Classifications

• • 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
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/07—Tetrapeptides
• • 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
  • 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
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P23/00—Anaesthetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

• a sustained release composition includes a biocompatible polymeric matrix and a kappa-opioid receptor agonist of formula I:
• the sustained release composition includes biocompatible polymeric matrix of ethylene vinyl acetate (EVA) copolymer.
• EVA polymer matrix is a rod shaped implantable device having a diameter of about 0.5 to about 10 mm, and a length of about 0.5 to 10 cm.
• the composition includes about 10 to about 85% kappa-opioid agonist of the total weight of the composition.
• a method of treating chronic pain in a subject includes administering to said subject in need thereof a sustained release composition comprising a biocompatible polymeric matrix and a kappa-opioid agonist of formula I, wherein the composition includes a therapeutically effective amount of the kappa-opioid agonist.
• the chronic pain is peripheral pain, visceral pain, thermal pain, bone pain, neuropathic pain, chronic low back pain, inflammatory pain, and pain associated with cancer.
• the kappa-opioid agonists of formula I exhibit high peripheral to CNS selectivity, and benefit patients with visceral and neuropathic pain.
• these kappa-opioid agonists of formula I are highly specific for kappa receptors with little or no agonist or antagonist activity to mu or delta receptors. In some embodiments, the kappa- opioid agonists of formula I do not cause CNS-dependent adverse effects. The kappa-opioid agonists of formula I may not cross blood-brain barrier to elicit side effects. BRIEF DESCRIPTION OF THE FIGURES
• FIG. 1 illustrates CR665 structure and various analogs of CR665 prepared by modifying the D-Arg residue at position 4 of CR665.
• FIG. 3 shows dose response (and EC 50 ) activation of kappa receptors by compounds #3, 7, 9, 11 and 17 in the DiscoveRx PathHunterTM Beta-Arrestin platform (95% confidence levels (nM); #3:1.38 to 18.67, #7:5.63 to 13.14, #9:15.34 to 54.48, #11:8.15 to 26.77, #17:47.2 to 166.0; CR665:9.07 to 13.14; Dynorphin:10.14 to 96.62). Individual points are the mean ⁇ SEM of 3-6 separate repeats.
• FIG. 4 shows activation of mu (A) and delta (B) opioid receptors by compounds 3, 7, 9, 11 and 17 in DiscoveRx PathHunterTM Beta-Arrestin platform.
• Lys- dermorphin and DADLE at 200 nM served as positive controls for mu and delta receptors, respectively. Individual points are the mean ⁇ SEM of 3-6 separate repeats. No activation was detected.
• FIG. 5 shows antagonism of mu (A) and delta (B) opioid receptors by compounds 3, 7, 9, 11 and 17 in the DiscoveRx PathHunterTM Beta-Arrestin platform. Naloxone served as a positive control antagonist for both mu and delta receptors whereas lys- dermorphin and DADLE at 200 nM were the control agonists, respectively.
• the mean ⁇ SEM of cells given no additions of agonist and/or antagonists is indicated by the x and error bars next to the words“No add”.
• FIG. 7 shows peripheral selectivity of compound 9.
• FIG.10 shows results of conditioned place preference procedure. JT09 (20 mg/kg, p.o.) had no effect on compartment placement in a conditioned place preference procedure.
• FIG. 11 shows results of a forced swim assay. Immobility time (in seconds) during the last trial of the forced swim test, 30 min after a single dose of JT09 (20 mg/kg, p.o.), salvinorin A (1 mg/kg, i.p.) or saline (2 mL, p.o.). Saline and JT09 were statistically indistinguishable in each trial (Student’s t-test, p ⁇ 0.05).
• FIG. 12 shows results of a locomotor activity test.
• Non-opioid analgesics include paracetamol and the NSAIDs, all of which target prostaglandin formation, usually through the inhibition of the COX-1 and COX-2 enzymes.
• Nonselective COX inhibitors result in adverse side-effects associated with COX-1 inhibition, including renal dysfunction, GI ulceration and inhibition of platelet aggregation.
• Opioids are the main class of analgesics used in the treatment of moderate to severe chronic pain. These compounds have various side effects including nausea, vomiting, constipation, depressed breathing and neurotoxicity. Most significantly, patients can become both addicted and tolerant to these agents, thus requiring dose escalations to maintain therapeutic value.
• opioid analgesic effects occurs through three receptors- mu, kappa, and delta. Activation of these receptors was long thought to occur only centrally, but in recent years, the receptors have been found in peripheral sensory neurons that can be modulated by endogenous opioids or opioid drugs. Opioids also have anti-inflammatory properties, hence they exhibit more pronounced analgesic effects in damaged (inflammatory) versus normal tissues. This appears to be a result of upregulation of the opioid receptors during inflammatory events and release of opioid peptides (endorphins, enkephalins, dynorphins and others) from immune calls.
• opioid peptides endorphins, enkephalins, dynorphins and others
• opioid analgesic effects also results in the upregulation of the opioid receptors, and corresponding greater opioid analgesic effects. Endogenous opioid peptides are released in response to damage of stimulatory neurons and by immune cells in response to inflammation, which is consistent with a regulated response to inflammation and attendant pain. Finally, recent studies suggest that systemically and centrally administered opioids may be acting predominantly (50-80%) as agonists of the peripheral opioid receptors. [0020] Opioids differentially target the three opioid receptors, both in the CNS and peripherally, which can lead to untoward side-effects. Agonists for the mu- receptor are the most currently used opioids, but suffer from induction of euphoria, addiction, respiratory depression, and GI tract inhibition.
• Kappa opioid agonists exhibit none of these effects, and have been shown in visceral pain models to be the most efficacious of the opioids.
