WO2018112408A1 - Formulations de fluticasone et leurs procédés d'utilisation - Google Patents

Formulations de fluticasone et leurs procédés d'utilisation Download PDF

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Publication number
WO2018112408A1
WO2018112408A1 PCT/US2017/066816 US2017066816W WO2018112408A1 WO 2018112408 A1 WO2018112408 A1 WO 2018112408A1 US 2017066816 W US2017066816 W US 2017066816W WO 2018112408 A1 WO2018112408 A1 WO 2018112408A1
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formulation
days
plga
release
formulations
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PCT/US2017/066816
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English (en)
Inventor
Neil Bodick
Ujjwal Joshi
J. Derek JACKSON
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Flexion Therapeutics, Inc.
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Publication of WO2018112408A1 publication Critical patent/WO2018112408A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • This disclosure relates to extended-release fluticasone propionate (FP) microparticle compositions and methods of using these extended-release FP microparticle for treating pain and/or inflammation in a subject, including pain and/or inflammation caused by inflammatory diseases such as osteoarthritis or rheumatoid arthritis.
  • FP fluticasone propionate
  • Corticosteroids influence all tissues of the body and produce various cellular effects. These steroids regulate carbohydrate, lipid, protein biosynthesis and metabolism, and water and electrolyte balance. Corticosteroids influencing cellular biosynthesis or metabolism are referred to as glucocorticoids while those affecting water and electrolyte balance are mineralocorticoids. Both glucocorticoids and mineralocorticoids are released from the cortex of the adrenal gland.
  • Corticosteroids are used in the treatment of a variety of indications, including immediate release formulations for use in treating osteoarthritis (OA) and other disorders and diseases associated with joint pain and/or inflammation.
  • OA osteoarthritis
  • OA is a growing worldwide epidemic. In the United States alone, OA is the most common joint disease, affecting approximately 27 million Americans, with numbers expected to grow as a result of aging, obesity and sports injuries.
  • IA intra-articular
  • formulations comprising extended-release microparticles comprising fluticasone propionate (FP) or a commercially available chemical analogue or a pharmaceutically-acceptable salt thereof and a poly(lactic-co-gly colic) acid (PLGA) copolymer matrix.
  • FP fluticasone propionate
  • PLGA poly(lactic-co-gly colic) acid
  • the formulations comprise extended-release microparticles comprising fluticasone propionate (FP) or a commercially available chemical analogue or a pharmaceutically-acceptable salt thereof and a poly(lactic-co-gly colic) acid (PLGA) copolymer matrix, wherein, FP comprises between 20% to 40% of the microparticles and wherein the PLGA has one or more of the following characteristics: (i) a molecular weight range of about 40 to 75 kDa; (ii) an inherent viscosity in the range of 0.4 to 0.8 dL/g; and/or (iii) a lactide:glycolide molar ratio of 65:35 to 85: 15.
  • FP fluticasone propionate
  • PLGA poly(lactic-co-gly colic) acid
  • the formulations comprise extended-release microparticles comprising fluticasone propionate (FP) or a pharmaceutically-acceptable salt thereof and a poly(lactic-co-gly colic) acid (PLGA) copolymer matrix, wherein, FP comprises between 20% to 40% of the microparticles and wherein the PLGA has one or more of the following characteristics: (i) a molecular weight range of about 40 to 75 kDa; (ii) an inherent viscosity in the range of 0.4 to 0.8 dL/g; and/or (iii) a lactide:glycolide molar ratio of 65:35 to 85: 15.
  • FP fluticasone propionate
  • PLGA poly(lactic-co-gly colic) acid
  • the copolymer matrix can be biodegradable.
  • the compositions are extended release formulations in which the fluticasone propionate is released over a prolonged period of time.
  • the compositions are extended release formulations in which the FP is released for at least four weeks or more, at least five weeks or more, at least six weeks or more, at least seven weeks or more, at least eight weeks or more, at least nine weeks or more, at least 10 weeks or more, at least 11 weeks or more, at least 12 weeks or more, at least 13 weeks or more, at least 14 weeks or more, at least 15 weeks or more, at least 16 weeks or more, at least 17 weeks or more, at least 18 weeks or more, at least 19 weeks or more, at least 20 weeks or more, at least 21 weeks or more, at least 22 weeks or more, at least 23 weeks or more, and/or at least 24 weeks or more.
  • FP is released for at least greater than 14 days; for between at least 14 days and 90 days; or for between at least 14 days and 180 days.
  • the extended release formulation may be a controlled- or sustained-release formulation.
  • the extended release formulations are sustained- or controlled-release formulations in which the fluticasone propionate is released at a uniform or substantially uniform rate over a prolonged period of time. In some embodiments, the extended release formulations are sustained- or controlled-release formulations in which the
  • FP is released at a uniform or substantially uniform rate for at least four weeks or more, at least five weeks or more, at least six weeks or more, at least seven weeks or more, at least eight weeks or more, at least nine weeks or more, at least 10 weeks or more, at least 11 weeks or more, at least 12 weeks or more, at least 13 weeks or more, at least 14 weeks or more, at least 15 weeks or more, at least 16 weeks or more, at least 17 weeks or more, at least 18 weeks or more, at least 19 weeks or more, at least 20 weeks or more, at least 21 weeks or more, at least 22 weeks or more, at least 23 weeks or more, and/or at least 24 weeks or more.
  • the microparticles have a mean diameter of between 20 ⁇ to 100 ⁇ (i.e. , 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,
  • the microparticles have a mean diameter in the range of 20-100 ⁇ , 20-90 ⁇ , 30-100 ⁇ , or 30-90 ⁇ . In some embodiments, the microparticles have a mean diameter of between 30 ⁇ to 60 ⁇ . In other embodiments, the median diameter or medium value of the particle size distribution (e.g. ,
  • D50 is between approximately 40 and 50 ⁇ . In some embodiments, D10 is between approximately 20 and 30 ⁇ and D90 is between approximately 80 and 90 ⁇ . It is understood that these ranges refer to the mean diameter of all microparticles in a given population. The diameter of any given individual microparticle could be within a standard deviation above or below the mean diameter.
  • the microparticles further comprise a polyethylene glycol (PEG) moiety, wherein the PEG moiety comprises between 25% to 0% weight percent of the microparticle (i.e. , 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, etc.%).
  • the PEG moiety is present as a PEG/PLGA block co-polymer.
  • the PEG moiety is included in the microsphere formulation as a separate excipient.
  • the populations, preparations and/or formulations of the invention do not require the presence of PEG to exhibit the desired FP extended and/or sustained release kinetics and bioavailability profile.
  • FP may comprise between 20% to 40% (i.e. , 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40%) of the microparticles, for example between 30% to 38% (i.e. , 30, 31, 32, 33, 34, 35, 36, 37, or 38%) of the microparticles, between 32% to 37% (i.e. , 32, 33, 34, 35, 36, or 37%) of the microparticles, or about 35% of the microparticles.
  • the molecular weight range of the PLGA may be about 40 to 75 kDa (i.e., 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or 75 kDa), for example, about 40 to 65 kDa (i.e., 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65) or about 40 to 60 kDa (i.e. , 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60,
  • the inherent viscosity is between 0.4 to 0.8 dL/g (i.e. , 0.4, 0.5, 0.6, 0.7, or 0.8 dL/g), for example, between 0.5 to 0.7 dL/g (i.e. , 0.5, 0.6, or 0.7 dL/g) or about 0.6 dL/g.
  • the lactide:glycolide molar ratio is 65:35 to 85: 15 (e.g. , 65:35, 66:34, 67:33, 68:32, 69:31, 70:30, 71 :29, 72:28, 73:27, 74:26, 75:25, 76:24, 77:23, 78:22, 79:21, 80:20, 81 : 19, 82: 18, 83: 17, 84: 16, or 85: 15), for example, 70:30 to 80:20 or about 75:25.
  • PLGA polymers can be defined by a combination of their average molecular weight range and their inherent viscosity. These characteristics for several exemplary commercially available PLGA polymers are shown in the table below. PLGA Polymer Molecular Weight Range Inherent Viscosity
  • PLGA polymers such as PLGA 3.5, which has a lower inherent viscosity and molecular weight, would not be a suitable choice, as polymer degradation would occur too quickly.
  • use of a 4A PLGA polymer also resulted in the polymer being cleared from the joint too quickly.
  • PLGA 8 which has a higher inherent viscosity and molecular weight, is also not a preferred choice, as the resulting polymer microspheres would persist longer than the FP (e.g., the FP dissolves and releases faster than the polymer degrades). Additionally, for 8E PLGA and 8515 6E PLGA (with a 40% FP load), a high burst release was observed. Thus, the following additional formulations falling between PLGA 4A and PLGA 8E and 8515 6E were examined:
  • DCM was used as the process solvent, and the batch size was 10-20g.
  • the solids were kept at 5%; for 7525 8E, previous batches were made at 3 % solids; for 7525 6A, 4% solids should work.
  • the % solids was increased to 5% in order to make the particles more dense and, thus, reduce burst. Because viscosity can help predict the disk speed needed to manufacture the FP formulations, it may be helpful to measure the viscosity before making the batch.
  • the PLGA polymer chosen would result in the FP and the PLGA polymer remaining in the formulation for approximately the same amount of time and FP release would occur continuously over a period of at least 6 months.
  • the PLGA polymer can comprise an end cap (e.g. , an ester end cap (“E”) and/or an acid end cap ("A”)).
