NZ623939B2 - Samidorphan (alks 33) in combination with opioid agonists - Google Patents

Abstract

The disclosure relates to a composition comprising a pharmaceutically effective amount of an opioid agonist and Compound-1, also known as samidorphan or ALKS 33. The opioid agonist may be buprenorphine, morphine, codeine, hydromorphone, hydrocodone, oxycodone, oxymorphone, dihydrocodeine, dihydromorphine or tramadol. The composition may be used to treat a depressive disorder. phine or tramadol. The composition may be used to treat a depressive disorder.

Description

SAMIDORPHAN (ALKS 33) IN COMBINATION WITH OPIOID AGONISTS BACKGROUND Opioids produce both analgesia and euphoria. The mood altering action of opioids in addition to the al dependence and addictive qualities of this class of drugs encourages abuse. Both chronic pain and prescription opioid abuse are prevalent and continue to exact a heavy toll on patients, physicians, and society. Individuals with c pain and co—occurring substance use disorders and/or mental health disorders, are at a higher risk for misuse of prescribed opioids. Treatment approaches that balance treating c pain while minimizing risks for opioid abuse, misuse, and diversion are much needed. [Sehgal N. et al., Pain Physician 2012; 15, 2150—1149].

The opioid neuropeptide system plays an important part in regulating mood disorders. [Machado—Viera R. et al., Depression and Anxiety, 28 (4) 2011, 267—281].

Opioid peptides and their receptors are potential candidates for the development of novel antidepressant treatment. The actions of nous opioids and opiates are mediated by three receptor types (u, 5 and K), which are coupled to different intracellular effector systems. [Berrocoso E. et al., Current Pharmaceutical , 15(14) 2009, 1612-22]. As such, agents that can te the actions of one or more of the opioid receptor types with selectivity and sensitivity are important to treat the various diseases and disorders regulated by the opioid system.

While opioid agonists have anti-depressant effects they are generally not used to treat depression. Long-term use of full a u-opioid agonist may result in the development of opioid-dependency in patients. In addition there are other undesirable side effects including additive potential, on, respiratory sion, nausea and constipation that will accompany acute and chronic opioid use. Buprenorphine is a u-opioid partial agonist which produces l u—opioid agonist effects and side effects such as additive potential and respiratory sion while producing maximal effects that are less than those of full agonists like heroin and one. At low doses buprenorphine produces sufficient u— agonist effect to enable opioid—addicted individuals to discontinue the misuse of opioids without encing withdrawal ms.

While there are many well-known opioid receptor g compounds, there is little evidence to guide the management of sion that has not responded to a course of antidepressants. Treatment-refractory depression is an important public health problem and large pragmatic trials are needed to inform clinical practice. [Stimpson et al., The British Journal of Psychiatry, (2002) 181: 284—294]. There still remains a need to develop effective treatments of mood disorders, in particular major depressive disorders.

SUMMARY OF THE INVENTION The invention relates to a composition comprising ceutically effective amounts of an opioid agonist and Compound—1: The invention further provides a method for treating an opioid receptor mediated disease or disorder comprising the step of administering a composition comprising Compound-1 and an opioid agonist. The ion r es a dosage form comprising pharmaceutically effective amounts of Compound-1 and an opioid agonist.

BRIEF DESCRIPTION OF THE GS The foregoing and other objects, es and advantages of the invention will be apparent from the following more particular ption of preferred embodiments of the invention, as illustrated in the accompanying drawings in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis d being placed upon illustrating the principles of the invention.

Efflux of dopamine in nucleus accumbens shell after administration of buprenorphine at 0.001 mg/kg, 0.01 mg/kg, 0.1 mg/kg and 1 mg/kg doses after subcutaneous (SC) administration.

Dopamine efflux following (SC) administration of buprenorphine at increasing doses. ion in the efflux of dopamine in nucleus ens shell following administration of Compound-1, Compound-10, naltrexone and nalmefene with Buprenorphine (0.1 mg/kg).

Increase in lity following increased concentrations of Compound—1 in forced swim test in WKY rats treated with Buprenorphine (0.1 mg/kg).

The effect of Compound—1 on dopamine efflux in WKY rats undergoing forced swim test after treatment with Buprenorphine (0.1 mg/kg).

The effect of Compound 1 on 5—Hydroxyindoleacetic acid (5—HIAA) release in WKY rats undergoing the forced swim test after treatment with Buprenorphine (0.1 mg/kg).

DETAILED DESCRIPTION OF THE INVENTION The invention relates to a composition comprising pharmaceutically effective amounts of an opioid agonist and Compound—1: The invention further provides a method for treating an opioid receptor mediated disease or disorder comprising the step of administering a composition comprising Compound-1 and an opioid t. The invention further es a dosage form comprising pharmaceutically effective amounts of Compound-1 and an opioid agonist.

