PCT
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`wo 99/01114
`(51) International Patent Classification 6 :
`A61K 9/50, BOlJ 13/02, B32B 5/16
`14 January 1999 (14.01.99)
`
`A1
`
`(11) International Publication Number:
`
`(43) International Publication Date:
`
`(81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR,
`BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, Fl, GB, GE,
`GH, GM, GW, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ,
`LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW,
`MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, Sl, ~K, SL,
`TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW, ARIPO
`patent (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), Eurasian
`patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
`patent (AT, BE, CH, CY, DE, DK, ES, Fl, FR, GB, GR,
`IE, IT, LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF,
`CG, Cl, CM, GA, GN, ML, MR, NE, SN, TD, TG).
`
`Published
`With international search report.
`
`(21) International Application Number:
`
`PCT/US98114000
`
`(22) International Filing Date:
`
`2 July 1998 (02.07.98)
`
`(30) Priority Data:
`60/051,601
`
`2 July 1997 (02.07.97)
`
`us
`
`except US):
`States
`designated
`all
`(for
`(71) Applicant
`EURO-CELTIQUE, S.A.
`[LU/LU];
`122,
`boulevard
`de la Petrusse, L-2330 Luxembourg (LU).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): GOLDENHEIM, Paul
`[US/US]; 4 Bald Hill Place, Wilton, CT 06897 (US).
`LACOUTURE, Peter [US/US]; 16 Ashford Lane, Newton,
`CT 06470 (US). DONIGI-GALE, Donna [US/US]; 22
`Fieldcrest Drive, Richfield, CT 06877 (US). CHASIN,
`Mark [US/US]; 3 Wayne Court, Manalapan, NJ 07726
`(US). SACKLER, Richard [US/US]; 25 Windrose Way,
`Greenwich, CT 06830 (US).
`
`(74) Agents: DAVIDSON, Clifford, M. et al.; Davidson, Davidson
`& Kappel, LLC, 15th floor, 1140 Avenue of the Americas,
`New York, NY 10036 (US).
`
`(54) Title: PROLONGED ANESTHESIA IN JOINTS AND BODY SPACES
`
`(57) Abstract
`
`Sustained release local anesthetic formulations are administered intra articularly and/or into body spaces/cavities. The formulation is
`preferably a plurality of injectable microparticles including a local anesthetic and an effective amount of a biocompatible, biodegradable,
`sustained release material prolonging the release of the local anesthetic and optionally a pharmaceutically acceptable, i.e., non-toxic,
`augmenting agent effective to prolong the duration of the local anesthesia for a time period longer than that obtainable without the
`augmenting agent.
`
`LUYE1004
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`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`
`AL
`AM
`AT
`AU
`AZ
`BA
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`cu
`cz
`DE
`DK
`EE
`
`Albania
`Armenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`Cilte d'Ivoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`ES
`FI
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People's
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`SI
`SK
`SN
`sz
`TD
`TG
`TJ
`TM
`TR
`TT
`UA
`UG
`us
`uz
`VN
`YU
`zw
`
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Turkmenistan
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`VietNam
`Yugoslavia
`Zimbabwe
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`PROLONGED ANESTHESIA
`IN JOINTS AND BODY SPACES
`
`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
`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 ofthe 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.
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`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. Patent 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. Patent 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. Patent No. 5,061,492 describes prolonged release microcapsules of a
`water-soluble drug in a biodegradable polymer matrix which is composed of a
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`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 50150 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. Patent 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. Patent 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
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`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 (Wallet 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 indication (Schnebel et al.,
`1988, Spine 13(3):354-7). However, it has not heretofore been known to use
`colchicine to prolong local anesthesia.
`A relatively long-acting local anesthetic, bupivacaine hydrochloride, is
`
`commercially available as Marcaine® Hydrochloride in sterile isotonic solutions with
`and without epinephrine (as bitartrate) 1:200,000 for injection via local infiltration,
`peripheral nerve block, and caudal and lumbar epidural blocks. After injection of
`Marcaine for caudal, epidural or peripheral nerve block in man, peak levels of
`bupivacaine in the blood are reached in 30 to 45 minutes, followed by a decline to
`insignificant levels during the next three to six hours.
