BACKGROUND

Technical Field

This disclosure relates to an injectable sustained release composition and a method of delivery of the same to reduce inflammation and to treat pain in joints, including pain caused by inflammatory diseases such as osteoarthritis or rheumatoid arthritis.

Description of the Related Art

Arthritis i.e., inflammation in the joints, consists of more than 100 different conditions which range from relatively mild forms of tendinitis and bursitis to crippling systemic forms, such as rheumatoid arthritis. It includes pain syndromes such as fibromyalgia and arthritis-related disorders, such as systemic lupus erythematosus, that involve every part of the body.

Generally, there are two types of arthritis:Rheumatoid arthritis (“RA”) and related diseases, which are immune-mediated systemic inflammatory joint diseases.Osteoarthritis (“OA”), which is a degenerative joint disease, the onset of which is typically mediated by previous joint injury or other factors.

The common denominator for all of these arthritic conditions, including RA and OA is joint and musculoskeletal pain. Often this pain is a result of inflammation of the joint lining which is the body's natural response to injury. Such inflammation and pain can prevent the normal use and function of the joint. Pain and disability from arthritis, joint degeneration, and surgery are generally treated by a combination of oral medications or intra-articular injections of steroid compounds designed to reduce inflammation. In addition, other compositions, such as hyaluronic acid products, have been injected to provide visco-supplementation. A distinct benefit of a corticosteroid injection is that the relief of localized inflammation in a particular body area is more rapid and powerful than what can be achieved with traditional anti-inflammatory oral medications, such as aspirin. A single injection also can avoid certain side effects that can accompany multiple doses of oral anti-inflammatory medications, notably irritation of the stomach. Injections can be administered easily in a doctor's office. Other advantages include the rapid onset of the medication's action. Unfortunately, injections also have some systemic side effects or are not effective for extended periods of time.

Short-term complications are uncommon. Long-term risks of corticosteroid injections depend on the dose and frequency of the injections. With higher doses and frequent administration, potential side effects include thinning of the skin, easy bruising, weight gain, puffiness of the face, acne (steroid acne), elevation of blood pressure, cataract formation, thinning of the bones (osteoporosis), and a rare but serious type of damage to the bones of the large joints (avascular necrosis). Furthermore, there is an interdependent feedback mechanism between the hypothalamus, which is responsible for secretion of corticotrophin-releasing factor, the pituitary gland, which is responsible for secretion of adrenocorticotropic hormone, and the adrenal cortex, which secretes cortisol, termed the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis may be suppressed by the administration of corticosteroids, leading to a variety of unwanted side effects.

Accordingly, there is a medical need to extend the local duration of action of corticosteroids, while reducing the systemic side effects associated with that administration. In addition, there is a need for sustained local treatment of pain and inflammation, such as joint pain, with corticosteroids that results in clinically insignificant or no measurable HPA axis suppression. In addition, there is a medical need to slow, arrest, reverse or otherwise inhibit structural damage to tissues caused by inflammatory diseases such as damage to articular tissues resulting from osteoarthritis or rheumatoid arthritis.

BRIEF SUMMARY

Described herein are pharmaceutical compositions, injectable dosage forms and method of using the same for treating inflammation and/or manage pain in a body compartment, such as a joint space, an epidural space, a vitreous body of an eye, a surgically created space, or a space adjacent to an implant.

One embodiment provides a pharmaceutical composition, comprising: a plurality of microparticles, the microparticle including: (1) a crystalline drug core of more than 70% by weight of the microparticle, the crystalline drug core including one or more crystals of fluticasone or a pharmaceutically acceptable salt or ester thereof; and (2) a polymeric shell encapsulating the crystalline drug core, the polymeric shell being in contact but immiscible with the crystalline drug core, wherein said microparticles when dissolution tested using United States Pharmacopoeia Type II apparatus exhibit a dissolution half-life of 12-20 hours, wherein the dissolution conditions are: 3 milligrams of microparticles in 200 milliliters of dissolution medium of 70% v/v methanol and 30% v/v of water at 25° C.

A further embodiment provides a pharmaceutical composition, comprising: a plurality of microparticles, the microparticle including: (1) a crystalline drug core of more than 70% by weight of the microparticle, the crystalline drug core including one or more crystals of fluticasone or a pharmaceutically acceptable salt or ester thereof; and (2) a polymeric shell encapsulating the crystalline drug core, the polymeric shell being in contact but immiscible with the crystalline drug core, wherein the microparticles are heat treated within a temperature range of 210-230° C. for at least one hour.