The invention further provides a composition comprising Compound-1 and an opioid t wherein the molar ratio of Compound—1:agonist is about 0:1.0, or about 0.5—4.0:1.0, or about 0.5—3.0:1.0, or about 0.5—2.5:1.0, or about 0.5—1.75:1.0, or about 0.75—1.5: 1.0, or about 0.9—1.3:1.0. The invention further provides an oral dosage form comprising a pharmaceutically effective amount of an opioid agonist and Compound—1 wherein the molar ratio of Compound—1:agonist is about 0.5—5.0:1.0, or about 0.5—4.0:1.0, or about 0.5—3.0:1.0, or about 5:1.0, or about 0.5—1.75:1.0, or about 0.75—1.5:1.0, or about 0.9—1.3: 1.0. The invention further provides a controlled e ation comprising Compound-1 and an opioid agonist.

The ion relates to a method of treating pain comprising the step of administering a pharmaceutically effective amount of Compound-1 in combination with a pharmaceutically effective amount of an opioid agonist to a patient in need thereof The invention further relates to a method of treating a depressive disorder comprising the step of administering Compound-l in combination with a partial opioid agonist to a patient in need thereof.

In one embodiment, the opioid agonist is other than a partial agonist. In one embodiment, the opioid agonist is a compound other than buprenorphine. In one embodiment, the partial agonist is a nd other than orphine.

In one ment, the opioid agonist is a partial agonist at u-opioid receptor (partial agonist). In one embodiment, the partial t is selected from butorphanol, ne, nalbulphine, ocine and buprenorphine. In one embodiment, the composition further comprises an additional agent for the treatment of depression such as a selective serotonin re-uptake inhibitor, serotonin reuptake inhibitor (SSRI), nin- norepinephrine ke inhibitor (SNRI), monoamine e inhibitor (MAOIs) and tricyclic antidepressants, or an antidepressant compound belonging to the heterocyclic class. In one embodiment, the additional epressant is selected from fluoxetine, norfluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram, bupropion, nefazodone, mirtazapine, venlafaxine, duloxetine, milnacipran, reboxetine, zimelidine, indalpine, ne, milnacipran, femoxetine and alaproclate.

In one embodiment, the invention relates to the treatment of depressive disorder comprising the step of administering Compound-l in combination with a partial opioid t to a patient in need thereof. In one embodiment, the partial opioid agonist is a compound other than buprenorphine. In one embodiment, the depressive disorder is selected from major depressive disorder, chronic depression, severe unipolar recurrent major depressive es, mic disorder, depressive neurosis and ic depression, melancholic depression, atypical depression, reactive depression, treatment resistant depression, al affective disorder and pediatric depression; premenstrual syndrome, premenstrual dysphoric disorder, hot flashes, bipolar disorders or manic depression, bipolar I disorder, bipolar II disorder and cyclothymic disorder. In a preferred embodiment, the disorder is major depressive disorder. In one embodiment, the major depressive disorder is resistant to two or more antidepressants, for example, antidepressants such as selective serotonin reuptake inhibitors (SSRIs), Serotonin— norepinephrine reuptake tors (SNRIs), Monoamine oxidase inhibitors (MAOIs) and lic antidepressants. In one embodiment, the disorder is treatment resistant depression. In one embodiment, the subject exhibits one or more sive symptoms selected from irritability, feelings of hopelessness and helplessness, inability to WO 88242 concentrate, sadness, insomnia, appetite loss, lack of interest in life’s ties, thoughts of suicide, ess, nausea, vomiting, hyperhidrosis, menorrhagia, pain in extremity, constipation, on, fatigue, feeling abnormal, flushing and ence. In one embodiment, the administration of said ition results in a release of between about 1 pg/sample to about 2 pg/sample of dopamine. In one embodiment, the molar ratio of Compound—l:agonist is about 0.5—5.0:l.0, or about 0.5—4.0:l.0, or about 0: 1.0, or about 0.5—2.5: 1.0, or about 0.5—1.75:l.0, or about 0.75—1.5: 1.0, or about 0.9—1.3: 1.0. In one ment the opioid agonist is other than a partial agonist. In one embodiment, the partial agonist is a compound other than buprenorphine.

Without being bound to any particular theory, it is postulated that the administration of some of the compositions of the invention may result in the modulation of the dopamine efflux. In one embodiment, administration of the composition results in dopamine efflux in the Nucleus Accumbens shell (NAc-sh) region of the mbic region of the brain of between about 1 pg/sample to about 10 pg/sample of dopamine, between about 1 pg/sample to about 5 pg/sample, or between about 1 pg/sample to about 2 pg/sample of dopamine. The dopamine efflux modulation can be determined by the methods described herein (Example 2).