• Potentially more promising are peptidic compounds, including FE20041 and FE200665 (CR665), which exhibit very high peripheral versus central activity and have shown benefit in patients with visceral and neuropathic pain, having the same analgesic effects as the early KOAs without the negative side-effects.
• these peptides are not orally active, which drastically restricts its potential use as a broad spectrum analgesic for peripheral pain.
• alkyl means a saturated hydrocarbon group which is straight-chained or branched. Alkyl may be heteroalkyl.
• substituted alkyl refers to an alkyl as just described in which one or more hydrogen atoms attached to carbon of the alkyl is replaced by another group.
• heteroalkyl refers to alkyl groups in which one or more C atoms are replaced by oxygen, nitrogen, sulfur or combinations thereof.
• alkenyl means a straight or branched alkyl group having one or more double carbon-carbon bonds. Alkenyl may be heteroalkenyl.
• substituted alkenyl refers to an alkenyl as just described in which one or more hydrogen atoms attached to carbon of the alkenyl is replaced by another group.
• heteroalkenyl refers to alkenyl groups in which one or more C atoms are replaced by oxygen, nitrogen, sulfur or combinations thereof.
• alkynyl means a straight or branched alkyl group having one or more triple carbon-carbon bonds. Alkynyl may be heteroalkynyl.
• substituted alkynyl refers to an alkynyl as just described in which one or more hydrogen atoms attached to carbon of the alkynyl is replaced by another group.
• heteroalkynyl refers to alkynyl groups in which one or more C atoms are replaced by oxygen, nitrogen, sulfur or combinations thereof.
• aryl means a monocyclic, bicyclic, or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons.
• aryl groups have from 6 to 20 carbon atoms or from 6 to 10 carbon atoms.
• Examples of aryl groups include, but are not limited to, phenyl, biphenyl, benzyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthyl, and the like.
• Aryl may be heteroaryl.
• the term“substituted aryl” refers to aryl as just described in which one or more hydrogen atoms attached to any carbon atoms is replaced by one or more functional groups.
• the term “heteroaryl” means an aromatic heterocycle having up to 20 ring-forming atoms (e.g., C) and having at least one heteroatom ring member (ring-forming atom) such as sulfur, oxygen, or nitrogen.
• the heteroaryl group has at least one or more heteroatom ring- forming atoms, each of which are, independently, sulfur, oxygen, or nitrogen.
• the term“arylalkyl” means a C 1-6 alkyl substituted by aryl.
• the term“heterocyclic ring” means a 5- to 7- membered mono- or bicyclic or 7- to 10-membered bicyclic heterocyclic ring system any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms chosen from N, O and S, and wherein the N and S heteroatoms may optionally be oxidized, and the N heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
• A“therapeutically effective amount” or“effective amount” of a composition is a predetermined amount calculated to achieve the desired effect, i.e., to supplement, promote, or increase nutritional health.
• the activity contemplated by the present methods includes both therapeutic and/or prophylactic treatment, as appropriate.
• the specific dose of a compound administered according to this invention to obtain therapeutic and/or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, and the condition being treated.
• the effective amount administered may be determined by a physician in the light of the relevant circumstances including the condition to be treated, the choice of compound to be administered, and the chosen route of administration.
• a therapeutically effective amount of compound of this invention is typically an amount such that when it is administered in a physiologically tolerable excipient composition, it is sufficient to achieve an effective systemic concentration or local concentration in the target tissue.
• pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• the term“consists of” or“consisting of” means that the device or method includes only the elements, steps, or ingredients specifically recited in the particular claimed embodiment or claim.
• CR665 is a D-amino acid containing tetrapeptide (D-Phe-D-Phe-D- Nle-D-Arg-NH-4-Picolyl) having the following structure:
• these k appa-opio id agonis ts of form ula I are highly specifi c for kapp a receptor s with litt le or no ag onist or a ntagonist activity to mu or delta re ceptors.
• the kapp a-opioid a gonists of formula I do not cause C NS-depen dent adve rse effect s.
• the kap pa-opioid agonists of formula I may not cro ss blood -brain bar rier to el icit side effects.
• the modifi ed analog s of CR 65 discl osed here in are p art of s ustained release compo sitions.
• the modif ied analog s of CR65 disclosed herein are ora lly-active compound s.
• the kap pa-opioid agonist is of formula I:
• R of formula I is represented by formula II or formula III as follows:
• n is an integer from 1 to 4.
• X may be–NR 2 R 3 or–N R 2 R 3 R 4 ;
• R 1 , R 2 , R 3 , R 4 are independently, hydrogen, C 1 -C 5 alkyl, C 1 -C 5 substituted alkyl, C 1 -C 5 alkenyl, C 1 -C 5 substituted alkenyl, C 1 -C 5 alkynyl, C 1 -C 5 substituted alkynyl, cycloalkyl, aryl, substituted aryl, or arylalkyl;
• R 7 may be hydrogen, C 1 -C 5 alkyl, C 1 -C 5 substituted alkyl, C 1 -C 5 alkenyl, C 1 - C 5 substituted alkenyl, C 1 -C 5 alkynyl, C 1 -C 5 substituted alkynyl, cycloalkyl, aryl, substituted aryl, arylalkyl, or–NR 8 R 9 ;
• R 5 , R 6 , R 8 , R 9 are independently, hydrogen, C 1 -C 5 alkyl, C 1 -C 5 substituted alkyl, C 1 -C 5 alkenyl, C 1 -C 5 substituted alkenyl, C 1 -C 5 alkynyl, C 1 -C 5 substituted alkynyl, cycloalkyl, aryl, substituted aryl, or arylalkyl;
• R 5 and R 9 taken together with the nitrogen atom to which they are attached form a heterocyclic ring
• R 6 and R 9 taken together with the nitrogen atom to which they are attached form a heterocyclic ring.