`In addition, polymer microparticles have long been used for both medical and
`non-medical applications where sustained release of an agent of interest is desired.
`Nevertheless, prior to the present invention, it would have been expected that
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`polymer microparticles in a joint space would scratch the extremely smooth and
`slippery opposed intra articular surfaces or otherwise irritate or inflame the joint.
`Thus, the need for an effective method and formulation for delivering pain relief and
`other pharmaceutical or diagnostic treatments to the intra articular space has remained
`unmet until the present invention. Further, the need for an effective method and
`formulation for delivering pain relief and other pharmaceutical or diagnostic
`treatments to all body spaces has remained unmet until the present invention.
`
`OBJECTS AND SUMMARY OF THE INVENTION
`It is an object of the present invention to provide a biodegradable sustained
`release dosage form for providing prolonged administration of an active agent for the
`treatment and/or diagnosis of joint pain and/or other intra articular conditions in
`humans and animals. More particularly, it is an object of the invention to provide a
`local anesthetic in a biocompatible, biodegradable sustained release form in
`combination with an amount of an augmenting agent effective to enhance and prolong
`local anesthesia in joints and body spaces/cavities.
`It is a further object of the present invention to provide a method for
`prolonging the effect of a local anesthetic agent in joints and/or body spaces/cavities
`and to further provide a prolonged and beneficial antiinflammatory effect.
`It is a further object of the present invention to provide a biocompatible, bio-
`degradable controlled release dosage form for providing prolonged local anesthetic
`treatment of body spaces in humans and animals, with or without other active agents
`described herein.
`In accordance with the above-mentioned objects and others, the invention is
`related to formulations and methods for the localized and prolonged intra articular
`administration of active agents by the intra articular administration of a sustained
`release formulation according to the invention.
`The sustained release formulation preferably comprises any agent suitable for
`the treatment or diagnosis of an intra articular condition.
`The method according to the invention includes, for example, administering
`into an articular joint, a formulation of a biocompatible sustained release material and
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`one or more active agents suitable for the purpose. The active agents can include one
`or more enzymes, anti-infectives, antibodies, and the like, diagnostic agents, as well
`as local anesthetics, local anesthesia augmenting agents and combinations thereof.
`The active agents are preferably a local anesthetic and a non-toxic augmenting
`agent effective to potentiate or prolong the action of the local anesthetic effect. The
`sustained release material is in the form, e.g., of a plurality of microparticles including
`local anesthetic and said microparticles are suspended in a pharmaceutically acceptable
`vehicle for injection.
`The formulation can include a local anesthetic augmenting agent, at least a
`portion of which is optionally incorporated in the sustained release material. In
`addition, at least a portion of the augmenting agent may optionally be in immediate
`release form.
`In one aspect, the sustained release material comprises a polymer such as
`polyanhydrides, copolymers of acid and glycolic acid, poly(lactic) acid, poly(glycolic)
`acid, polyesters, polyorthoesters, proteins, polysaccharides and/or combinations
`thereof. Preferably, the polymers are biodegradable so that manual removal is avoided.
`Alternatively, the polymers are biocompatible and not biodegradable, in those
`circumstances wherein it is desirable to physically remove and/or wash out a local
`anesthetic formulation inserted into a joint space.
`The sustained release formulation can contain any quantity of local anesthetic
`compatible with the selected polymer formulation. Preferably, the local anesthetic is
`incorporated into the sustained release material at a percent loading of 0.1% to 90% by
`weight. Any local anesthetic known to the art may be employed. Preferred local
`anesthetics include bupivacaine, ropivacaine, dibucaine, etidocaine, tetracaine,
`lidocaine, xylocaine, mixtures thereof, and/or salts and derivatives thereof.