In one embodiment, the invention relates to a composition comprising a pharmaceutically effective amount of Compound-l and an opioid agonist wherein upon administration of said composition to a patient for the treatment of pain said stration results in the reduction of dopamine release by about 10% to about 60% in comparison to dopamine release upon stration of the agonist alone, wherein said dopamine release is measured two hours after administering said composition. In one embodiment, the reduction of dopamine release is between about 20% to about 40% or between about 25% to about 35%.

In one ment, the stration of the composition of an agonist in combination with Compound—l results in the reduction of visual analog scale (VAS) score for “feeling high” of between about 20% to about 60% in comparison with the administration of the agonist alone. In one embodiment, the ion in VAS score is between about 25% to about 55% or between about 30% to about 50%. In one embodiment, the VAS score is reduced between about 20% to about 60% while the dopamine release is between about lpg/sample to about 10pg/sample.

In one embodiment, the opioid agonist is selected from alfentanil, allylprodine, alphaprodine, anileridine, morphine, bezitramide, brifentanil, carfentanil, azene, codeine, moramide, desomorphine, diampromide, diamorphone, dihydrocodeine, omorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, none, eptazocine, ethoheptazine, ethylthiambutene, ethylmorphine, etonitazene, etorphine, fentanyl, heroin, hydrocodone, odeine, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levallorphan, levomethadone, levophenacylmorphan, lofentanil , meperidine (pethidine), cine, methadone, metopon, 4-methoxymethylfentanyl, 3-methylfentanil, mirfentanil , 6-monoacetylmorphine, morphine, morphineglucuronide, ohmefentanyl , oxycodone, oxymorphone, propoxyphene, ocine, propiram, propoxyphene, racemorphan, sufentanil, adol, tramadol, tilidine.

In a preferred ment, the opioid agonist is selected from morphine, codeine, hydromorphone, hydrocodone, oxycodone, oxymorphone, dihydrocodeine, dihydromorphine and tramadol. In one embodiment, the molar ratio of Compoundl st is about 0.5—5.0:l.0, or about 0.5—4.0: 1.0, or about 0.5—3.0: 1.0, or about 0.5— 2.5: 1.0, or about 0.5—1.75: 1.0, or about 0.75—1.5: 1.0, or about 0.9—1.3:l.0 wherein said agonist is selected from morphine, codeine, hydromorphone, hydrocodone, oxycodone, oxymorphone, dihydrocodeine, omorphine and tramadol.

The invention further provides a method for treating an opioid receptor mediated disease or disorder comprising the step of administering a composition comprising Compound-l and an opioid agonist. In one embodiment, the opioid receptor mediated e or disorder is pain. In one embodiment the disease or disorder is selected from the group consisting of moderate to severe cancer pain, moderate to severe post—surgical pain, pain following physical trauma, pain associated with cardiac infarction and inflammatory pain.

In one embodiment, the invention relates to the treatment of pain wherein the opioid agonist is selected from alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, brifentanil, tanil, clonitazene, codeine, moramide, rphine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, fentanyl, heroin, hydrocodone, hydrocodeine, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levallorphan, levomethadone, levophenacylmorphan, lofentanil , dine (pethidine), metazocine, methadone, metopon, 4-methoxymethylfentanyl, 3-methylfentanil, mirfentanil 6- monoacetylmorphine, morphine, morphineglucuronide, ohmefentanyl , one, oxymorphone, propoxyphene, pentazocine, propiram, propoxyphene, racemorphan, sufentanil, tapentadol, tramadol, tilidine.

In a preferred embodiment, the invention relates to the treatment of pain n the opioid agonist is selected from morphine, e, hydromorphone, hydrocodone, one, oxymorphone, dihydrocodeine, dihydromorphine and tramadol.

The terms “compound” “drug”, and “prodrug” as used herein all include pharmaceutically acceptable salts, co-crystals, solvates, hydrates, polymorphs, enantiomers, diastereoisomers, racemates and the like of the compounds, drugs and prodrugs of the compounds listed herein.

As used herein, the term tive amount of the subject compounds,” with t to the subject method of treatment, refers to an amount of the subject compound which, when delivered as part of desired dose regimen, brings about management of the disease or disorder to clinically acceptable standards.

“Treatment” or “treating” refers to an approach for obtaining beneficial or desired clinical results in a t. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviation of symptoms, diminishment of extent of a disease, stabilization (i.e., not worsening) of a state of disease, preventing occurrence or recurrence of disease, delay or slowing of disease progression, ration of the disease state, and remission (whether partial or total).