• Non-limiting embodiments of formula II include:
• non-limiting examples of formula III include:
• R 5 and R 9 taken together with the nitrogen atom to which they are attached form a heterocyclic ring as follows:
• R 6 and R 9 taken together with the nitrogen atom to which they are attached form a heterocyclic ring as follows:
• the stereochemistry at C ⁇ and C ⁇ C-atoms of the R group in formula I is independently, either R or S.
• Non-limiting embodiments of formula III are:
• Non-limiting embodiments of formula II are:
• kappa-opioid agonist of formula I may have the following substitutions at each of, independently, R 1 , R 2 , R 3 , and R 4 , as shown in Table 1.
• kappa-opioid agonist of formula I may have the following substitutions at each of, independently, R 5 , R 6 , R 7 , R 8 , and R 9 , as shown in Table 2.
• kappa- opioid agonists include kappa-opioid agonists of formula I and other kappa-opioid agonists known in the art unless otherwise indicated.
• Sustained (or controlled) release refers to the gradual release of kappa-opioid agonist from the composition over a period of time. While there may be an initial burst phase, in some embodiments, it is preferred that the release display relatively linear kinetics, thereby providing a constant supply of the kappa-opioid agonist over the release period.
• the release period may vary from several hours to several months, depending upon the kappa-opioid agonist and its intended use. It is desirable that the release of the kappa-opioid agonist from the composition over the treatment period be relatively constant.
• the duration of the release period may be controlled by, inter alia, the composition of the biocompatible polymer matrix, the concentration of the kappa- opioid agonist, the locus of administration, and, addition of release profile modifying agents.
• EVA ethylene vinyl acetate copolymer
• other nonerodible materials may be used.
• Examples of other suitable materials include silicone, hydrogels such as crosslinked poly(vinyl alcohol) and poly(hydroxy ethylmethacrylate), acyl substituted cellulose acetates and alkyl derivatives thereof, partially and completely hydrolyzed alkylene- vinyl acetate copolymers, unplasticized polyvinyl chloride, crosslinked homo- and copolymers of polyvinyl acetate, crosslinked polyesters of acrylic acid and/or methacrylic acid, polyvinyl alkyl ethers, polyvinyl fluoride, polycarbonate, polyurethane, polyamide, polysulphones, styrene acrylonitrile copolymers, crosslinked poly(ethylene oxide), poly(alkylenes), poly(vinyl imidazole), poly(esters), poly(ethylene terephthalate), polyphosphazenes, and chlorosulphonated polyolefines, and combinations thereof.
• silicone such as crosslinked poly(vinyl alcohol) and poly(hydroxy
• PLA poly- lactides
• PGA poly-glycolides
• PBS polybutylene succinate
• PHA polyhydroxyalkanoate
• PCL polycaprolactone acid lactone
• PHB polyhydroxybutyrate
• PHB glycolic amyl
• PHB PHB and PHV copolymer
• PEG poly lactic acid
• PEG polyethylene glycol
• the sustained release composition may contain a polymer matrix and about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, or about 80% to about 85% of kappa-opioid agonist by weight of the total composition.
• the sustained release compositions may contain one or more kappa-opioid agonists of formula I.
• the ratio of the polymer matrix to the kappa- opioid agonist may be from about 0.001:1 weight % to about 9:1 weight %, about 0.001:1 weight % to about 5:1 weight %, or about 0.001:1 weight % to about 0.05:1 weight %. Specific examples include about 0.001:1 weight %, about 0.005:1 weight %, about 0.01:1 weight %, about 0.05:1 weight %, about 0.1:1 weight %, about 0.5:1 weight %, about 1:1 weight %, about 2:1 weight %, about 3:1 weight %, about 4:1 weight %, about 9:1 weight %, and ranges between any of the two values.
• the sustained release compositions may be implantable (e.g., an implantable device).
• the sustained release composition be in the form of tablets, rod-shaped structures, or cylindrical structures, and may be produced using an extrusion process, wherein ground EVA is blended with kappa-opioid agonist, melted, and extruded into rod-shaped structures. Rods are cut into individual implantable devices of the desired length, packaged, and sterilized prior to use. Other methods for encapsulating therapeutic compounds in implantable polymeric, nonerodible sustained release matrices are well known to those of skill in the art.
• EVA implantable devices are about 0.5 cm to about 10 cm, about 1.5 cm to about 5 cm, about 2 cm to about 6 cm, or about 2 cm to about 3 cm in length. EVA implantable devices are about 0.5 mm to about 10 mm, about 1.5 mm to about 5 mm, or about 2 mm to about 3 mm in diameter. [0060] Once the kappa-opioid agonist of formula I begins to release from the composition, the release process may continue for additional time period (sustained release period).
• sustained release period may be for about 1 week to about 1 month, about 1 week to about 3 months, about 1 week to about 6 months, about 1 week to about 9 months, about 1 week to about 12 months, about 1 week to about 15 months, about 1 week to about 18 months, or about 1 week to about 24 months.
• drug delivery proceeds at a near constant rate. For example, for a period of about 1 week to 7 weeks, about 2% of drug within the composition may be released. In other embodiments, for a period of about 1 week to 10 weeks, about 3% of drug will be released. In additional embodiments, for a period of about 1 week to 15 weeks, about 4% of drug will be released.
• the release rate may also be modified by changing the vinyl acetate content in the EVA polymer matrix.
• the vinyl acetate content is often about 2% to about 50%, more often about 10% to about 35%, most often about 30% to about 35% by weight of the copolymer. In one embodiment, the vinyl acetate content is about 33% by weight of the copolymer.
• the sustained release compositions disclosed herein may further contain a hydrogel.
