Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1998-07-02
2001-06-19
Azpuru, Carlos A. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
Reexamination Certificate
active
06248345
ABSTRACT:
FIELD OF THE INVENTION
The present invention is related to sustained release formulations for the administration of locally active agents and/or diagnostic agents in sustained release form intra articularly or in other body spaces. In particular embodiments, the invention provides methods and compositions for the administration of local anesthetics as well as compositions and methods for augmenting the duration and potency of local anesthesia, in patients in need thereof, and for obtaining additional beneficial effects, in intra articular locations and in all human or animal body spaces.
BACKGROUND OF THE INVENTION
Is Symptomatic treatment of joint pain has hereto been based on the use of systemic treatment with steroidal and nonsteroidal antiinflammatory agents and analgesics as well as localized injection of steroidal antiinflammatories, e.g., intra articular injection, and local anesthetics, either intra articular or proximal to the innervation of the painful joint. Localized treatment is generally preferred over systemic treatment, particularly when treating severe, localized joint pain, in order to avoid the untoward systemic effects associated with the high levels of both steroidal and nonsteroidal antiinflammatory agents otherwise required. Local anesthetics alone have previously been injected into joint spaces to relieve pain, with mixed results.
While compounds utilized as general anesthetics reduce pain by producing a loss of consciousness, local anesthetics act by producing a loss of sensation in the localized area of administration in the body. The mechanism by which local anesthetics induce their effect, while not having been determined definitively, is generally thought to be based upon the ability to interfere with the initiation and transmission of the nerve impulse. The duration of action of a local anesthetic is proportional to the time during which it is in actual contact with the nervous tissues. Consequently, procedures or formulations that maintain localization of the drug at the nerve greatly prolong anesthesia.
Local anesthetics are potentially toxic, yet must remain at the site long enough to allow sufficient time for the localized pain to subside. Therefore, it is of great importance that factors such as the choice of drug, concentration of drug, and rate and site of administration of drug be taken into consideration when contemplating their use.
Different devices and formulations are known in the art for administration of local anesthetics. For example, local anesthetics can be delivered in solution or suspension by means of injection, infusion, infiltration, irrigation, topically and the like. Injection or infusion can be carried out acutely, or if prolonged local effects are desired, localized anesthetic agents can be administered continuously by means of a gravity drip or infusion pump. Thus, local anesthetics such as bupivacaine have been administered by continuous infusion, e.g., for prolonged epidural or intrathecal administration.
Sustained release carriers for local anesthetics have been described. For example, U.S. Pat. Nos. 4,725,442 and 4,622,219 (Haynes) are directed to methoxyflurane-containing microdroplets coated with a phospholipid prepared by sonication, which are suitable for intradermal or intravenous injection into a patient for inducing local anesthesia. Such microdroplets are said to cause long-term local anesthesia when injected intradermally, giving a duration of anesthesia considerably longer than the longest acting conventional local anesthetic (bupivacaine).
U.S. Pat. No. 5,188,837 (Domb) relates to a microsuspension system containing lipospheres having a layer of a phospholipid imbedded on their surface. The core of the liposphere is a solid substance to be delivered, or the substance to be delivered is dispersed in an inert vehicle. The substance to be delivered can be, e.g., nonsteroidal anti-inflammatory compounds, local anesthetics, water insoluble chemotherapeutic agents and steroids.
Other formulations directed to injectable microcapsules, etc. are known. For example, U.S. Pat. No. 5,061,492 describes prolonged release microcapsules of a water-soluble drug in a biodegradable polymer matrix which is composed of a copolymer of glycolic acid and a lactic acid. The microcapsules are prepared as an injectable preparation in a pharmaceutically acceptable vehicle. The particles of water soluble drug are retained in a drug-retaining substance dispersed in a matrix of the lactic/glycolic acid copolymer in a ratio of 100/1 to 50/50 and an average molecular weight of 5,000-200,000. The injectable preparation is made by preparing a water-in-oil emulsion of an aqueous layer of drug and drug retaining substance and an oil layer of the polymer, thickening and then water-drying.
U.S. Pat. No. 4,938,763 (Dunn, et al.) is related to a biodegradable polymer for use in providing syringe able, in-situ forming, solid biodegradable implants for animals. In one aspect of this reference, a thermosetting system is utilized which utilizes copolymers which may be derived from polylactides and/or polyglycolides, combinations and mixtures of these and other polymers.
U.S. Pat. No. 4,293,539 (Ludwig, et al.) is directed to controlled release formulations comprised of a microbial agent dispersed throughout a copolymer derived from lactic acid and glycolic acid. The copolymer is derived from 60-95% lactic acid and 40-5% glycolic acid by weight, and has a molecular weight of 6,000-35,000. An effective amount of the copolymeric formulation is administered by subcutaneous or intramuscular administration.
WO 94/05265 describes improved biodegradable sustained release systems consisting of a polymeric matrix incorporating a local anesthetic for the prolonged administration of the local anesthetic agent. The devices are selected on the basis of their degradation profiles: release of the topical anesthetic in a linear, controlled manner over the period of preferably two weeks and degradation in vivo with a half-life of less than six months, more preferably two weeks, to avoid localized inflammation. The disclosure states that an anti-inflammatory can be incorporated into the polymer with the local anesthetic to reduce encapsulation for optimal access of drug to its site of action. The anti-inflammatories that are said to be useful include steroids such as dexamethasone, cortisone, prednisone, and others routinely administered orally or by injection.
Several non-glucocorticoids have been reported to prolong the action of local anesthetics. Epinephrine in immediate release form is known by those of ordinary skill in the art to briefly prolong the action of immediate release local anesthetics by inducing vasoconstriction adjacent to the site of injection. However, the duration of prolongation provided by immediate release epinephrine is on the order of about an hour, at best, in a highly vascularized tissue. This strategy is also severely limited by the risk of gangrene due to prolonged impairment of blood flow to local tissues. Dextrans and alkalinizing agents have also been suggested as local anesthesia prolonging agents, but have heretofore been reported to be ineffective for this purpose (Bonica et al., 1990, “Regional Analgesia With Local Anesthetics”
THE MANAGEMENT OF PAIN
, Second Edition, Volume II, Published, Lea & Febiger, Chapter 94, pages 1890-1892).
Colchicine has been shown to suppress injury-induced ectopic nerve discharge in a model system of chronic pain utilizing injured nerve (Wall et al.), 1995, Textbook of Pain, Third Edition, Publ., Churchill Livingston, pages 94-98; Devol et al., 1991
, A Group Report: Mechanisms of neuropathic pain following peripheral injury
. In: Basbaume A I, et al (eds).
TOWARDS A NEW PHARMACOTHERAPY OF PAIN
, Dahlem Konferenzen, Wiley, Chichester pp. 417-440; Devor et al., 1985
, Pain
, 22:127-137 at 128; and Devor, 1983
, Pain
. 16:73-86). It has been reported in one study that colchicine was given for the treatment of low-back pain, although oral colchicine has been shown to be ineffective for the same indica
Chasin Mark
Donigi-Gale Donna
Goldenheim Paul
Lacouture Peter
Sackler Richard
Azpuru Carlos A.
Davidson Davidson & Kappel, LLC.
Euro-Celtique S.A.
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