  • an end cap e.g. , an ester end cap (“E") and/or an acid end cap (“A")
  • ester end cap e.g. , ester vs. acid
  • A acid end cap
  • PLGA polymers with an ester end cap persist longer (i.e. , take longer to degrade) than acid end caps.
  • the choice of acid or ester end cap is an important one.
  • the choice of end cap is less important, and does not have as much of an impact on the duration of the formulation.
  • lactide:glycolide molar ratio is also important in order to achieve the desired in vitro release kinetics. Lactic acid tends to be more crystalline, and, as such, when higher ratios of lactic acid are used, less FP is found to be embedded in the resulting PLGA microparticles. Therefore, changing the molar ratio of lactide:glycolide in the PLGA will alter the release rate of FP from the formulations described herein.
  • a molar ratio of 85: 15 showed a faster burst of FP from the microparticles, while a 50:50 molar ratio would result in microparticles that would degrade too quickly, making a 6 month release profile impossible.
  • the FP formulations described herein ideally have a molar ratio between 65:35 to 85: 15, preferably 70:30 to 80:20, more preferably about 75:25.
  • the PLGA polymer and FP will persist in the formulation for approximately the same amount of time. Therefore, the PLGA polymer should be chosen to insure that the polymer does not degrade faster or slower than the FP. Fine tuning of the release kinetics of the FP formulations can be accomplished by altering the nature of the PLGA polymer (i.e., by selecting the appropriate molecular weight, the appropriate inherent viscosity, the appropriate lactide:glycolide molar ratio, and/or the appropriate end cap).
  • FP comprises about 35% of the microparticles and wherein the poly(lactic-co-gly colic) acid copolymer has a molecular weight range of about 40 to 60 kDa, an inherent viscosity of about 0.6 dL/g; and a lactide:glycolide molar ratio of 75:25.
  • a formulation may include 35% FP in a 75:25 PLGA 6A (i.e. , a PLGA polymer with a lactide:glycolide molar ratio of 75:25, a molecular weight range between 40 and 60 kDa, an inherent viscosity of about 0.6 dL/g, and an acid end cap).
  • this FP formulation as one that would have the desired in vitro release kinetics was the result of much experimental testing to optimize each of the variables (i.e. , amount of FP, PLGA molecular weight, PLGA inherent viscosity, PLGA lactide:glycolide molar ratio, and/or PLGA end cap).
  • formulations described herein can additionally comprise an effective amount of one or more pharmaceutically acceptable carriers.
  • FP formulations described herein can release the corticosteroid for at least 14 days at a rate that does not adversely suppress the hypothalamic-pituitary-adrenal axis (HPA axis).
  • HPA axis hypothalamic-pituitary-adrenal axis
  • FP formulations of the disclosure produce and maintain the synovial fluid concentration of FP that produces maximal analgesic effect for an extended period of time, e.g., at least 24 days, at least 42 days, at least 49 days, at least 50 days, at least 55 days, at least 56 days, at least 60 days, at least 63 days, at least 65 days, at least 70 days, at least 75 days, at least 77 days, at least 80 days, at least 84 days, at least 85 days, at least 90 days, at least four months or longer, at least five months or longer, at least six months or longer, at least seven months or longer, at least eight months or longer, at least nine months or longer, at least 10 months or longer, at least 11 months or longer, or at least 12 months or longer.
  • maximal analgesic effect is a level of analgesic effect, observed after administration of a formulation of the disclosure, which is greater than the acute analgesic effect provided by standard, non-extended release FP suspensions.
  • Ranges of synovial fluid concentrations are provided throughout the disclosure. Those of ordinary skill in the art will appreciate that these ranges are values based on samples from various subjects, e.g. , the mean value from the detected levels at which the patients reported maximal analgesic effect. These values may vary slightly from sample to sample.
  • synovial concentrations provided herein are a target synovial fluid concentration, and patients having synovial fluid concentrations slightly outside the ranges provided herein, e.g., between about 0.95 ng/ml to about 157.58 ng/ml for fluticasone propionate, may still achieve and maintain maximal analgesic effect over a prolonged duration.
  • the synovial fluid concentration of fluticasone propionate is maintained at a level in the range of about 0.95 ng/ml to about 157.58 ng/ml, or any value in between the range of about 0.95 ng/ml to about 157.58 ng/ml.
  • the synovial fluid concentration of the fluticasone propionate is maintained by administering at least one additional dose of FP.
  • at least one additional dose of FP is administered as an extended release, e.g., a controlled- or sustained- release formulation.
  • FP is released from the formulation for a duration of at least between 14 days and 90 days.
  • FP is released from the formulation for a duration of at least between 30 days and 90 days.
  • FP is released from the formulation for a duration of at least 3 months or 90 days.
  • FP is released from the formulation for a duration of at least 6 months or 180 days.
  • FP is released from the formulation for a duration of at least 12 months or 1 year.
  • FP is released from the formulation for a duration of at least between 3 months and 12 months.
  • FP is released from the formulation for a duration of at least between 3 months and 6 months. In some embodiments, FP is released from the formulation for a duration of at least between 6 months and 12 months.
  • the fluticasone propionate is released from the formulation for a duration of at least between 14 days and 90 days. In some embodiments, FP is released from the formulation for a duration of at least between 30 days and 90 days. In some embodiments, FP is released from the formulation for a duration of at least 3 months or 90 days. In some embodiments, FP is released from the formulation for a duration of at least 6 months or 180 days. In some embodiments, FP is released from the formulation for a duration of at least 12 months or 1 year. In some embodiments, FP is released from the formulation for a duration of at least between 3 months and 12 months. In some
  • FP is released from the formulation for a duration of at least between 3 months and 6 months. In some embodiments, FP is released from the formulation for a duration of at least between 6 months and 12 months.
  • the formulation is administered as one or more injections.
  • the injection is one or more local injections at a site of pain.
  • the injection is one or more intra-articular or peri-articular injections.
  • any of the formulations described herein can be used in methods of treating pain or inflammation in a patient by administering an effective amount of the formulation to a patient.
  • the formulation may additionally contain a pharmaceutically acceptable carrier.
  • the present invention provides any of the formulations described herein for use in a method of treating pain or inflammation in a patient.
  • the formulation releases the corticosteroid for at least 14 days at a rate that does not adversely suppress the hypothalamic-pituitary- adrenal axis (HPA axis).
  • HPA axis hypothalamic-pituitary- adrenal axis
  • the formulation releases FP for between at least 14 days and 90 days.
  • the methods may additionally involve the step of maintaining a synovial fluid concentration of the FP in the range of about 0.95 ng/ml to about 157.58 ng/ml.
  • the synovial fluid concentration of the FP is maintained for a duration of at least 90 days, at least 180 days, or at least 12 months.
  • the FP is released from the formulation for a duration of at least between 3 months and 12 months.
  • the synovial fluid concentration of FP is maintained by administering at least one additional dose of FP.
  • This at least one additional dose can be administered as an extended release formulation.
  • the patient is a human. In other embodiments, the patient is a non-human mammal.
  • the formulation is administered as one or more injections.
  • the injection may be one or more local injections (i.e. , one or more local injections at a site of pain).
  • these injections may be one or more intra-articular and/or peri-articular injections.
  • the patient has osteoarthritis, rheumatoid arthritis, acute gouty arthritis, juvenile arthritis, psoriatic arthritis, ankylosing spondylitis, and/or synovitis.
  • the patient has a joint disorder of a joint tissue.
  • the patient may have acute bursitis, sub-acute bursitis, acute nonspecific tenosynovitis, epicondylitis, and/or Morton's neuroma.
  • the patient has radicular pain, neurogenic claudication secondary to lumbar spinal stenosis, or back pain.
  • the radicular pain may include, but is not limited to, sciatica, radicular pain of the arm, radicular pain of the neck, radicular pain of the lumbar, and/or radicular pain of the thorax.
  • the patient has a disorder of the dermal tissue, including, but not limited to, alopecia areata, discoid lupus, erythematosus, keloids, localized hypertrophic, infiltrated inflammatory lesions of granuloma annulare, lichen planus, lichen simplex chronicus (neurodermatitis), psoriasis, psoriatic plaques, and/or necrobiosis lipoidica diabeticorum.
  • alopecia areata including, but not limited to, alopecia areata, discoid lupus, erythematosus, keloids, localized hypertrophic, infiltrated inflammatory lesions of granuloma annulare, lichen planus, lichen simplex chronicus (neurodermatitis), psoriasis, psoriatic plaques, and/or necrobiosis lipoidica diabeticorum.
  • the patient has asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, seasonal or perennial allergic rhinitis, serum sickness, transfusion reactions, bullous dermatitis herpetiformis, exfoliative dermatitis, mycosis fungoides, pemphigus, severe erythema multiforme (Stevens-Johnson syndrome), primary or secondary adrenocortical insufficiency in conjunction with mineralocorticoids, congenital adrenal hyperplasia, hypercalcemia associated with cancer, nonsupportive thyroiditis, exacerbations of regional enteritis and ulcerative colitis, acquired (autoimmune) hemolytic anemia, congenital (erythroid), hypoplastic anemia (Diamond blackfan anemia), pure red cell aplasia, secondary thrombocytopenia, trichinosis with neurologic or myocardial involvement, tuberculosis meningitis with subarachnoid block or impending block, palliative management of leukin, chronic erythem
  • the FP formulations provided herein are effective at treating pain and/or inflammation with minimal long-term side effects associated with corticosteroid
  • the FP formulations provided herein maintain sufficiently high synovial fluid concentrations of FP to be effective at treating pain and/or inflammation while producing sufficiently low systemic concentrations of FP to avoid adverse suppression of the HPA axis.