• Non- limiting examples of hydrogels include methyl cellulose (MC), ethyl cellulose (EC), ethyl methyl cellulose (EMC), hydroxyethyl cellulose (HEC), hydroxylpropyl cellulose (HPC), hydroxymethyl cellulose (HMC), hydroxypropylmethyl cellulose (HPMC), ethylhydroxyethyl cellulose (EHEC), hydroxyethylmethy cellulose (HEMC), methylhydroxyethyl cellulose (MHEC), methylhydroxypropylcellulose (MHPC), and hydroxyethylcarboxymethyl cellulose (HECMC).
• MC methyl cellulose
• EMC ethyl cellulose
• EMC hydroxyethyl cellulose
• HPC hydroxylpropyl cellulose
• HPMC hydroxymethyl cellulose
• EHEC hydroxyethylmethy cellulose
• MHEC methylhydroxyethyl cellulose
• MHPC methylhydroxypropylcellulose
• the sustained release compositions can be in forms which include, but are not limited to, softgels, tablets, capsules, cachets, pellets, pills, powders and granules.
• Topical dosage forms include, but are not limited to, solutions, powders, fluid emulsions, fluid suspensions, semi-solids, ointments, pastes, creams, gels and jellies, and foams.
• Parenteral dosage forms include, but are not limited to, solutions, suspensions, emulsions, and dry powder.
• Formulations can also be in the form of films, pads, wafers, injectables, hydrogels, and the like.
• the sustained release compositions may be in the form of a drug reservoir such as injectable microparticles, passive transdermal/transmucosal drug delivery or electrotransport drug delivery systems.
• a drug reservoir such as injectable microparticles, passive transdermal/transmucosal drug delivery or electrotransport drug delivery systems.
• inventive formulations described herein can be combined with suitable carriers to prepare alternative drug dosage forms (e.g., oral capsule, topical ointment, rectal and/or vaginal suppositories, buccal patches, or an aerosol spray).
• the sustained release compositions may further comprise pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like.
• pharmaceutically acceptable diluents fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like.
• Sustained release compositions disclosed herein can comprise suitable solid or gel phase carriers or excipients.
• suitable solid or gel phase carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as, e.g., polyethylene glycols.
• the pharmaceutical excipient may include, without limitation, binders, coating, disintegrants, fillers, diluents, flavors, colors, lubricants, glidants, preservatives, sorbents, sweeteners, conjugated linoleic acid (CLA), gelatin, beeswax, purified water, glycerol, any type of oil, including, without limitation, fish oil or soybean oil, or the like.
• CLA conjugated linoleic acid
• gelatin beeswax
• purified water glycerol
• any type of oil including, without limitation, fish oil or soybean oil, or the like.
• the compositions may include one or more disintegrant component, such as croscarmellose sodium, carmellose calcium, crospovidone, alginic acid, sodium alginate, potassium alginate, calcium alginate, an ion exchange resin, an effervescent system based on food acids and an alkaline carbonate component, clay, talc, starch, pregelatinized starch, sodium starch glycolate, cellulose floc, carboxymethylcellulose, hydroxypropylcellulose, calcium silicate, a metal carbonate, sodium bicarbonate, calcium citrate, or calcium phosphate.
• disintegrant component such as croscarmellose sodium, carmellose calcium, crospovidone, alginic acid, sodium alginate, potassium alginate, calcium alginate, an ion exchange resin, an effervescent system based on food acids and an alkaline carbonate component, clay, talc, starch, pregelatinized starch, sodium starch glycolate, cellulose floc, carboxymethylcellulose
• the compositions may include one or more diluent component, such as mannitol, lactose, sucrose, maltodextrin, sorbitol, xylitol, powdered cellulose, microcrystalline cellulose, carboxymethyl-cellulose, carboxyethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, starch, sodium starch glycolate, pregelatinized starch, a calcium phosphate, a metal carbonate, a metal oxide, or a metal aluminosilicate.
• diluent component such as mannitol, lactose, sucrose, maltodextrin, sorbitol, xylitol, powdered cellulose, microcrystalline cellulose, carboxymethyl-cellulose, carboxyethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, starch, sodium starch glyco
• the compositions may include one or more optional lubricant component, such as stearic acid, metallic stearate, sodium stearyl fumarate, fatty acid, fatty alcohol, fatty acid ester, glyceryl behenate, mineral oil, vegetable oil, paraffin, leucine, silica, silicic acid, talc, propylene glycol fatty acid ester, polyethoxylated castor oil, polyethylene glycol, polypropylene glycol, polyalkylene glycol, polyoxyethylene-glycerol fatty ester, polyoxyethylene fatty alcohol ether, polyethoxylated sterol, polyethoxylated castor oil, polyethoxylated vegetable oil, or sodium chloride.
• optional lubricant component such as stearic acid, metallic stearate, sodium stearyl fumarate, fatty acid, fatty alcohol, fatty acid ester, glyceryl behenate, mineral oil, vegetable oil, paraffin, leucine, silica,
• a method to treat chronic pain in a subject involves administering a sustained release composition comprising a kappa-opioid agonist of formula I, wherein the sustained release composition releases a therapeutically effective amount of the kappa opioid agonist over a sustained period of time.
• the chronic pain may be peripheral pain, visceral pain, thermal, bone, and neuropathic pain, and pain associated with cancer.
• chronic pain examples include pain related to psychosis, stroke, fibromyalgia, irritable bowel syndrome, chronic arthropathy, inflammatory pain, post herpetic neuralgia, trigeminal neuralgia, migraine, chronic low back pain, refractory angina pectoris (chest pains), interstitial cystitis (inflammation around bladder) and other visceral pains.
• the kappa-opioid agonists of formula I exhibit high peripheral to CNS selectivity, and benefit patients with visceral and neuropathic pain.
• the kappa-opioid agonists of formula I are highly specific for kappa receptors with little or no agonist or antagonist activity to mu or delta receptors. In some embodiments, the kappa-opioid agonists of formula I do not cause CNS-dependent adverse effects.