`Augmenting agents useful in potentiating pain relief and/or extending the
`
`duration of activity include, for example glucocorticosteroids, alphaxalone,
`allotetrahydrocortisone, aminopyrine, benzamil, clonidine, minoxidil,
`dehydroepiandrosterone, dextran, diazepam, diazoxide, ouabain, digoxin, spantide,
`taxol, tetraethylammonium, valproic acid, vincristine, a catecholamine in sustained
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`release form, 1-[6-[[17-beta-3-methoxyestra-1,3,5(10)-triene-17-yl]amino]hexl]-1-H-
`pyrrole-2,5-dione, and active derivatives, analogs and mixtures thereof.
`Useful glucocorticoid agents include, for example, dexamethasone, cortisone,
`
`prednisone, hydrocortisone, beclomethasone dipropionate, betamethasone,
`flunisolide, methylprednisone, paramethasone, prednisolone, triamcinolone,
`alclometasone, amcinonide, clobetasol, fludrocortisone, diflorasone diacetate,
`fluocinolone acetonide, fluocinonide, fluorometholone, flurandrenolide, halcinonide,
`medrysone.
`One skilled in the art will appreciate that an augmenting agent can be optionally
`included in the extended duration local anesthetic formulation in an amount compatible
`with, e.g., the extended release material and/or in an amount selected to enhance or
`prolong the duration of pain relief to the extent desired. For example, an augmenting
`agent, or combinations of augmenting agents, is incorporated into the formulation
`substrate at a percent loading ranging from about 0.001% to about 30% by weight,
`preferably from about 0.005% to about 15%, by weight.
`The augmenting agent is preferably effective to prolong the duration of local
`anesthesia in a treated joint from about 15% to about 1400% of the duration oflocal
`anesthesia induced by sustained release local anesthetic without the augmenting agent.
`Dextran augmenting agents may have any suitable molecular weight, but
`preferably have a molecular weight ranging from about 20 kDa to about 200 kDa and
`are optionally incorporated into said substrate at a percent loading ranging from about
`0.01% to about 30% by weight.
`In addition, an augmenting agent can include or comprise a vasoconstrictor
`agent in sustained release form. Preferred vasoconstrictor agents include, for example,
`clonidine, guanfacine, guanabenz, dopa, methyldopa, ephedrine, amphetamine,
`methamphetamine, methylphenidate, ethylnorepinephrine, ritalin, pemoline,
`epinephrine, norepinephrine, dopamine, metaraminol, phenylephrine, methoxamine,
`mephentermine, ephedrine, methysergide, ergotamine, ergotoxine, dihydroergotamine,
`sumatriptan and analogs, including active metabolites, derivatives and mixtures of any
`of the foregoing.
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`The invention also provides formulations effective to provide localized pain
`relief when administered into an intra articular space. The formulation includes, for
`example, a local anesthetic incorporated in a sustained release formulation, an effective
`amount of a biocompatible material, and an amount of an augmenting agent effective to
`prolong the duration of the local anesthesia.
`Microparticles according to the invention that are suitable for deposit at a site in '
`a patient in need of local anesthesia can optionally be prepared in lyophilized form, e.g.,
`for rehydration prior to use.
`The formulation, e.g., in the form of lyophilized particles is also desirably
`prepared in unit dosage form that is sterilized and provided in a container including an
`amount of such lyophilized particles sufficient to induce prolonged local anesthesia in
`at least one patient upon suspension in a solution acceptable for deposit into a patient.
`Examples demonstrate prolongation of the duration of local anesthesia with the
`greater prolongation being provided by the combination of a local anesthetic with either
`a glucorticoid or a non-glucocorticoid augmenting agent.
`Preferably, the formulation is in a form suitable for suspension in isotonic
`saline, physiological buffer or other solution acceptable for injection into a patient.
`In certain preferred embodiments of the invention, the local anesthetic is
`prepared in matrices of biodegradable controlled release injectable microspheres.
`Optionally, the augmenting agent is incorporated into these matrices along with the
`local anesthetic.
`In further embodiments, a suspension comprising a plurality ofbiocompatible,
`biodegradable controlled release microspheres comprising a local anesthetic agent,
`together with an augmenting agent is incorporated in the controlled release
`microspheres, or dissolved or suspended in the suspension of microspheres. The
`suspension is, for example, suitable for administering the microspheres by injection.