  • a minimum joint concentration of at least 1 ng/mL is required for a given FP formulation to have efficacy.
  • the FP formulations are suitable for administration, for example, local administration by injection into a site at or near the site of a patient's pain and/or
  • an extended release formulation of FP and a PLGA copolymer matrix is administered locally to treat pain and inflammation.
  • Local administration of an FP formulation can occur, for example, by injection into the intra-articular space or peri-articular space at or near the site of a patient's pain.
  • Local administration of the FP formulation can occur, for example, by intra-articular, intrathecal, epidural, or intra-bursal administration.
  • an extended release form e.g. , a sustained release form, of FP is administered (e.g.
  • an extended release form such as, e.g. , a sustained release form, of FP is administered (e.g. , by single injection or as sequential injections) into an intra-articular space to slow, arrest, reverse or otherwise inhibit structural damage to tissues associated with progressive disease such as, for example, the damage to cartilage associated with progression of osteoarthritis.
  • FP acts through the reduction of inflammation
  • concentration ranges cited here for maximizing analgesic effect will also be effective in slowing or stopping structural progression.
  • the FP formulations described herein are also useful in the treatment of a systemic disorder for which FP treatment would be required or otherwise therapeutically beneficial.
  • FP formulations when administered to a patient, exhibit an improved benefit or other therapeutic outcome in the treatment of a disease, for example a joint related disorder, as compared to the administration, for example administration into the intraarticular space of a joint, of an equivalent amount of a non-extended release FP formulation or suspension, absent any particulate suspension, microparticle, or other type of extended- release formulation, incorporation, admixture, or encapsulation.
  • the improved benefit can be any of a variety of laboratory or clinical results.
  • administration of an extended- release FP formulation is considered more successful than administration of FP absent any microparticle or other extended-release formulation if, following administration of the extended-release FP formulations, one or more of the symptoms associated with the disease is alleviated, reduced, inhibited or does not progress to a further, i.e. , worse, state, to a greater extent than the level that is observed after administration of FP absent any microparticle or other extended-release formulation.
  • Administration of an extended-release FP formulation is considered more successful than administration of FP absent any microparticle or other extended-release formulation if, following administration of the extended-release FP formulations, anti-inflammatory activity is sustained for a longer period than the level that is observed after administration of FP absent any microparticle and/or any other extended- release formulation.
  • FP formulations provided herein can be used in combination with any of a variety of therapeutics, also referred to herein as "co-therapies.”
  • the FP formulations can be used in combination with a non-extended release FP (or other corticosteroid) solution or suspension, which provides high local exposures for between 1 day and 14 days following administration and which produce systemic exposures that may be associated with transient suppression of the HPA axis.
  • a non-extended release FP or other corticosteroid
  • the same corticosteroid i.e., FP
  • the non-extended release component contains a corticosteroid that is different from that of the extended release FP formulation, i.e. , the non-extended release component does not include FP.
  • the period of extended release is between 30 days and 12 months. In some co-therapy embodiments, the period of extended release is between 90 days and 12 months. In some co-therapy embodiments, the period of extended release is at least 3 months. In some co-therapy embodiments, the period of extended release is at least between 3 months and 12 months. In some co-therapy embodiments, the period of extended release is at least between 3 months and 6 months. In some co-therapy
  • the period of extended release is at least between 6 months and 12 months. In some co-therapy embodiments, the period of sustained release is between 30 days and 12 months. In some co-therapy embodiments, the period of sustained release is between 90 days and 12 months. In some co-therapy embodiments, the period of sustained release is at least 3 months. In some co-therapy embodiments, the period of sustained release is at least between 3 months and 12 months. In some co-therapy embodiments, the period of sustained release is at least between 3 months and 6 months. In some co-therapy embodiments, the period of sustained release is at least between 6 months and 12 months.
  • the high local exposure attributable to the non- extended release component lasts for between 1 day and 28 days. In some co-therapy embodiments, the high local exposure attributable to the non-extended release component lasts for between 1 day and 21 days. In some co-therapy embodiments, the high local exposure attributable to the non-extended release component lasts for between 1 day and 14 days. In some co-therapy embodiments, the high local exposure attributable to the non- extended release component lasts for between 1 day and 10 days. In some co-therapy embodiments, the high local exposure attributable to the non-extended release component lasts between 1 days and 8 days.
  • the high local exposure attributable to the non-extended release component lasts between 1 days and 6 days. In some co-therapy embodiments, the high local exposure attributable to the non-extended release component lasts for between 1 day and 4 days.
  • Suitable additional agents for use in combination with the FP formulations provided herein include hyaluronic acid preparations including but not limited to Synvisc One, Gel 200 and Supartz; NSAIDS including but not limited to aspirin, celecoxib
  • Biologicales including but not limited to Actemra (tocilizumab), Enbrel (etanercept), Humira (adalimumab), Kineret (anakinra), Orencia (abatacept), Remicade (infliximab), Rituxan (rituximab), Cimzia (certolizumab), and Simponi (golimumab); disease modifying agents including but not limited to methotrexate, Plaquenil (hydroxychloroquine) and Azulfidine (sulfasal
  • the FP formulation and additional agent are formulated into a single therapeutic composition, and the FP formulation and additional agent are administered simultaneously.
  • the FP formulation and additional agent are separate from each other, e.g., each is formulated into a separate therapeutic composition, and the FP formulation and the additional agent are administered simultaneously, or the FP formulation and the additional agent are administered at different times during a treatment regimen.
  • the FP formulation is administered prior to the administration of the additional agent, the FP formulation is administered subsequent to the administration of the additional agent, or the FP formulation and the additional agent are administered in an alternating fashion.
  • the FP formulation and additional agent are administered in single doses or in multiple doses.
  • the FP formulation and the additional agent are administered by the same route. In some embodiments, the FP formulation and the additional agent are administered via different routes.
  • the microparticles are manufactured using a solvent evaporation process wherein the FP is dispersed in a lactic acid-gly colic acid copolymer organic solution and the mixture is treated to remove the solvent from the mixture, thereby producing microparticles.
  • the solvent evaporation process can utilize a spray drying or fluid bed apparatus to remove the solvent and produce microparticles.
  • the solvent evaporation process utilizes a spinning disk.
  • the method of manufacturing comprises the steps of: (a) dispersing the FP and the PLGA in an organic solvent to produce a FP-PLGA mixture; (b) atomizing the FP-PLGA mixture into micro-droplets by adding the FP-PLGA mixture to a spinning disk; and (c) treating the FP-PLGA mixture to remove the solvent, thereby producing the formulation.
  • step (c) may comprise a solvent evaporation process to remove the solvent.
  • the solvent evaporation process can utilize a drying chamber.
  • the method comprises step (d) collecting the microparticles using a cyclone separator.
  • the method comprises step (e) using a secondary drying step to remove residual solvents.
  • the method comprises step (f) sieving the collected microparticles.
  • step (f) can use a 150 ⁇ m sieve.
  • the spinning disk rotates at a speed of approximately 3300 rpm inside a temperature-controlled chamber maintained at 38-45° C.
  • the solvent is dichloromethane (DCM), acetone, EtOAc, benzyl alcohol, PLGA 7525 4A, PLGA 8515 7E, PLGA 7525 3.5E, and PLA 5A.
  • Determination of the solubility threshold of various solvents can be determined using standard methods known in the art. For example, an excess of drug can be incubated with stirring or agitation for a duration of time (i.e., 4 hours, 24 hours, 48 hours, 7 days, etc.). After incubation, the resultant solution can be clarified by filtration and/or centrifugation and analyzed for content using HPLC, UV, or other similar methods.
  • thermodynamic solubility of FP in different solvents is shown in the table below:
  • solubility of fluticasone in PLGA was determined to 1.4%.
  • solubility threshold four formulations categorized as above and below solubility threshold:
  • Formulations containing FP in amounts below the solubility threshold of the solvent do not exhibit the desired in vitro release kinetics. Specifically, formulations with less than 20% drug load resulted in the suboptimal in vitro release of FP. However, it was surprisingly found that formulations containing FP in amounts that exceeded the solubility threshold (i.e. , above 1.4% mg/mg concentration of FP in spraying suspension) demonstrated the desired extended release kinetic profile. (See Figure 4).
  • FP should comprise between 20-40% of the microparticles, preferably 30-38% of the microparticles, more preferably 32-37% of the microparticles (e.g. , about 35%) in order to insure that the amount of FP in the formulation is sufficiently above the solubility threshold of the solvent (e.g. , DCM) to insure that formulation manufacturing is reproducible.
  • the solvent e.g. , DCM
  • Figure 1 is a graph depicting the in vitro release rate of various fluticasone propionate (FP)/PLGA microparticle formulations in 7% SDS media.
  • Figure 2 is a graph depicting the in vitro release rate of various FP/PLGA microparticle formulations in 7% SDS media.
  • Figures 3A and 3B are graphs depicting the in vitro release rates for various FP/PLGA microparticle formulations.
  • Figure 3A depicts the FP/PLGA microparticle formulations that include 75:25 PLGA
  • Figure 3B depicts the FP/PLGA microparticle formulations that include 85: 15 PLGA.