• the term“subject” includes animals which can be treated using the methods of the invention. Examples of animals include mammals, such as mice, rabbits, rats, horses, goats, dogs, cats, pigs, cattle, sheep, and primates (e.g. chimpanzees, gorillas, and, preferably, humans).
• one or more anti-inflammatory agents are coadministered along with kappa-opioid agonist of formula I.
• the anti-inflammatory agent may be encapsulated within the same polymeric matrix as kappa-opioid agonist or in a separate polymeric matrix that does not contain kappa-opioid agonist, or may be administered via a different route, such as orally or via injection, either simultaneously with administration of the kappa-opioid agonist-containing sustained release compositions or at a different time, or on a different schedule such as for example multiple dosing of an oral or injectable formulation.
• the anti-inflammatory agent may be a steroid, a NSAID, and/or an antihistamine.
• an antioxidant is incorporated into the kappa- opioid agonist-containing polymeric matrix and is coadministered along with kappa- opioid agonist.
• agents that may be included in the polymeric matrix are dexamethasone, triamcinolone, betamethasone, clobetasol, cortisone, hydrocortisone, or a pharmaceutically acceptable salt thereof, or a nonsteroidal anti-inflammatory agent (“NSAID”), examples of which include but are not limited to diclofenac potassium diclofenac sodium, diclofenac sodium with misoprostol, diflunisal, etodolac, fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate sodium, mefenamic acid, meloxicam, nabumetone, naproxen, naproxen sodium, oxaprozin, piroxicam, sulindac, tolmetin, COX-2 inhibitors (e.g., celecoxib, rofecoxib, valdecoxib), acetylated salicy
• the methods of the invention include administration of another substance in conjunction with administration of kappa- opioid agonist sustained release composition.
• Such substances include, but are not limited to, levodopa, dopamine agonists, catechol-O-methyltranserase inhibitors, or monoamine oxidase inhibitors, administered orally or intravenously.
• the method includes administering the sustained release composition as an adjuvant therapy.
• the method includes administering the sustained release composition as a neo-adjuvant therapy.
• the sustained release composition can be administered with other treatments, such as radiation therapy, chemotherapy, targeted therapy, gene therapy, or hormone therapy.
• the sustained release compositions can be used in combination with other agents that are administered systemically.
• the sustained release compositions may be administered in combination with one or more anticancer agents which include tamoxifen, toremifen, raloxifene, droloxifene, iodoxyfene, megestrol acetate, anasfrozole, letrazole, borazole, exemestane, flutamide, nilutamide, bicalutamide, cyproterone acetate, goserelin acetate, luprolide, finasteride, herceptin, methotrexate, 5-fluorouracil, cytosine arabinoside, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mithramycin, cisplatin, carboplatin, melphalan, chloram
• the sustained release compositions may be administered in combination with one or more cytokines which include, without limitation, a lymphokine, tumor necrosis factors, tumor necrosis factor-like cytokine, lymphotoxin, interferon, macrophage inflammatory protein, granulocyte monocyte colony stimulating factor, interleukins including, without limitation, interleukin-1, interleukin-2, interleukin-6, interleukin-12, interleukin-15, and interleukin-18.
• cytokines include, without limitation, a lymphokine, tumor necrosis factors, tumor necrosis factor-like cytokine, lymphotoxin, interferon, macrophage inflammatory protein, granulocyte monocyte colony stimulating factor, interleukins including, without limitation, interleukin-1, interleukin-2, interleukin-6, interleukin-12, interleukin-15, and interleukin-18.
• the amount of compounds to be administered is that amount which is therapeutically effective.
• the dosage to be administered will depend on the characteristics of the subject being treated, e.g., the particular animal or human being treated, age, weight, health, types of concurrent treatment, if any, and frequency of treatments, and can be easily determined by one of skill in the art (e.g., by the clinician).
• the dimensions of the sustained release compositions commensurate with the size and shape of the region selected as the site of administration and will not migrate from the insertion site following implantation, injection or other means of depot administration.
• the sustained release compositions may be rigid, or somewhat flexible so as to facilitate both insertion of the implant at the target site and accommodation of the implant.
• the sustained release compositions may be particles, sheets, patches, plaques, fibers, microcapsules and the like and may be of any size or shape compatible with the selected site of insertion.
• the sustained release composition may be administered by a catheter.
• the sustained release composition may be administered by a syringe.
• the sustained release composition is formulated so that the composition can be readily implanted (e.g., by injection) into the desired location to form a mass that can remain in place for the period suitable for controlled release of the kappa-opioid agonist and for any additional benefit of mechanical support if applicable.
• the mechanical and rheological properties suitable for injectable depot compositions are known in the art.
• an alternative embodiment of the invention provides for a rod depot implant.
• Other embodiments include a drug depot implant comprising a hollow depot, the hollow depot comprising a therapeutic agent that provides a concentration gradient for targeted delivery of the agent to the synovial joint, the disc space, the spinal canal, or the soft tissue surrounding the spinal canal of a subject.
• the sustained release composition is directly administered to the area of the chronic pain by, for example, local infusion during surgery, topical application (e.g., in conjunction with a wound dressing after surgery), injection, means of a catheter, means of a suppository, or means of an implant.
• An implant can be of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers. Suppositories generally contain active ingredients in the range of 0.5% to 10% by weight.
• a controlled release system can be placed in proximity of the pain.
• a micropump may deliver controlled doses directly into the area of the pain, thereby finely regulating the timing and concentration of the pharmaceutical composition.
• the kappa-opioid agonists disclosed herein may not be part of sustained release compositions.
• the kappa-opioid agonists may be in compositions that can be administered systemic, parenteral, topical, or oral.
• administration can be, but is not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, buccal, ocular routes, or intravaginally, by inhalation, by depot injections, or by implants.