`In yet additional embodiments of the present invention, the local anesthetic is
`incorporated into a controlled release matrix having the augmenting agent coated on the
`surface thereof.
`In yet additional embodiments of the invention, the formulation comprises a
`local anesthetic core; an augmenting agent present in the core in an amount effective to
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`prolong the effect of the local anesthetic in an environment of use, and a biocompatible,
`biodegradable coating on the core providing a slow release of the local anesthetic
`.and/or augmenting agent in an environment of use.
`In further embodiments, a portion or all of the local anesthetic is incorporated
`onto an outer surface of the coated substrate and a portion or all of the augmenting
`agent is optionally incorporated in the core, so that, e.g., augmenting agent continues to ,
`be released after the local anesthetic has dispersed from the controlled release material.
`The augmenting agent may be systemically administered by injection or
`infiltration, instillation, oral dosing or other method to obtain the desired prolongation
`of effect. Systemic administration, (e.g., oral or intravenous) while effective, will
`require a higher total dose of an augmentation agent than with local administration in
`proximity to the local anesthetic.
`The controlled release local anesthetic dosage form may be injected or
`infiltrated, with or without an augmenting agent, at the site where the anesthetic is to be
`released. This can be prior to surgery, at the time of surgery, or following removal
`(discontinuation) or reversal of a systemic anesthetic.
`In one preferred embodiment, the formulation is prepared in the form of
`microspheres. The microspheres may be prepared as a homogenous matrix of a local
`anesthetic with a biodegradable controlled release material, with the augmenting agent
`optionally incorporated therein. The microspheres are preferably prepared in sizes
`suitable for infiltration and/or injection, and injected at the site where the anesthetic is
`to be released before surgery, during the time of surgery, or following removal or
`reversal of systemic anesthetic.
`Examples of intra articular joints where the formulations useful in the invention
`can be administered include knee, elbow, hip, sternoclavicular, temporomandibular,
`carpal, tarsal, wrist, ankle, and any other joint subject to arthritic conditions; examples
`of bursae where the formulations useful in the invention can be administered include
`acromial, bicipitoradial, cubitoradial, deltoid, infrapetellar, ishchiadica, and other bursa
`known to those skilled in the art to be subject to pain.
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`The formulations of the invention are also suitable for administration in all body
`spaces/cavities, including but limited to pleura, peritoneium, cranium, mediastinum,
`pericardium, bursai, epidural, intrathecal, intraocular, etc.
`The invention is further directed to the use of a formulation comprising (a)
`controlled release microparticles comprising a local anesthetic and an effective amount
`of a biocompatible, biodegradable sustained release material prolonging the release of -
`the local anesthetic from the formulation, and (b) a non-toxic augmenting agent in an
`amount effective to prolong the effect of the local anesthetic in-vivo, to treat localized
`joint pain or pain arising from a body space.
`Preferably, at least a portion of said augmenting agent is incorporated into said
`microparticles.
`The microparticles are preferably suspended in a pharmaceutically acceptable
`vehicle for injection. The formulation may further comprise an active agent selected
`from the group consisting of an enzyme, an anti-infective agent, an antibody, a
`diagnostic aid, a radio-opaque dye, a magnetic resonance imaging dye, a radiolabeled
`agent, and combinations thereof. Preferably, at least a portion of said further active
`agent is incorporated into said microparticles. The local anesthetic is preferably
`incorporated into the microparticles at a percent loading of 0.1 % to 90% by weight.
`In certain preferred embodiments, the local anesthetic is bupivacaine, the augmenting
`agent is dexamethasone, and the sustained release material is a poly(lactide co-
`glycolide). In further preferred embodiments, the microparticles comprise local
`anesthetic in a percent loading between 0.1% and 90%, preferably between 65 and
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`80%, and augmenting agent is a glucocorticosteroid agent present in a weight percent
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`relative to the local anesthetic from 0.005% to 15%.