  • Figure 4 is a graph showing the in vitro release kinetics for four FP formulations, including formulations above and below the solubility threshold of DCM.
  • Figure 5 is a graph demonstrating the pharmacokinetics of FP in the formulations described herein. As shown in this figure, a long Mean Residence Time [Median MRTO-last (hours)] across all formulations with median values ranging between 1326.89 and 1971.88 hours was observed in this study. Plasma PK also indicated an extended AUCO-last
  • Figure 6 is a graph demonstrating individual animal concentration-time profiles of fluticasone propionate in plasma (linear and log-linear scales).
  • Figures 7A-C are a series of graphs showing PK parameters computed for each formulation tested in Example 2.
  • Figure 7A shows Cmax (pg/mL);
  • Figure 7B shows AUCo-inf (h*pg/mL); and
  • Figure 7C shows MRTo-iast (h).
  • Figures 8A-C are a series of graphs showing the % percent cumulative release for all FP formulations tested.
  • the labels for each of the formulations tested include one or more of the following: the percent of FP (i.e. , 35, 30, 25, or 20%), the lactic acid:gly colic acid molar ratio in the PLGA (i.e. , 7525), the type of PLGA polymer selected (including the endcap) (i.e., 4A, 6A, or 8E), and/or the solvent used (i.e., DCM).
  • the percent of FP i.e. , 35, 30, 25, or 20%
  • the lactic acid:gly colic acid molar ratio in the PLGA i.e. , 7525
  • the type of PLGA polymer selected i.e., 4A, 6A, or 8E
  • the solvent used i.e., DCM
  • FIG. 8B shows the % cumulative release for 7525 3.5E PLGA at varying percentages of solids. The particles made at higher solids (high viscosity) showed lower burst.
  • Figure 8C shows the % cumulative release for 8515 PLGA formulations using different endcaps and at varying polymer concentrations. As expected, formulations with lower % solids show higher burst and release rate.
  • Figures 9A-B are a series of graphs showing the in vivo pharmacokinetic studies.
  • Figure 9A shows the % released following subcutaneous administration (in rats) of various 7525 PLGA polymers.
  • the same formulation recipe made with a different process solved showed a different in vitro release profile. This observation was attributed to the fact that the polymer solutions made in two different solvents will have different viscosities and that will govern how the particle is formed, which can impact particle attributes like morphology and in vitro release. Thus, acetone with lower viscosity showed faster release rate. This trend was neither predictable nor expected.
  • Figure 9B shows the % released following subcutaneous administration (in rats) of 7525 8E PLGA. This was the first data that indicated that, when a formulation is made below the solubility threshold, the burst and release rate should be lower. As shown in this figure, just by changing the drug load, the release rate changed dramatically, even when the same polymer was used. The super long duration of in vitro release achieved with 15% 7525 8E was quite unexpected.
  • Figure 10 shows tolerability and PGPS results (from an animal model for arthritis pain ⁇ see world wide web at bolderbiopath.com/study/strep-cell-wall-ankle-reactivation- arthritis-pgps)) for a FP formulation with a 40% FP drug load in 7525 4A PLGA. This is the same 40% 7525 4A formulation from Figure 9B, supra. This formulation was chosen to be put in PGPS study, and, thus, plotted separately.
  • Figure 11 is a graph showing the in vitro release data for the formulations used in the pharmacokinetic studies described in Example 2, infra. These are the same formulations from Figure 8A, supra. Because these were four lead formulations that were utilized in the dog pharmacokinetic study, they were plotted separately.
  • the disclosure provides extended release formulations and methods for the treatment of pain and inflammation using fluticasone propionate (FP) or a commercially available chemical analogue or a pharmaceutically acceptable salt thereof.
  • FP fluticasone propionate
  • the compositions and methods provided herein use extended release microparticle formulations that include fluticasone propionate or a commercially available chemical analogue or a pharmaceutically acceptable salt thereof and a poly(lactic-co-gly colic) acid copolymer (PLGA) copolymer matrix.
  • the FP/PLGA microparticle formulations provided herein are effective at treating pain and/or inflammation with minimal prolonged suppression of the hypothalamic-pituitary- adrenal (HP A) axis and/or other long term side effects commonly seen with corticosteroid administration.
  • HP A hypothalamic-pituitary- adrenal
  • the FP formulations provided herein deliver FP in a dose and in an extended release manner such that levels of Cortisol suppression are at or below 35% by day 14 post- injection.
  • the FP formulations provided herein deliver FP in a dose and in an extended release manner such that the levels of Cortisol suppression are negligible and/or undetectable by 14 days post-injection.
  • the FP formulations in these embodiments are effective in the absence of any significant HPA axis suppression.
  • Administration of the FP formulations provided herein can result in an initial "burst" of HPA axis suppression, for example, within the first few days, within the first two days, and/or within the first 24 hours post-injection, but by day 14 post-injection, suppression of the HPA axis is less than 35% (i.e., less than 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1%).
  • OA osteoarthritis
  • an extended release formulation of fluticasone propionate and PLGA polymer matrix is administered locally to treat pain and inflammation.
  • Local administration of an FP/PLGA microparticle formulation can occur, for example, by injection into the intra-articular space, peri-articular space, soft tissues, lesions, epidural space, perineural space, or the foramenal space at or near the site of a patient's pain.
  • an extended release form of FP is administered (e.g., by single injection or as sequential injections) into an intra-articular space for the treatment of pain, for example, due to osteoarthritis, rheumatoid arthritis, gouty arthritis, bursitis, tenosynovitis, epicondylitis, synovitis or other joint disorder.
  • an extended release formulation of FP and a PLGA copolymer matrix is administered (e.g. , by single injection or as sequential injections) into an intra-articular space or into soft tissues to slow, arrest, reverse or otherwise inhibit structural damage to tissues associated with progressive disease such as, for example, the damage to cartilage associated with progression of osteoarthritis.
  • corticosteroids such as FP
  • corticosteroids such as FP
  • the HPA axis the interdependent feedback mechanism between the hypothalamus, the pituitary gland and the adrenal cortex, may be suppressed by the administration of corticosteroids, leading to a variety of unwanted side effects.
  • the extent of HPA axis suppression, and related inhibition of endogenous Cortisol production, has been attributed to the potency of the corticosteroid, the dose, systemic concentration, protein binding, rate of elimination (Meibohm et al.
  • the formulations and methods of the disclosure can achieve immediate relief of the acute symptoms (e.g. , pain and inflammation) of these diseases or conditions and additionally provide an extended or long term therapy (e.g. , slowing, arresting, reversing or otherwise inhibiting structural damage to tissues associated with progressive disease), while avoiding long term systemic side effects associated with corticosteroid administration, including, for example, HPA suppression.
  • an extended or long term therapy e.g. , slowing, arresting, reversing or otherwise inhibiting structural damage to tissues associated with progressive disease
  • corticosteroid administration including, for example, HPA suppression.
  • a formulation is provided wherein a microparticle matrix (such as, for example, matrices that contain or are derived from PLGA, PLA, hydrogels, hyaluronic acid, etc.) incorporates fluticasone propionate, and the FP microparticle formulation provides at least two weeks, preferably at least three weeks, including up to and beyond 30 days, or 60 days, or 90 days, or 120 days, or 180 days, or 210 days, or 270 days, or beyond 270 days ⁇ i.e. , 1 year or more) of a sustained, steady state release of the FP.
  • a microparticle matrix such as, for example, matrices that contain or are derived from PLGA, PLA, hydrogels, hyaluronic acid, etc.
  • the FP microparticle formulation provides at least two weeks, preferably at least three weeks, including up to and beyond 30 days, or 60 days, or 90 days, or 120 days, or 180 days, or 210 days, or 270 days, or beyond 270 days
  • the FP microparticle formulations of the disclosure retain sustained efficacy even after the FP is no longer resident at the site of administration, for example, in the intraarticular space, and/or after the FP is no longer detected in the systemic circulation.
  • the FP microparticle formulation retains sustained efficacy even after the FP microparticle formulation ceases to release therapeutically effective amounts of FP.
  • the FP released by the microparticle formulation retains efficacy for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, at least six weeks, at least seven weeks, at least eight weeks, at least nine weeks, at least 12 weeks, at least 15 weeks, at least 18 weeks, at least 21 weeks, at least 24 weeks, or more than 24 weeks post-administration.
  • a controlled or sustained-release formulation wherein a microparticle matrix (such as, for example, matrices that contain or are derived from PLGA, hydrogels, hyaluronic acid, etc.) incorporates fluticasone propionate, and the formulation may or may not exhibit an initial rapid release, also referred to herein as an initial "burst" of the FP for a first length of time of between 0 and 14 days (i.e.
  • a microparticle matrix such as, for example, matrices that contain or are derived from PLGA, hydrogels, hyaluronic acid, etc.
  • 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days for example, between the beginning of day 1 through the end of day 14, in addition to the sustained, steady state release of FP for a second length of time of at least two weeks, preferably at least three weeks, including up to and beyond 30 days, or 60 days, or 90 days, or 120 days, or 180 days, or beyond 180 days. It should be noted that when FP levels are measured in vitro, an occasional initial burst of FP release from the
  • microparticle formulation can be seen, but this initial burst may or may not be seen in vivo.