• administration can be at the site of tumor resection.
• modes of administration of the composition of the present invention can be, but are not limited to, sublingual, injectable (including short-acting, depot, implant and pellet forms injected subcutaneously or intramuscularly), or by use of vaginal creams, suppositories, pessaries, vaginal rings, rectal suppositories, intrauterine devices, and transdermal forms such as patches and creams.
• the pharmaceutical composition can be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
• compositions for oral use can be obtained by adding a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
• suitable excipients include, but are not limited to, fillers such as sugars, including, but not limited to, lactose, sucrose, mannitol, and sorbitol; cellulose preparations such as, but not limited to, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and polyvinyl-pyrrolidone (PVP).
• fillers such as sugars, including, but not limited to, lactose, sucrose, mannitol, and sorbitol
• cellulose preparations such as, but not limited to, maize starch, wheat starch, rice starch, potato starch, gelatin, gum trag
• disintegrating agents can be added, such as, but not limited to, the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
• the hydrogel formulation is preferably encapsulated by a retardant coating, e.g., a bioerodible polymer. Upon dissolution or erosion of the encapsulating material, the hydrogel core becomes exposed and the drug contained within the gel can be released for enteric adsorption.
• a retardant coating e.g., a bioerodible polymer.
• Bioerodible coating materials may be selected from a variety of natural and synthetic polymers, depending on the agent to be coated and the desired release characteristics.
• Exemplary coating materials include gelatins, carnauba wax, shellacs, ethylcellulose, cellulose acetate phthalate or cellulose acetate butyrate. Release of the agent is controlled by adjusting the thickness and dissolution rate of the polymeric coat.
• Dragee cores can be provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active doses.
• compositions which can be used orally include, but are not limited to, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
• the push-fit capsules can contain the active ingredients in admixture with filler such as, e.g., lactose, binders such as, e.g., starches, and/or lubricants such as, e.g., talc or magnesium stearate and, optionally, stabilizers.
• the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
• stabilizers can be added.
• compositions for oral administration should be in dosages suitable for such administration.
• the compositions can take the form of, e.g., tablets or lozenges formulated in a conventional manner.
• compositions for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
• a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
• a pressurized aerosol the dosage unit can be determined by providing a valve to deliver a metered amount.
• Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
• the compositions of the present invention can also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
• the compositions of the present invention can also be formulated as a depot preparation. Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
• the compositions of the present invention can be applied to a plaster, or can be applied by transdermal, therapeutic systems that are consequently supplied to the organism.
• Packs and Kits [0093]
• the sustained release compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
• the pack may for example comprise metal or plastic foil, such as a blister pack.
• the pack or dispenser device may be accompanied by instructions for administration.
• the invention also provides kits for carrying out the therapeutic regimens of the invention. Such kits comprise in one or more containers having therapeutically or prophylactically effective amounts of the sustained release compositions in pharmaceutically acceptable form.
• the sustained release compositions in a vial of a kit of the invention may be in the form of a pharmaceutically acceptable solution, e.g., in combination with sterile saline, dextrose solution, or buffered solution, or other pharmaceutically acceptable sterile fluid.
• the complex may be lyophilized or desiccated; in this instance, the kit optionally further comprises in a container a pharmaceutically acceptable solution (e.g., saline, dextrose solution, etc.), preferably sterile, to reconstitute the complex to form a solution for injection purposes.
• a kit of the invention further comprises a needle or syringe, preferably packaged in sterile form, for injecting the complex, and/or a packaged alcohol pad. Instructions are optionally included for administration of sustained release compositions by a clinician or by the patient.
• the kit may contain at least one implantable, nonerodible device of the type herein described, capable of delivering long-term therapeutic levels of kappa-opioid agonist, in suitable packaging, along with instructions providing information to the user and/or health care provider regarding subcutaneous implantation and use of the system for treating a condition for which kappa-opioid agonist administration is therapeutically beneficial.
• the effective dose of the kappa-opioid agonist that is released from the sustained release compositions may range from about 0.1 to 3000, 0.2 to 900, 0.3 to 800, 0.4 to 700, 0.5 to 600, 0.6 to 500, 70 to 400, 80 to 300, 90 to 200, or 100 to 150 micrograms/day.
• the dose may range from approximately 10 to 20, 21 to 40, 41 to 80, 81 to 100, 101 to 130, 131 to 150, 151 to 200, 201 to 280, 281 to 350, 351 to 500, 501 to 1000, 1001 to 2000, or 2001 to 3000 nanograms/day.
• the dose may be at least approximately 20, 40, 80, 130, 200, 280, 400, 500, 750, 1000, 2000, or 3000 micrograms/dose.
• the dose may be at least approximately 20, 40, 80, 130, 200, 280, 400, 500, 750, 1000, 2000, or 3000 nanograms/dose.
• the effective dose of the kappa-opioid agonist that is released results in a plasma concentration of approximately 0.1, 1, 2.5, 5, 7.5, 10, 15, 20, 30, 40, or 50 micrograms/liter.
• the effective dose of the kappa-opioid agonist that is released results in a plasma concentration of approximately 0.1, 1, 2.5, 5, 7.5, 10, 15, 20, 30, 40, or 50 nanograms/liter.
• the resulting circulating concentration of the kappa-opioid agonist is approximately 0.1 to 50, 1 to 40, 2.5 to 30, 5 to 20, or 7.5 to l0 micrograms/liter.
• the resulting circulating concentration of the kappa-opioid agonist is approximately 0.1 to 50, 1 to 40, 2.5 to 30, 5 to 20, or 7.5 to l0 nanograms/liter. In other embodiments, the resulting circulating concentration of the kappa-opioid agonist is approximately 0.1 to 1, 1.1 to 2.4, 2.5 to 5, 5.1 to 7.4, 7.5 to 10, 11 to 15, 16 to 20, 21 to 30, 31 to 40, or 41 to 50 micrograms/liter.