`The invention further is directed to the use of a formulation comprising (a)
`controlled release microparticles comprising a local anesthetic and an effective amount
`of a biocompatible, biodegradable sustained release polymer selected from
`polyanhydrides, copolymers of lactic acid and glycolic acid, poly(lactic) acid,
`poly(glycolic) acid, polyesters, polyorthoesters, proteins, polysaccharides and
`combinations thereof, providing an in-vitro release of said local anesthetic of from 10
`to 60 percent after 24 hours, from 20 to 80 percent release after 48 hours, and from
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`PCT/US98/14000
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`40 to 100 percent release after 72 hours; and (b) a non-toxic augmenting agent in an
`amount effective to prolong the effect of the local anesthetic in-vivo, for providing
`pain relief a body space selected from pleura, peritoneium, cranium, mediastinum,
`pericardium, bursai, epidural, intrathecal, and intraocular, or from intra articular joints
`selected from knee, elbow, hip, sternoclavicular, temporomandibular, carpal, tarsal,
`wrist, ankle, and any other joint subject to arthritic conditions, or from bursae selected
`from acromial, bicipitoradial, cubitoradial, deltoid, infrapetellar, ishchiadica, and other
`bursa known to those skilled in the art to be subject to pain, and which formulation
`when administered in-vivo for at least about 24 hours, and preferably for 3-5 days.
`The formulation may in certain embodiments preferably comprise a second active
`agent selected from an enzyme, an anti-infective agent, an antibody, a diagnostic aid,
`a radio-opaque dye, a magnetic resonance imaging dye, a radiolabeled agent, and
`combinations thereof.
`
`BRIEF DESCRIPTION OF THE FIGURES
`Figure 1 charts for n=2 test animal, the local concentrations verses time, in
`hours, ofbupivacaine concentrations at an intramuscular site of an injection of extended
`duration local anesthetic ("EDLA"), in the form ofbupivacaine-containing
`microspheres. The local concentrations are determined by microdialiysis conducted at
`the site of injection and calibrated by a perfusion of a known bupivacaine
`concentration. The dotted curve shows local concentrations following release of
`bupivacaine from EDLA and the solid curve shows local concentrations following
`injection ofbupivacaine HCl (1 mg) in immediate release form.
`Figure 2 charts the presence of plasma bupivacaine in each of three test animals
`after the injection ofEDLA in the form ofbupivacaine-containing microspheres.
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`DETAILED DESCRIPTION
`Accordingly, in a surprising and unexpected finding, methods are provided for
`the administration of microparticles in a form suitable for injection and containing one
`or more active agents suitable for treating and/or diagnosing a disease or painful
`condition in one or more articular joints in a patient in need thereof. Thus, the
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`invention provides a safe and effective procedure for the intra articular administration
`of such active agents in sustained release form without causing damage, irritation or
`inflammation to the treated tissue. Prior to the invention, it was believed that the
`microparticles might cause injury and thus be intolerable intra articularly. However, as
`demonstrated herein, the microparticles were adequately tolerated. In further
`embodiments, the microparticles are administered into a body space or cavity.
`Thus, the present invention provides formulations and methods for the safe and
`effective treatment of localized joint conditions by the administration, e.g., by injection,
`infusion or infiltration of extended duration local anesthetic microparticles into an intra
`articular space and/or body space in need of such treatment.
`In a preferred aspect, the invention provides methods for relieving localized
`joint pain and/or inflammation. In this aspect of the invention, the formulations
`according to the invention include an effective amount of a local anesthetic agent and
`preferably an amount of an augmenting agent, e.g., a glucocorticosteroid or
`nonglucocorticoid agent that may be provided in any form suitable for intra articular
`placement, including forms molded for insertion into a joint space, pastes, solutions and
`the like. The augmentation of efficacy provided by the use of the augmenting agent
`cannot be predicted based on in-vitro release (dissolution) of the local anesthetic in
`sustained release form. The inclusion of the augmenting agent within the sustained
`release formulations of the invention does not substantially alter or prolong the in-vitro
`dissolution rate of the local anesthetic agent from the formulation; yet, the same
`formulation when administered in-vivo provides a rapid onset of local anesthesia and a
`significant increase in the time period of local anesthesia