  • a controlled or sustained-release formulation is provided wherein a microparticle matrix (such as, for example, matrices that contain or are derived from PLGA, hydrogels, hyaluronic acid, etc.) incorporates fluticasone propionate, and the formulation may or may not exhibit an initial rapid release, also referred to herein as an initial "burst" of the FP for a first length of time of between 0 and 14 days (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days), e.g.
  • the length of sustained release is between 21 days and 90 days (i.e.
  • the length of sustained release is between 21 days and 60 days. In some embodiments, the length of sustained release is between 14 days and 30 days. In some embodiments, the length of release of the initial "burst" component is between 0 and 10 days, for example between the beginning of day 1 through the end of day 10. In some
  • the length of release of the initial "burst" component is between 0 and 6 days, for example between the beginning of day 1 through the end of day 6. In some embodiments, the length of initial "burst,” component is between 0 and 2 days, for example between the beginning of day 1 through the end of day 2. In some embodiments, the length of initial "burst" component is between 0 and 1 day, for example between the beginning of day 1 through the end of day 1.
  • the FP microparticle formulation may provide an initial release of FP at the site of administration, for example, in the intra-articular space and/or peri-articular space.
  • the controlled or sustained release of the FP microparticle formulations continues to provide therapeutic (e.g., intraarticular and/or peri-articular) concentrations of FP to suppress inflammation, maintain analgesia, and/or slow, arrest or reverse structural damage to tissues for an additional period of therapy following administration.
  • the length of sustained release is between 21 days and 90 days (i.e.
  • the length of sustained release is between 21 days and 60 days.
  • the length of sustained release is between 14 days and 30 days. In some embodiments, the length of release of the immediate release form is between 1 day and 14 days. In some embodiments, the length of release of the immediate release form is between 1 day and 10 days. In some embodiments, the length of release of the immediate release form is between 1 day and 8 days. In some embodiments, the length of release of the immediate release form is between 1 day and 6 days. In some embodiments, the length of release of the immediate release form is between 1 day and 4 days.
  • the synovial fluid concentration of FP is maintained for a duration of at least 50 days. In some embodiments, the synovial fluid concentration of FP is maintained for a duration of at least 75 days. In some embodiments, the synovial fluid concentration of FP is maintained for a duration of at least 90 days. In some embodiments, the synovial fluid concentration of FP is maintained for a duration of at least four months or longer. In some embodiments, the synovial fluid concentration of FP is maintained for a duration of at least five months or longer. In some embodiments, the synovial fluid concentration of FP is maintained for a duration of at least six months or longer.
  • the synovial fluid concentration of FP is maintained for a duration of at least seven months or longer. In some embodiments, the synovial fluid concentration of FP is maintained for a duration of at least eight months or longer. In some embodiments, the synovial fluid concentration of FP is maintained for a duration of at least nine months or longer. In some embodiments, the synovial fluid concentration of FP is maintained for a duration of at least 10 months or longer. In some embodiments, the synovial fluid
  • the synovial fluid concentration of FP is maintained for a duration of at least 11 months or longer. In some embodiments, the synovial fluid concentration of FP is maintained for a duration of at least 12 months or longer. In some embodiments, the synovial fluid concentration of FP is maintained for a duration in the range of about 3 months to at least about 12 months.
  • the synovial fluid concentration of FP is maintained by administering at least one additional dose of FP.
  • at least one additional dose of FP is administered as an extended- release formulation.
  • at least one additional dose of FP is administered as an extended release, e.g., a controlled- or sustained- release formulation.
  • FP is released from the formulation for a duration of at least between 14 days and 90 days (i.e. , 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days).
  • FP is released from the formulation for a duration of at least between 30 days and 90 days (i.e.
  • FP is released from the formulation for a duration of at least 3 months.
  • FP is released from the formulation for a duration of at least between 3 months and 12 months. In some embodiments, FP is released from the formulation for a duration of at least between 3 months and 6 months. In some embodiments, FP is released from the formulation for a duration of at least between 6 months and 12 months.
  • the disclosure also provides methods for maximizing analgesic effect and maintaining maximal analgesic effect over a prolonged duration in a patient with a disease or disorder associated with joint pain and/or joint inflammation by administering to a subject in need thereof an extended release FP/PLGA formulation, e.g., a controlled- or sustained- release FP/PLGA formulation, and maintaining a synovial fluid concentration of FP of at least about 0.95 ng/ml for a duration of at least 24 days, for example, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months.
  • an extended release FP/PLGA formulation e.g., a controlled- or sustained- release FP/PLGA formulation
  • the method includes maintaining a synovial fluid concentration of FP of at least about 0.95 ng/ml to about 157.58 ng/ml for a duration of at least 24 days, for example, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months. Definitions
  • the terms "patient” or “subject” are used interchangeably herein to refer to any mammal, including humans, domestic and farm animals, and zoo, sports, and pet animals, such as dogs, horses, cats, and agricultural use animals including cattle, sheep, pigs, and goats.
  • One preferred mammal is a human, including adults, children, and the elderly. Even more preferred humans would be those with type I or type II diabetes with chronic, non-healing infected wounds.
  • a subject may also be a pet animal, including dogs, cats and horses.
  • Preferred agricultural animals would be cattle and goats.
  • "patient” refers to a human diagnosed with a disease or condition that can be treated in accordance with the disclosure described herein. In some embodiments it is contemplated that the formulations described herein may also be used in horses and other animals.
  • Delivery refers to any means used to place the drug into a patient. Such means may include without limitation, placing matrices into a patient that release the drug into a target area.
  • matrices may be delivered by a wide variety of methods, e.g., injection by a syringe, placement into a drill site, catheter or cannula assembly, or forceful injection by a gun type apparatus or by placement into a surgical site in a patient during surgery.
  • treatment and “treating” a patient refer to reducing, alleviating, stopping, blocking, delaying the onset of, delaying the progression of the disease state and/or the symptoms of the disease state, or preventing the symptoms of pain and/or inflammation in a patient.
  • treatment and “treating” includes partial alleviation of symptoms as well as complete alleviation of the symptoms for a time period. The time period can be hours, days, months, or even years.
  • an “effective” amount or a “therapeutically effective amount” of a drug or pharmacologically active agent is meant a nontoxic but sufficient amount of the drug or agent to elicit or provide the desired effect, e.g., analgesia.
  • An appropriate "effective" amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • pharmaceutically acceptable and “veterinarily acceptable” refer to a pharmaceutically- or veterinarily-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material.
  • Each component must be “pharmaceutically acceptable” or “veterinarily acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation. It must also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • An amount of FP that does not "suppress the hypothalamic-pituitary-adrenal axis (HPA axis)" refers to the amount of the extended release FP delivered locally to relieve pain due to inflammation, which provides a systemic concentration that will not have a clinically significant effect or "adverse effect" on the HPA axis. Suppression of the HPA axis is generally manifested by a reduction in endogenous glucocorticoid production. It is useful to consider both basal and augmented production of endogenous glucocorticoids. Under ordinary, “unstressed” conditions, glucocorticoid production occurs at a normal, basal level.
  • Endogenous Cortisol production may be determined by measuring glucocorticoid concentrations in plasma, saliva, urine or by any other means known in the art. It is known that systemic concentrations of corticosteroids such as FP can suppress the HPA axis, which does not necessarily portend complete HPA failure. (See Derendorf et al, Clin Pharmacol Ther. 39(3) (1986):313-7; Habib, Clin Rheumatol 28 (2009): 749-756).
  • transient suppression is generally considered to be acceptable without clinically significant effect, more persistent suppression, i.e. , weeks, would be deemed clinically detrimental.
  • administration of the formulation may result in a clinically acceptable HPA suppression, particularly during the initial release period of the therapy.
  • administration of the formulation will not result in any significant level of HPA suppression, including no detectable HPA suppression, particularly during the initial release period of the therapy.
  • additional FP may be released into the plasma.
  • the plasma levels during this period will generally be less than those during the initial release period, if any FP release occurs, and will not be associated with HPA axis suppression.
  • the adverse events associated with exogenous corticosteroid administration e.g., hyperglycemia, hypertension, altered mood, etc. will generally not be observed.
  • the formulation can be considered as avoiding clinically significant (or adverse) suppression of the HPA axis where the endogenous Cortisol level is substantially the same in the steady state between a patient population receiving a therapeutically beneficial amount of an immediate release formulation and those receiving a therapeutically beneficial amount of a sustained release formulation. Such a formulation would be deemed to have no clinically significant effect on the HPA axis.
  • glucocorticoid production may be assessed by administering various doses of
  • Certain embodiments disclosed herein provide for controlling the release of FP, as may be desired, to achieve either no measurable effect on endogenous glucocorticoid production or a target, or a measurable effect that is, however, without adverse clinical consequence.
  • corticosteroids such as FP
  • FP corticosteroids
  • HPA axis sensitivity appears to diminish with time, steroid, and dose.
  • standard doses of familiar corticosteroids such as FP
  • HPA axis suppression i.e. , after desensitization has occurred
  • plasma concentration of FP can be a useful surrogate for synovial fluid concentration.
  • plasma concentrations greater than 200 pg/mL will perturb the HPA axis, thereby resulting in systemic toxicity.
  • administering refers to any mode of transferring, delivering, introducing, or transporting any of the formulations described herein to a subject in need of treatment.
  • modes include, but are not limited to, intra-articular, oral, topical, intravenous, intraperitoneal, intramuscular, intradermal, intranasal, and subcutaneous administration.