Yet another embodiment provides a unit dosage form of a corticosteroid for injecting into a body compartment, comprising: a plurality of microparticles, the microparticle including: (1) a crystalline drug core of more than 70% by weight of the microparticle; and (2) a polymeric shell encapsulating the crystalline drug core, wherein the crystalline drug core includes one or more crystals of a corticosteroid selected from fluticasone, fluticasone furoate, and fluticasone propionate, and the polymeric shell is in contact but immiscible with the crystalline drug core, wherein the unit dosage form is capable of sustained-release of the corticosteroid over a period of 2-12 months while maintaining a minimum therapeutically effective concentration of the corticosteroid within the body compartment.

Yet a further embodiment provides a method of decreasing inflammation or managing pain in a patient in need thereof comprising administering to the patient, via injection to a body compartment, a therapeutically effective amount of a pharmaceutical composition for sustained release of a corticosteroid wherein the pharmaceutical composition comprises a plurality of microparticles and a pharmaceutically acceptable vehicle, the microparticle including: (1) a crystalline drug core of more than 70% by weight of the microparticle; and (2) a polymeric shell encapsulating the crystalline drug core, and wherein the crystalline drug core includes one or more crystals of fluticasone or a pharmaceutically acceptable salt or ester thereof, and the polymeric shell is in contact but immiscible with the crystalline drug core.

A further embodiment provides a method for forming coated microparticles, comprising: providing a crystalline drug core including one or more crystals of a corticosteroid, forming a polymeric shell by coating one or more coats of a polymeric solution having a biodegradable polymer and a solvent; allowing the solvent to dry to provide coated microparticles; and heating the coated microparticles at 210-230° C. for at least one hour.

Yet another embodiment provides a method of decreasing inflammation or managing pain in a patient in need thereof comprising: administering to the patient, via a single injection to a body compartment, a unit dosage form for sustained release of a corticosteroid wherein the unit dosage form comprises a plurality of microparticles and a pharmaceutically acceptable vehicle, wherein the crystalline drug core includes one or more crystals of a corticosteroid selected from fluticasone, fluticasone furoate, and fluticasone propionate, and the polymeric shell is in contact but immiscible with the crystalline drug core, and wherein, following the single injection, the corticosteroid is released over a period of 2-12 months while maintaining a minimum therapeutically effective concentration of the corticosteroid within the body compartment.

The present disclosure further provides a corticosteroid which is administered locally as a sustained release dosage form (with or without an immediate release component) that results in efficacy accompanied by clinically insignificant or no measurable effect on endogenous cortisol production.

The present disclosure further provides a membrane based, diffusion-driven release mechanism with drug particle sizing large enough to allow high drug loading, but small enough to be injected intra-articularly.

The present disclosure further provides a use of an intra-articularly injected, therapeutically effective amount of a pharmaceutical preparation for sustained release of a corticosteroid selected from the group consisting of fluticasone, fluticasone furoate, and fluticasone propionate, comprising a multiplicity of coated microparticles, said coated microparticles having a mean diameter in a range of 50 μm to 400 μm and wherein the microparticles are particles comprised of greater than 70% corticosteroid by weight, to decrease inflammation and to reduce pain in a patient.

As provided herein, corticosteroids (“drug” or “therapeutic agent”) are coated with a semi-permeable polymeric shell and injected into the joint. Water then diffuses through the polymer and dissolves the drug core (D) creating a saturated solution inside the membrane (C) and essentially sink conditions outside the particle (c). This concentration gradient drives a constant (zero order) release of drug from the drug particle as long as there is some drug core remaining to maintain a saturated solution. The period of release can be tuned by altering the permeability of the polymer coating.

The present disclosure further relates to the delivery of compositions to reduce inflammation and to treat pain in joints, including pain caused by inflammatory diseases such as osteoarthritis or rheumatoid arthritis and to slow, arrest or reverse structural damage to tissues caused by an inflammatory disease, for example damage to articular and/or peri-articular tissues caused by osteoarthritis or rheumatoid arthritis.

By way of the method of the present disclosure, there is provided a means to reduce morbidity due to arthritis by employing and administering to a patient a long-lasting injectable, intra-articular drug delivery composition. While intra-articular steroids have been a mainstay of treatment for arthritis for more than 50 years, for many patients, multiple steroid injections are necessary with attendant risks and side effects. There is provided herein a platform and method to overcome these side effects via a sustained release delivery method, which can provide pseudo-zero order release, without an initial burst, on the order of months for low solubility steroids. An intra-articular injectable formulation for this use and with these properties has never been described in the literature.