• the resulting circulating concentration of the kappa-opioid agonist is approximately 0.1 to 1, 1.1 to 2.4, 2.5 to 5, 5.1 to 7.4, 7.5 to 10, 11 to 15, 16 to 20, 21 to 30, 31 to 40, or 41 to 50 nanograms/liter.
• an implantable device of the invention may release kappa-opioid agonist of formula I in vitro or in vivo at a rate of about 0.01 to about 10 mg/day, about 0.1 to about 10 mg/day, about 0.25 to about 5 mg/day, or about 1 to about 3 mg/day in vitro or in vivo.
• an implantable device of the invention may release kappa-opioid agonist continuously in vivo at a rate that results in a plasma level of at least about 0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 5, or 10 ng/ml of the agonist in the subject.
• Hotplate Model evaluates central pain attenuation in a rodent after applying an acute thermal stimuli.
• the rat is treated with compound and assessed over time on a hotplate analgesia meter (Columbus Instruments, Columbus, OH), essentially a flat surface maintained at 53.0+/-0.2 o C.
• %MPE percent of maximal possible effect
• PathHunterTM Beta-Arrestin GPCR Functional Profiling and Screening cell lines that express the individual opioid receptors were obtained from DiscoveRx (Fremont, CA). These cells express the kappa (or mu or delta) opioid receptor fused to a proprietary ⁇ -galactosidase enzyme fragment and the ⁇ -arrestin gene fused to an enzyme acceptor (the remaining fragment of ⁇ -galactosidase). Upon activation of the receptor, ⁇ -arrestin is recruited to the GPCR and the ⁇ -galactosidase is activated through enzyme complementation. Cells were grown using standard cell culture techniques and then plated at 30,000 cells/well in 90 ⁇ l in a 96 well white, clear bottom plate and incubated overnight.
• Dilutions were prepared in dilution buffer (HBBS, 20 mMHepes, 0.1%BSA) and 10 ⁇ l added per well. Plates were then incubated for 90 min at 37oC in a water-saturated atmosphere. Plates were then allowed to come to room temp and DiscoveRx‘s proprietary developing agent added as recommended by the manufacturer. This agent contains a detergent, 6-O- ⁇ -galactopyranosyl-luciferen and luciferase. Plates were then incubated for 1 hr at room temperature before being read on a luminometer. Antagonist studies were performed in an identical manner except after the overnight incubation 10 ⁇ l media was removed and replaced with drug or naloxone at the indicated concentration.
• Fig. (1) illustrates the series of KOA peptide derivatives that were synthesized and evaluated. All feature modifications to the Position 4 D-Arg residue, and were chosen to provide a range of structures to initially probe potential structure-activity relationships (SARs) at this position.
• mice were orally gavaged with each test compound (20 mg/kg) and rested for 20 min before receiving an i.p. (intraperitoneal) injection with 2 ml/kg of 3% acetic acid.
• Control rats were given an i.p. injection of morphine (10 mg/kg) and rested for 20 min before receiving an i.p. injection with 2 ml/kg of 3% acetic acid.
• animals were rested for an additional 10 min before being placed in a 10 x 10 inch Plexiglas chamber.
• a video of each rat was then recorded for next 20 min. The video was subsequently scored blindly by an investigator who examined each rat every 20 sec for the entire 20 min (60 individual observations).
• Hot Plate Model evaluates central pain attenuation in a rodent after applying an acute thermal stimuli. Experimental rats were orally gavaged with lead compounds JT07 or JT09 (20 mg/kg) and rested for 20 min prior to being placed on the hotplate. Control rats received i.p.
• %MPE percent of maximal possible effect
• each chamber was equipped with a balanced metal arm and spring leash attached to a swivel (Instech). Tygon® tubing extended through the leash and was connected to a 10 ml syringe mounted on an infusion pump located outside the sound-attenuating cubicle. Rats were anesthetized with i.p.
• Ketorolac 2.0 mg/kg, i.p. Sigma, St. Louis, MO, USA was given just prior to surgery as an analgesic.
• a response on the active lever resulted in activation of the pump for a 2-s infusion (50 ⁇ l bolus infusion) and presentation of a stimulus complex consisting of a 5-s tone (78 dB, 4.5 kHz) and a white stimulus light over the active lever, followed by a 20-s time out.
• Responses occurring during the time out and on the inactive lever were recorded, but had no scheduled consequences.
• Rats were trained initially to press a lever for a sucrose pellet (45mg) in a single 6 hr session. The following day, a response on the lever no longer resulted in sucrose reward, but instead produced an IV infusion of JT09 (20 mg/kg/inf).
• JT09 was replaced with cocaine (50ug/50ul bolus infusion) and the lever replaced with a nose poke aperture.
• Cocaine was chosen for comparison purposes because it is readily self- administered.
• Conditioned Place Preference To test whether JT09 was able to condition appetitive behaviors, we used a conditioned place procedure. On day one, rats were habituated to a three-compartment apparatus for 10 min. One compartment was black with a grid floor and the other white with a rod floor. A smaller center compartment was gray with a solid floor. The amount of time spent in each compartment was recorded. The side in which the rats spent the least amount of time on habituation day was paired with JT09, in that rats receive the compound via oral gavage immediately before compartment placement.
• Rats On alternating days, rats were treated with saline and confined in the opposite compartment. Rats were confined to each compartment for 25 minutes. Test rats were orally gavaged with saline and given access to the entire apparatus for 10 minutes. The amount of time spent in each compartment was recorded.