  • Site of a patient's pain refers to any area within a body causing pain, e.g. , a knee joint with osteoarthritis, a knuckle with osteoarthritis, nerve root causing sciatic pain, nerve fibers growing into annular tears in discs causing back pain, temporomandibular joint (TMJ) pain, for example TMJ pain associated with temporomandibular joint disorder (TMJD) or pain radiating from epidural or perineural spaces.
  • the pain perceived by the patient may result from inflammatory responses, mechanical stimuli, chemical stimuli, thermal stimuli, as well as allodynia.
  • the site of a patient's pain can comprise one or multiple sites in the spine, such as between the cervical, thoracic, or lumbar vertebrae, or can comprise one or multiple sites located within the immediate area of inflamed or injured joints such as the shoulder, hip, hand, knuckle, or other joints.
  • a “biocompatible” material refers to a material that is not toxic to the human body, it is not carcinogenic and it should induce limited or no inflammation in body tissues.
  • a “biodegradable” material refers to a material that is degraded by bodily processes (e.g. , enzymatic) to products readily disposable by the body or absorbed into body tissue. The biodegraded products should also be biocompatible with the body.
  • such polymers may be used to fabricate, without limitation: microparticles, micro-spheres, matrices, microparticle matrices, micro-sphere matrices, capsules, hydrogels, rods, wafers, pills, liposomes, fibers, pellets, or other appropriate pharmaceutical delivery compositions that a physician can administer into the joint.
  • the biodegradable polymers degrade into nontoxic residues that the body easily removes or break down or dissolve slowly and are cleared from the body intact.
  • the polymers may be cured ex- vivo forming a solid matrix that incorporates the drug for controlled release to an inflammatory region. Suitable
  • biodegradable polymers may include, without limitation natural or synthetic biocompatible biodegradable material.
  • Natural polymers include, but are not limited to, proteins such as albumin, collagen, gelatin synthetic poly(aminoacids), and prolamines; glycosaminoglycans, such as hyaluronic acid and heparin; polysaccharides, such as alginates, chitosan, starch, and dextrans; and other naturally occurring or chemically modified biodegradable polymers.
  • Synthetic biocompatible biodegradable materials include, but are not limited to, poly(lactide- co-glycolide) (PLGA), polylactide (PLA), polyglycolide (PG), polyhydroxybutyric acid, poly(trimethylene carbonate), polycaprolactone (PCL), polyvalerolactone, poly(alpha- hydroxy acids), poly(lactones), poly(amino-acids), poly(anhydrides), polyketals
  • the biocompatible biodegradable material can include a combination of
  • biocompatible biodegradable materials can be a triblock, or other multi-block, formation where a combination of biocompatible biodegradable polymers are joined together.
  • the triblock can be PLGA-PEG-PLGA.
  • fluticasone proprionate (FP) comprises between X % to Y % of the microparticles
  • the expression "wherein fluticasone proprionate (FP) comprises between X % to Y % of the microparticles" is understood to mean that the microparticles comprise X % to Y % fluticasone proprionate, by weight of the microparticles.
  • a corticosteroid formulation e.g. , an FP formulation
  • Local injection of the formulations described herein into articular or peri-articular spaces may be useful in the treatment of, for example, juvenile rheumatoid arthritis, sciatica and other forms of radicular pain (e.g.
  • the FP formulations provided herein are useful in treating, alleviating a symptom of, ameliorating and/or delaying the progression of sciatica. In one embodiment, the FP formulations provided herein are useful in treating, alleviating a symptom of, ameliorating and/or delaying the progression of temporomandibular joint disorder (TMJD).
  • TMJD temporomandibular joint disorder
  • an FP formulation administered to a patient suffering from an inflammatory disease such as osteoarthritis or rheumatoid arthritis, is considered successful if any of a variety of laboratory or clinical results is achieved.
  • administration of an FP formulation is considered successful if one or more of the symptoms associated with the disease is alleviated, reduced, inhibited or does not progress to a further, i.e. , worse, state.
  • Administration of an FP formulation is considered successful if the disease, e.g. , an arthritic or other inflammatory disease, or any symptom thereof enters remission or does not progress to a further, i.e. , worse, state.
  • efficacy of administration of an FP microparticle formulation is assessed using any of a variety of art-recognized methods. For example, efficacy can be assessed using weekly average of daily (24 hour) pain intensity score, Western Ontario & McMaster University Osteoarthritis Index (WOMAC ® , available on the WOMAC website) and patient and clinical global impression of change. Efficacy can also be assessed by monitoring evidence of inflammation in a patient. For example, evidence of inflammation can be assessed by monitoring signs of local inflammation including tenderness, swelling, redness/heat, effusion, and Baker's cyst, and synovitis (as assessed with imaging
  • Fluticasone propionate belongs to a class of drugs known as corticosteroids, specifically glucocorticoids, which are hormones that predominantly affect the metabolism of carbohydrates and, to a lesser extent, fat and protein. Corticosteroid molecules have the following basic structure
  • corticosteroids There are four classes of corticosteroids (Class A, Class B, Class C, and Class D) (See e.g. , Foti et al. "Contact Allergy to Topical Corticosteroids: Update and Review on Cross-Sensitization.” itece «i Patents on Inflammation & Allergy Drug Discovery 3 (2009): 33-39; Coopman et al., "Identification of cross-reaction patterns in allergic contact dermatitis to topical corticosteroids.” Br J Dermatol 111 (1989): 27-34).
  • FP is a Class D corticosteroid, which are clobetasone or hydrocortisone esterified types with a long chain on C17 and/or C21 and with no methyl group on CI 6.
  • FP is the propionate salt form of fluticasone, a synthetic tri-fluorinated glucocorticoid receptor agonist with anti-allergic, anti-inflammatory, and anti-pruritic effects.
  • the structure of FP is shown below:
  • FP is approximately 20 times more potent than triamcinolone acetonide (TCA) but higher plasma protein binding (PPB).
  • TCA triamcinolone acetonide
  • PPB plasma protein binding
  • Binding and activation of the glucocorticoid receptor results in the activation of lipocortin that, in turn, inhibits cytosolic phospholipase A2, which triggers cascade of reactions involved in synthesis of inflammatory mediators, such as prostaglandins and leukotrienes.
  • cytosolic phospholipase A2 which triggers cascade of reactions involved in synthesis of inflammatory mediators, such as prostaglandins and leukotrienes.
  • mitogen-activated protein kinase (MAPK) phosphatase 1 is induced, which thereby leads to dephosphorylation and inactivation of Jun N-terminal kinase directly inhibiting c-Jun mediated transcription.
  • transcriptional activity of nuclear factor (NF)-kappa-B is blocked, thereby inhibits the transcription of cyclooxygenase 2, which is essential for prostaglandin production.
  • fluticasone propionate examples include fluticasone propionate and/or pharmaceutically acceptable salts thereof.
  • Embodiments of the disclosure include using extended release, e.g., controlled- or sustained-release, FP formulations delivered to treat pain at dosages that do not exhibit adverse side effects that can be seen with long-term administration of corticosteroids, including, by way of non-limiting example, adverse suppression of the HPA axis.
  • extended release e.g., controlled- or sustained-release, FP formulations delivered to treat pain at dosages that do not exhibit adverse side effects that can be seen with long-term administration of corticosteroids, including, by way of non-limiting example, adverse suppression of the HPA axis.
  • Total Dose Delivered (mg/month), adjusted for individual intra-articular corticosteroid characteristics, for expected suppression of endogenous Cortisol production at steady state.
  • Plasma FP concentration associated with target levels of Cortisol inhibition at steady state Plasma FP concentration associated with target levels of Cortisol inhibition at steady state.
  • the disclosure encompasses any extended release fluticasone propionate (FP) formulation, e.g. , any controlled- or sustained-release FP formulation, that produces and maintains maximal analgesic effect in a patient for an extended period of time post administration.
  • FP fluticasone propionate
  • Suitable formulations can vary in composition, components, dosing, etc., provided that the FP formulation is effective to deliver the FP over an extended period of time and to maintain a synovial fluid concentration of FP in the desired range.
  • the extended release formulation e.g. , the sustained release formulation
  • a matrix such as for example, a hydrogel-based matrix, a hyaluronic acid-based matrix, and/or a biodegradable polymer-based matrix.
  • the hydrogel is a polyurethane hydrogel, a polyacrylate hydrogel, a gelatin hydrogel, a carboxymethyl cellulose hydrogel, a pectin hydrogel, an alginate hydrogel, and/or a hyaluronic acid hydrogel.
  • the biodegradable polymer is selected from, but not limited to, PLGA, PLA, PGA, polycaprolactone, polyhydroxybutyrate,
  • polyorthoesters polyalkaneanhydrides, gelatin, collagen, oxidized cellulose, and/or polyphosphazene.
  • the extended release formulation e.g. , the sustained release formulation
  • the extended release formulation includes a biodegradable polymer microparticle formulation.
  • the manufacture of extended release microparticles, e.g. , sustained-release microparticles, or methods of making biodegradable polymer microparticles are known in the art.
  • the extended release formulation e.g. , the sustained release formulation
  • a biodegradable polymer that may include, without limitation, natural or synthetic biocompatible biodegradable materials.
  • Natural polymers include, but are not limited to, proteins such as albumin, collagen, gelatin synthetic poly(aminoacids), and prolamines; glycosaminoglycans, such as hyaluronic acid and heparin; polysaccharides, such as alginates, chitosan, starch, and dextrans; and other naturally occurring or chemically modified biodegradable polymers.
