles in the dosage form is such that the median particle size (D 50 This is such that the diameter is approximately 160 μm.

[0062] When used in this specification, D 90 The term refers to a particle size in which 90% by mass of the particles are sized below that particle size within the particle size distribution of the particles. In some embodiments, the D of the particles in the dosage form 90 The particle size is at least less than or equivalent to 250 μm (i.e., 250 μm or less). In some embodiments, the D of the fine particles in the dosage form 90 This range is 180μm~250μm, or 180μm~185μm, or 185μm~190μm, or 190μm~195μm, or 195μm~200μm, or 200μm~205μm, or 205μm~210μm, or 210μm~215μm, or 215μm~220μm, or 225μm~230μm, or 230μm~235μm, or 235μm~240μm, or 240μm~245μm, or 245μm~250μm.

[0063] In some embodiments, the particle size distribution of the fine particles in the dosage form is such that 90% by mass of the fine particles are less than approximately 180 μm (i.e., D 10 The particle size is such that it has a particle size of ~180 microns. In some embodiments, the particle size distribution of the fine particles in the dosage form is such that 90% by mass of the fine particles is less than about 185 μm (i.e., D 10 The particle size is such that it has a particle size of ~185 microns. In some embodiments, the particle size distribution of the fine particles in the dosage form is such that 10% by mass of the fine particles is less than about 190 μm (i.e., D 10 The particle size is such that it has a particle size of ~190 microns. In some embodiments, the particle size distribution of the fine particles in the dosage form is such that 10% by mass of the fine particles is less than about 195 μm (i.e., D 10 The particle size is such that it has a particle size of ~195 microns. In some embodiments, the particle size distribution of the fine particles in the dosage form is such that 90% by mass of the fine particles is less than about 200 μm (i.e., D 10 The particle size is such that it has a particle size of ~200 microns. In some embodiments, the particle size distribution of the fine particles in the dosage form is such that 90% by mass of the fine particles is less than about 205 μm (i.e., D 90The particle size is such that it has a particle size of ~205 microns. In some embodiments, the particle size distribution of the fine particles in the dosage form is such that 90% by mass of the fine particles is less than about 210 μm (i.e., D 90 The particle size is such that it has a particle size of ~210 microns. In some embodiments, the particle size distribution of the fine particles in the dosage form is such that 90% by mass of the fine particles is less than about 220 μm (i.e., D 90 The particle size is such that it has a particle size of ~220 microns. In some embodiments, the particle size distribution of the fine particles in the dosage form is such that 90% by mass of the fine particles is less than about 225 μm (i.e., D 90 The particle size is such that it has a particle size of ~225 microns. In some embodiments, the particle size distribution of the fine particles in the dosage form is such that 90% by mass of the fine particles is less than about 230 μm (i.e., D 90 The particle size is such that it has a particle size of ~230 microns. In some embodiments, the particle size distribution of the fine particles in the dosage form is such that 90% by mass of the fine particles is less than about 235 μm (i.e., D 90 The particle size is such that it has a particle size of ~235 microns. In some embodiments, the particle size distribution of the fine particles in the dosage form is such that 90% by mass of the fine particles is less than about 240 μm (i.e., D 90 The particle size is such that it has a particle size of ~240 microns. In some embodiments, the particle size distribution of the fine particles in the dosage form is such that 90% by mass of the fine particles is less than about 245 μm (i.e., D 90 The particle size is such that it has a particle size of ~245 microns. In some embodiments, the particle size distribution of the fine particles in the dosage form is such that 90% by mass of the fine particles is less than about 250 μm (i.e., D 90 These have a particle size of approximately 250 microns.

[0064] Table 4 summarizes vehicle compositions suitable for the embodiments of this disclosure, including the EP-104IAR drug used in clinical trials. [Table 4]

[0065] Further embodiments can be provided by combining the various embodiments described above. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned herein and / or enumerated in the application datasheet are incorporated herein by reference in their entirety. The aspects of the embodiments may be modified as necessary to adopt the concepts of various patents, applications, and publications in order to provide further embodiments.

[0066] In light of the detailed description above, these and other modifications may be made to the embodiments. In general, the terms used in the following claims should not be construed as limiting the claims to any particular embodiment disclosed herein and in the claims, but rather as encompassing all possible embodiments along with the full scope of the equivalent claims to which rights are granted. Accordingly, the claims are not limited by this disclosure.

Claims

1. A dosage form comprising fluticasone propionate, wherein the dosage form delivers a maximum plasma concentration of fluticasone propionate in the subject in the range of approximately 5 to 600 pg / g / mL after a single intra-articular injection (C) ｍａｘ ) and within a range of approximately 2 hours to 2 days ｍａｘ The dosage form provides the fluticasone propionate ester in the form of a plurality of microparticles, each of which microparticles comprises a crystalline core of fluticasone propionate ester coated with a polyvinyl alcohol film.

2. The dosage form according to claim 1, comprising approximately 11 mg to 30 mg of fluticasone propionate.

3. The dosage form according to claim 1, comprising approximately 25 mg of fluticasone propionate.

4. The dosage form according to any one of claims 1 to 3, wherein the dosage form provides a plasma concentration of fluticasone propionate in the range of about 1 to 150 pg / mL for at least 24 weeks.

5. The dosage form according to any one of claims 1 to 3, wherein the dosage form provides a half-life of fluticasone propionate ester of at least 12 weeks.

6. The dosage form according to any one of claims 1 to 3, wherein the dosage form provides the subject with an average serum concentration of about 250 nmol / L or more of cortisol over a period of at least 24 weeks.

7. The size distribution of the plurality of fine particles in the dosage form is (i) 90% of the total mass (D ９０ ) is 250 microns or less, (ii) 50% of the total mass (D ５０ ) having an average size in the range of 120 to 160 microns, (iii) 10% of the total mass (D １０ The dosage form according to any one of claims 1 to 7, wherein the diameter is less than 65 microns.

8. The plurality of the microparticles in the dosage form have the following size distribution: (i) D of the microparticles in the dosage form １０ is at least 65 microns, (ii) D of the microparticles in the dosage form ５０ is in the range of 120 microns to 160 microns, (iii) D of the microparticles in the dosage form ９０ is 250 microns or less, provided that D １０ is less than D ５０ , and D ９０ is greater than D ５０ The dosage form according to any one of claims 1 to 7.

9. The dosage form according to any one of claims 1 to 8, wherein the subject has moderate OA pain with a WOMAC pain score in the range of 3.5 to 6.5, and the dosage form reduces the subject's WOMAC pain score.

10. The dosage form according to any one of claims 1 to 8, wherein the subject has an OA with a WOMAC pain score in the range of 3.5 to 9.5, and the dosage form reduces the subject's WOMAC pain score.

11. A dosage form according to any one of claims 1 to 8, for use in reducing or alleviating pain in the joints of the subject.

12. A dosage form according to any one of claims 1 to 8, for use in the treatment of osteoarthritis in the aforementioned subject.

13. The dosage form according to claim 11 or claim 12, wherein the subject has the WOMAC pain score in the range of 3.5 to 9.5 before the injection.

14. The dosage form according to claim 13, wherein the subject has a WOMAC pain score in the range of 3.5 to 6.5 before the injection.

Images