• Forced Swim Assay The most common reason for discontinuing development of kappa agonists is the induction of dysphoria, which is mediated through CNS kappa receptors. To test for this side effect, we used an established model: the repeated forced swim assay. Rats were placed in a container with 30°C water without an escape avenue. Time spent immobile during the last 4 min of each trial was recorded.
• Immobility was defined by a posture in which the forelimbs were motionless in front of the body, hind legs display limited motion, and the tail is directed outward. On day one, rats were placed in the water for 15 min. On the following day, placements consisted of four trials lasting 6 min each, separated by 10 mins. Salvorin A (1 mg/kg, i.p.) or JT09 (20 mg/kg, p.o.) were administered immediately before the first placement. Time spent immobile is a diagnostic of dysphoria and typically increases with each trial. Salvinorin A (a centrally available kappa agonist) was used as a positive control due to its known anti-depressant-like effects such as dysphoria. [0120] Locomotor Open Field Test.
• the MTD is a dose that does not produce mortality, a loss of more than 10% body weight, or overt signs of toxicity.
• Six rats were included at each dose level (50, 70, and 90 mg/kg, p.o.). The animals were observed twice daily; body weights and detailed clinical observations for behavioral toxicity (porphyrin staining, changes in activity levels, changes in grooming habits, convulsions, catalepsy, muscular rigidity, and excessive vocalization) were made daily for 4 days after dosing at each level. Doses were chosen based on the compound’s ED 50 for analgesic potency. [0122] Multiple Dose Study. Rats were be orally treated with JT09 daily at its ED90 (30 mg/kg) for 14 consecutive days.
• Rats were administered the various compounds by oral gavage at a screening dose of 20 mg/kg 20 min before i.p. injection with 2 ml/kg of 3% acetic acid. Ten minutes later, animals were assessed for writhing as described in the methods section. As shown in Figure 8, several of the JT Pharma compounds (JT07, JT09, and JT22) were able to significantly block outward physical signs of peripheral pain in this model. Thus, several of the Arg modifications can impart CR665 with the ability to cross the gut barrier.
• JT07 and JT09 were statistically significantly different from saline when assessing the percentage of time writhing (Student’s t-test, p ⁇ 0.05), and were indistinguishable in potency when compared to morphine (Student’s t-test, p ⁇ 0.05). JT07 and JT09 were selected for further analysis. [0125] Screening of CNS-Mediated Pain in KOAs. As an initial screen for analgesic activity, JT07 and JT09 were evaluated in the hotplate analgesic model using a standard oral dose of 20 mg/kg. Percent maximum possible effect was analyzed for each compound and compared to morphine (10 mg/kg, i.p.).
• JT07 and JT09 did not show analgesic activity and were significantly different from morphine (Student’s t-test, p ⁇ 0.05).
• the maximum tolerated dose is used to determine the highest dose of JT09 that can be administered without promoting unacceptable side-effects.
• JT09 binds potently to activate the kappa-opioid receptor with an EC50 of 29.9 nM, while having an agonist selectivity for kappa- over both mu- and delta-opioid receptors of minimally >33,400 and likely much greater. Most importantly, JT09 exhibits oral activity at a sufficiently potent EC 50 of 4.7 mg/kg, while having a peripheral versus central selectivity of at least 900-fold.
• JT09 and morphine exhibit comparable analgesic activity in the acetic acid-induced writhing model for peripheral pain.
• morphine was a potent analgesic, while JT09 exhibited no analgesic effects at the highest concentrations we were able to test. This indicates that administration of JT09 does not significantly attenuate centrally-mediated pain as it is unable to cross the blood brain barrier.
• Other potential centrally mediated side effects of morphine which combine to make it a less than ideal drug, also were evaluated with JT09. Two different testing methods were utilized to examine the abuse liability of JT09.
• the most reliable test of abuse liability is a contingent drug self- administration model, in which rats are trained to press a lever for intravenous drug delivery. JT09 failed to maintain lever responding in rats over a five-day period, with the number of infusions decreasing over the last four days in comparison to day one. Positive controls demonstrated that the rats were not deficient in reward processing as cocaine administration resulted in the expected increase in the number of lever presses over the seven-day period of the procedure.
• Addiction is another major issue associated with centrally mediated analgesics such as morphine.
• To test for the promotion of dysphoria we examined rats in the forced swim assay, comparing JT09 to salvinorin A (a centrally-active KOA).
• Dysphoria is measured in the amount of time spent immobile during the last four minutes of each test trial.
• JT09 did not induce more than a baseline time of immobility, in contrast to rats administered salvinornin A.
• locomotor boxes to determine the activity levels of rats after receiving JT09 and morphine, which is highly sedative as a result of its ability to act centrally.
• JT09 did not appear to elicit sedation due to its high peripheral selectivity, making the CR665 derivative JT09 successfully improved over early KOAs and morphine by elimination of its ability to induce centrally mediated effects.
• JT09 is orally active and peripherally restricted, with the potential for clinical and out-patient use as an analgesic.
• the EC50 of JT09 is at a druggable level for an oral analgesic, and appears as efficacious as morphine in alleviating peripheral pain.
• JT09 does not promote the negative CNS-mediated effects associated with morphine, including sedation, dysphoria, tolerance, and addiction.
• Example 3 Preparation of Implantable Devices [0135] Implantable devices will be prepared using an extrusion process in a Microtruder device (Rancastle, RC-025-CF-RF).
• EVA is ground into smaller particle sizes prior to extrusion.
• the extrusion process is performed under argon gas to prevent oxidation of kappa-opioid agonists, if needed.
• All blends of copolymer and drug(s) are prepared by rolling in a 120 ml amber bottle for approximately 10 minutes. The blend is then fed through the Microtruder. Parameters used for extrusion are known in the art. [0136] All of the materials used during the extrusion process are protected from light to prevent light-catalyzed oxidation. The extruder is set to the required temperatures and allowed to reach equilibrium.

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