  • Synthetic biocompatible biodegradable materials include, but are not limited to the group comprising of, poly(lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide (PG), polyhydroxybutyric acid, poly(trimethylene carbonate), polycaprolactone (PCL), polyvalerolactone, poly(alpha-hydroxy acids), poly(lactones), poly(amino-acids), poly(anhydrides), polyketals poly(arylates),
  • the extended release formulation e.g. , the sustained- release microparticle or other sustained-release formulation
  • the sustained- release microparticle or other sustained-release formulation is poly(d,l-lactic-co-gly colic acid) (PLGA) or is PLGA-based.
  • PLGA polymers are commercially available from a number of sources. If not purchased from a supplier, then the biodegradable PLGA copolymers may be prepared by the procedure set forth in U.S. Pat. No. 4,293,539 (Ludwig, et al), the disclosure of which is hereby incorporated by reference in its entirety.
  • Ludwig prepares such copolymers by condensation of lactic acid and gly colic acid in the presence of a readily removable polymerization catalyst (e.g., a strong acid ion-exchange resin such as Dowex HCR-W2-H).
  • a readily removable polymerization catalyst e.g., a strong acid ion-exchange resin such as Dowex HCR-W2-H.
  • any suitable method known in the art of making the polymer can be used.
  • PLGA-based microspheres can be made by, but not limited to, spray drying, solvent evaporation, phase separation, fluidized bed coating or combinations thereof.
  • a suitable biodegradable polymer is dissolved in an organic solvent.
  • Suitable organic solvents for the polymeric materials include, but are not limited to acetone, halogenated hydrocarbons such as chloroform and methylene chloride, aromatic hydrocarbons such as toluene, halogenated aromatic hydrocarbons such as chlorobenzene, and cyclic ethers such as dioxane.
  • the organic solvent containing a suitable biodegradable polymer is then mixed with a non-solvent or anti-solvent such as silicone based solvent. By mixing the miscible non-solvent in the organic solvent, the polymer precipitates out of solution in the form of liquid droplets.
  • the liquid droplets are then mixed with another non-solvent, such as heptane or petroleum ether, to form the hardened microparticles.
  • the microparticles are then collected and dried. Process parameters such as solvent and non-solvent selections, polymer/solvent ratio, temperatures, stirring speed and drying cycles are adjusted to achieve the desired particle size, surface smoothness, and narrow particle size distribution.
  • Phase separation or phase inversion procedures entrap dispersed agents in the polymer to prepare microparticles. Phase separation is similar to coacervation of a biodegradable polymer.
  • a non-solvent such as petroleum ether
  • the polymer is precipitated from the organic solvent to form microparticles.
  • a suitable biodegradable polymer is dissolved in an aqueous miscible organic solvent.
  • Suitable water miscible organic solvents for the polymeric materials include, but are not limited to acetone, acetonitrile, and tetrahydrofuran.
  • the water miscible organic solvent containing a suitable biodegradable polymer is then mixed with an aqueous solution containing salt.
  • Suitable salts include, but are not limited to electrolytes such as magnesium chloride, calcium chloride, or magnesium acetate and non-electrolytes such as sucrose.
  • the polymer precipitates from the organic solvent to form microparticles, which are collected and dried. Process parameters such as solvent and salt selection, polymer/solvent ratio, temperatures, stirring speed and drying cycles are adjusted to achieve the desired particle size, surface smoothness, and narrow particle size distribution.
  • the microparticles may be prepared by the process of Ramstack et al, 1995, described in published international patent application WO 95/13799, the disclosure of which is incorporated herein in its entirety.
  • the Ramstack et al. process essentially provides for a first phase, including an active agent and a polymer, and a second phase, that are pumped through a static mixer into a quench liquid to form microparticles containing the active agent.
  • the first and second phases can optionally be substantially immiscible and the second phase is preferably free from solvents for the polymer and the active agent and includes an aqueous solution of an emulsifier.
  • a suitable biodegradable polymer is dissolved in a suitable solvent and then sprayed through nozzles into a drying environment provided with sufficient elevated temperature and/or flowing air to effectively extract the solvent.
  • a suitable biodegradable polymer can be dissolved or dispersed in supercritical fluid, such as carbon dioxide.
  • supercritical fluid such as carbon dioxide.
  • the polymer is either dissolved in a suitable organic solvent, such as methylene chloride, prior to mixing in a suitable supercritical fluid or directly mixed in the supercritical fluid and then sprayed through a nozzle.
  • Process parameters such as spray rate, nozzle diameter, polymer/solvent ratio, and temperatures, are adjusted to achieve the desired particle size, surface smoothness, and narrow particle size distribution.
  • the drug is dissolved in an organic solvent along with the polymer.
  • the solution is then processed, e.g. , through a Wurster air suspension coating apparatus to form the final microcapsule product.
  • the microcapsule product is formed using a spinning disk methodology, e.g., a Southwest Research Institute (SwRI) technology.
  • SwRI Southwest Research Institute
  • the microparticles can be prepared in a size distribution range suitable for local infiltration or injection.
  • the diameter and shape of the microparticles can be manipulated to modify the release characteristics.
  • other particle shapes such as, for example, cylindrical shapes, can also modify release rates of an extended release FP formulation, e.g. , a sustained release FP formulation, by virtue of the increased ratio of surface area to mass inherent to such alternative geometrical shapes, relative to a spherical shape.
  • an extended release FP formulation e.g. , a sustained release FP formulation
  • microparticles have a volumetric mean diameter ranging between about 20 to 500 (i.e., 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, or 500) microns.
  • volumetric mean diameter ranging between about 20 to 500 (i.e., 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380
  • the microparticles have a volumetric mean diameter of between 20 to about 100 microns (i.e., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 ,60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 microns).
  • Biodegradable polymer microparticles that deliver extended release FP formulations may be suspended in suitable aqueous or non-aqueous carriers which may include, but are not limited to water, saline,
  • oils low melting waxes, fats, lipids, liposomes and any other pharmaceutically acceptable substance that is lipophilic, substantially insoluble in water, and is biodegradable and/or eliminable by natural processes of a patient's body. Oils of plants such as vegetables and seeds are included.
  • oils made from corn, sesame, canola, soybean, castor, peanut, olive, arachis, maize, almond, flax, safflower, sunflower, rape, coconut, palm, babassu, and cottonseed oil; waxes such as carnoba wax, beeswax, and tallow; fats such as triglycerides, lipids such as fatty acids and esters, and liposomes such as red cell ghosts and phospholipid layers.
  • FP When intra-articularly delivered FP is incorporated into a biodegradable polymer (i.e., microparticles) for sustained release into a joint at a dosage that does not suppress the HP A axis, preferred loadings of said corticosteroid are from about 20% to about 40% (w/w) of the polymer, preferably about 30% to about 38%, more preferably about 32% to about 37% of the polymer. In some embodiments, FP comprises about 35% of the polymer.
  • FP As the biodegradable polymers undergo gradual bio-erosion within the joint, FP is released to the inflammatory site.
  • the pharmacokinetic release profile of FP by the biodegradable polymer may be first order, zero order, bi- or multi-phasic, to provide desired treatment of inflammatory related pain.
  • the bio-erosion of the polymer and subsequent release of FP may result in a controlled release of FP from the polymer matrix.
  • single phase release of FP is more preferable than bi-phasic or multiphasic release.
  • the release rate of a corticosteroid, e.g. , fluticasone propionate (FP), from a formulation can be modulated or stabilized by adding one or more pharmaceutically acceptable excipient(s) to the formulation.
  • additional excipient(s) may include any useful ingredient added to the biodegradable polymer depot that is not a corticosteroid or a biodegradable polymer.
  • additional excipient(s) may include a mixture of multiple polymers added to the biodegradable polymer depot to adjust the release profile as necessary.
  • compositions may include without limitation lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, PEG, polysorbate 20, polysorbate 80, polyvinylpyrrolidone, cellulose, water, saline, syrup, methyl cellulose, and carboxymethyl cellulose.
  • An excipient for modulating the release rate of corticosteroid, e.g., FP, from the formulation may also include without limitation pore formers, pH modifiers, solubility enhancers, reducing agents, antioxidants, and free radical scavengers.
  • FP formulations of the disclosure can be effected by intra-articular injection or other injection using a needle.
  • needles having a gauge of about 14-28 gauge are suitable. It will be appreciated by those skilled in the art that FP formulations of the present disclosure may be delivered to a treatment site by other conventional methods, including catheters, infusion pumps, pens devices, injection guns and the like.
  • a fluticasone propionate microparticle formulation can occur, for example, by injection into the intra-articular space, peri-articular space, soft tissues, lesions, epidural space, perineural space, or the foramenal space at or near the site of a patient's pain and/or structural tissue damage.
  • Local injection of the formulations described herein into articular or peri-articular spaces may be useful in the treatment of, for example, juvenile rheumatoid arthritis, sciatica and other forms of radicular pain (e.g., arm, neck, lumbar, thorax), psoriatic arthritis, acute gouty arthritis, Morton's neuroma, acute and subacute bursitis, acute and subacute nonspecific tenosynovitis and epicondylitis, acute rheumatic carditis and ankylosing spondylitis.
  • radicular pain e.g., arm, neck, lumbar, thorax
  • psoriatic arthritis e.g., acute gouty arthritis
  • Morton's neuroma e.g., acute and subacute bursitis, acute and subacute nonspecific tenosynovitis and epicondylitis
  • Injection of the microparticles described herein into soft tissues or lesions may be useful in the treatment of, for example, alopecia areata, discoid lupus, erythematosus; keloids, localized hypertrophic, infiltrated inflammatory lesions of granuloma annulare, lichen planus, lichen simplex chronicus (neurodermatitis), psoriasis and psoriatic plaques; necrobiosis lipoidica diabeticorum, and psoriatic arthritis.
  • Injection of the microparticles described herein into epidural spaces may be useful in the treatment of, for example, Neurogenic Claudication (NC).
  • NC Neurogenic Claudication
  • Intramuscular or other soft tissues or lesions injections may also be useful in providing systemic exposures that are effective in the control of incapacitating allergic conditions (including but not limited to asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, seasonal or perennial allergic rhinitis, serum sickness, transfusion reactions), bullous dermatitis herpetiformis, exfoliative dermatitis, mycosis fungoides, pemphigus, severe erythema multiforme (Stevens-Johnson syndrome), Primary or secondary adrenocortical insufficiency in conjunction with mineralocorticoids where applicable; congenital adrenal hyperplasia, hypercalcemia associated with cancer, nonsupportive thyroiditis, exacerbations of regional enteritis and ulcerative colitis, acquired (autoimmune) hemolytic anemia, congenital (erythroid) hypoplastic anemia (Diamond blackfan anemia), pure red cell aplasia, select cases of secondary thrombocytopenia, trichinosis with neurologic
  • the FP microparticle formulations provided herein are useful in treating, alleviating a symptom of, ameliorating and/or delaying the progression of sciatica. In one embodiment, FP microparticle formulations provided herein are useful in treating, alleviating a symptom of, ameliorating and/or delaying the progression of
  • TMJD temporomandibular joint disorder
  • the FP microparticle formulations provided herein are useful in treating, alleviating a symptom of, ameliorating and/or delaying the progression of Neurogenic Claudication (NC) secondary to lumbar spinal stenosis (LSS).
  • LSS implies spinal canal narrowing with possible subsequent neural compression (classified by anatomy or etiology).
  • Neurogenic Claudication (NC) is a hallmark symptom of lumbar stenosis, in which the column of the spinal cord (or the canals that protect the nerve roots) narrows at the lower back. This narrowing can also occur in the spaces between the vertebrae where the nerves leave the spine to travel to other parts of the body.
  • microparticles of the disclosure are used to treat, alleviate a symptom of, ameliorate and/or delay the progression in patients suffering from NC secondary to LSS.
  • the FP microparticle formulations can be administered, for example, by epidural steroid injection (ESI).
  • a FP microparticle formulation to a patient suffering from an inflammatory disease such as osteoarthritis or rheumatoid arthritis, is considered successful if any of a variety of laboratory or clinical results is achieved.
  • administration of an FP microparticle formulation is considered successful if one or more of the symptoms associated with the disease is alleviated, reduced, inhibited or does not progress to a further, i.e. , worse, state.
  • Administration of an FP microparticle formulation is considered successful if the disease, e.g., an arthritic or other inflammatory disease, enters remission or does not progress to a further, i.e., worse, state.
  • a pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration.
  • Solutions or suspensions used for intra-articular application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as
  • ethylenediaminetetraacetic acid EDTA
  • buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes, single, or multiple dose vials made of glass or plastic.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions.
  • the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable suspensions can be prepared by incorporating the active compound(s) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • methods of preparation are vacuum drying and freeze-drying that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of FP formulations calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the FP formulations and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an FP formulations for the treatment of individuals.
  • any of the FP formulations described herein may be used in the manufacture of the medicament, for example, a medicament for treating inflammation and/or pain.
  • kits for treating inflammation and/or pain containing any of the formulations described herein, optionally along with instructions for use.
  • Articles of manufacture are also provided, which include a vessel containing any of the formulations described herein and instructions for use for the treatment of
  • compositions described herein can be included in a container, pack, or dispenser together with instructions for administration.
  • Fluticasone propionate PLGA formulations were produced as described herein. Fluticasone propionate was chosen for these studies due to its very low solubility and that it is approximately 20-fold more potent at the glucocorticosteroid (GC) receptor than
  • TCA triamcinolone acetonide
  • Table 2 shows four formulations that were prepared and tested in the studies presented herein. Table 2. Fluticasone Propionate PLGA Formulation Characteristics, Round 1
  • the purpose of this study is to estimate and compare the pharmacokinetic profiles of four formulations of Fluticasone propionate (FP) in PLGA microspheres following intraarticular injection in the knee in Beagle dogs.
  • FP Fluticasone propionate
  • the pharmacokinetic objective of the study is to determine and compare the plasma pharmacokinetic profile of the test formulations (Fluticasone PLGA microsphere Formulation#12, Fluticasone PLGA microsphere Formulation#14, Fluticasone PLGA microsphere Formulation#16, Fluticasone PLGA microsphere Formulation# 18) following a single intra-articular injection to the Beagle dogs.
  • Blood samples (a target of 3 mL each) were collected from all animals at the following targeted time points relative to Day 1 dosing: At 2, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; and in the morning of Days 7, 14, 21, and 28 and every 2 weeks thereafter up to 6 months post-dose, including on the last day of the study (Day 197). On the last study day synovial fluid was harvested from the inject knee to assay for any residual FP still in the injected knee.
  • the study population for pharmacokinetic analysis consists of 4 animals in each of 4 treatment groups: Formulation #12 (30% 4A), Formulation #14 (35% 6A), Formulation #16 (25% 6A), Formulation #18 (30% 8E).
  • Bioanalytical assay for FP was completed with an LC-MS/MS assay.
  • a summary of the bioanalytical methods is as follows.
  • pharmacokinetic parameters including area under the plasma concentration versus time cure form time up to infinity (AUCo-inf); area under the plasma concentration versus time cure from time 0 up to the last quantifiable time (AUCo-t); apparent clearance, calculated as Dose / AUCo-inf (CL/F); maximum concentration (Cmax); last plasma concentration (Ciast); time of maximum concentration (tmax); time of last concentration (tiast); terminal half-life (ti/ 2 ); mean residence time, calculated as AUMCo-iast / AUCo-iast, where AUMC is the area under the first moment concentration curve to the last concentration value above LLOQ (MRTo-iast); and volume of distribution (Vz/F) were computed for each study animal using non-compartmental methods for plasma pharmacokinetic parameter estimates.
  • AUCo-inf area under the plasma concentration versus time cure from time 0 up to the last quantifiable time
  • apparent clearance calculated as Dose /
  • Plasma FP concentrations were summarized using descriptive statistics (including N, mean, standard deviation (SD), median, geometric mean and percent coefficient of variation (CV%) for each formulation.
  • BLOQ Concentrations below the limit of quantification
  • FP concentrations that were below the limit of quantification (BLQ) were assigned a value of zero when they preceded quantifiable samples in the initial portion of the profile.
  • BLOQ values embedded between two quantifiable data points were treated as missing when calculating area under the curve.
  • BLOQ values occurring at the end of the collection interval were treated as missing data.
  • PK parameters Cmax, AUCo-inf and MRTo-iast computed for each formulation suggest a proportional, linear, exposure of FP.
  • Figure 7A (Cmax), and Figure 7B (AUCo-inf) and Figure 7C (MRTo-iast) present plots with linear regression for formulation proportional exposure.
  • Plasma PK also indicated an extended AUCo-iast (Geometric Mean range: 125647.45 to 135903.36 h*pg/mL) and AUCo-iirf (Geometric Mean range: 136490.14 to 172088.49 h*pg/mL) due to detectable concentrations at Day 197, further supporting a long MRT, and long exposure duration to FP.

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Abstract

La présente invention concerne des compositions de microparticules de propionate de fluticasone à libération prolongée (FP) et des procédés d'utilisation de ces microparticules de FP à libération prolongée pour traiter la douleur et/ou l'inflammation chez un sujet, y compris la douleur et/ou l'inflammation provoquées par des maladies inflammatoires telles que l'ostéoarthrite ou la polyarthrite rhumatoïde.
PCT/US2017/066816 2016-12-15 2017-12-15 Formulations de fluticasone et leurs procédés d'utilisation WO2018112408A1 (fr)

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EP3595776A4 (fr) * 2017-03-17 2020-09-30 Flexion Therapeutics, Inc. Formulations à libération prolongée de fluticasone et leurs procédés d'utilisation

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US20040139624A1 (en) * 2002-12-19 2004-07-22 Chickering Donald E. Methods and apparatus for making particles using spray dryer and in-line jet mill
US20120288534A1 (en) * 2010-08-04 2012-11-15 Neil Bodick Corticosteroids for the Treatment of Joint Pain

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Publication number Priority date Publication date Assignee Title
US20040139624A1 (en) * 2002-12-19 2004-07-22 Chickering Donald E. Methods and apparatus for making particles using spray dryer and in-line jet mill
US20120288534A1 (en) * 2010-08-04 2012-11-15 Neil Bodick Corticosteroids for the Treatment of Joint Pain
US20150025050A1 (en) * 2010-08-04 2015-01-22 Flexion Therapeutics, Inc. Corticosteroids for the Treatment of Joint Pain

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3595776A4 (fr) * 2017-03-17 2020-09-30 Flexion Therapeutics, Inc. Formulations à libération prolongée de fluticasone et leurs procédés d'utilisation

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