As used herein, the term “major depressive disorder” (MDD) is used as that term is understood in art, and refers to a diagnosis that is guided by diagnostic criteria listed in stic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) or 1CD- , or in similar nomenclatures. ts suffering from “treatment resistant depression” include: (1) those who fail to respond to standard doses (i.e., significantly superior to placebo in double—blind studies) of antidepressants (such as a monoamine e inhibitors (MAOIs), lic antidepressants , tetracyclic antidepressants (TeCAs), ive serotonin reuptake inhibitors (SSRls), and serotonin-norepinephrine reuptake inhibitors (SNRls)) administered continuously for a minimum duration of 6 weeks, and (2) those who fail to respond to standard doses of an antidepressant (such as a monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants ), selective serotonin reuptake tors (SSRls), and serotonin-norepinephrine reuptake inhibitors )) (monotherapy) administered continuously for a minimum duration of 12 weeks.

One criteria for determining whether a t's depression is treatment resistant to an antidepressant is if a Clinical Global Impression-Improvement (CGI—I) score of 1 (very much improved) or 2 (much ed) is not achieved by the end of a 6, 8, or 12 week trial. The CGI-I scale is defined in Guy, W. (ed.): ECDEU Assessment Manual for Psychopharmacology, Revised, DHEW Pub. No. (ADM) 76—33 8, Rockville, Md., National Institute of Mental Health, 1976.

Patients suffering from "pain" include c pains, such as athic pain, and post-operative pain, chronic lower back pain, cluster headaches, herpes gia, phantom limb pain, central pain, dental pain, neuropathic pain, opioid-resistant pain, visceral pain, surgical pain, bone injury pain, pain during labor and delivery, pain resulting from burns, including sunburn, post-partum pain, migraine, angina pain, and genitourinary tract-related pain including cystitis, nociceptive pain or ption.

The ceutical compositions of the present ion comprise a therapeutically effective amount of a nd of the t invention formulated together with one or more pharmaceutically acceptable carriers or excipients.

As used , the term "pharmaceutically acceptable carrier or excipient" means a non-toxic, inert solid, semi-solid, gel or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; cyclodextrins such as alpha- (0t), beta- ([3) and gamma- (y) cyclodextrins; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; ed tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium te, as well as ng agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and idants can also be present in the ition, according to the judgment of the formulator.

The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. In a preferred ment, administration is parenteral administration by injection.

The pharmaceutical compositions of this invention may contain any conventional non—toxic ceutically—acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to e the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrastemal, intrathecal, intralesional and ranial injection or infusion techniques.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, ons, suspensions, syrups and elixirs. In addition to the active nds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, l,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, ng, and perfuming agents.

Injectable preparations, for example, sterile able aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a e injectable suspension or emulsion, such as INTRALIPID®, LIPOSYN® or OMEGAVEN®, or solution, in a nontoxic parenterally acceptable t or solvent, for example, as a solution in l,3-butanediol. INTRALIPID® is an intravenous fat emulsion containing 10-30% soybean oil, l-lO% egg yolk phospholipids, l-lO% glycerin and water.

LIPOSYN® is also an intravenous fat emulsion ning 2-15% safflower oil, 2-15% soybean oil, 0.5—5% egg phosphatides 1—10% glycerin and water. OMEGAVEN® is an emulsion for infusion containing about 5-25% fish oil, 05—10% egg atides, 1—10% glycerin and water. Among the acceptable vehicles and ts that may be employed are water, Ringer's solution, USP and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a t or suspending medium. For this e any bland fixed oil can be employed ing synthetic mono- or diglycerides. In on, fatty acids such as oleic acid are used in the preparation of inj ectables.

The injectable ations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid itions which can be dissolved or dispersed in sterile water or other e injectable medium prior to use.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and ore melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as nary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) ents such as kaolin and ite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and es thereof In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight hylene glycols and the like.

The solid dosage forms of s, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they e the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a d manner.

Examples of embedding compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may n, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures f.

Powders and sprays can contain, in addition to the compounds of this ion, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or es of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlled ry of a nd to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to se the flux of the compound across the skin. The rate can be lled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

For pulmonary delivery, a therapeutic composition of the invention is ated and administered to the patient in solid or liquid particulate form by direct administration e. g., inhalation into the respiratory system. Solid or liquid particulate forms of the active compound prepared for practicing the t invention include particles of able size: that is, particles of a size sufficiently small to pass through the mouth and larynx upon tion and into the bronchi and i of the lungs. Delivery of aerosolized therapeutics is known in the art (see, for e US. Pat. No. 068 to VanDevanter et al., US. Pat. No. 5,508,269 to Smith et al., and WO 98/43650 by Montgomery).

EXAMPLES Example 1. A randomized, double—blind, placebo—controlled study was conducted evaluating the safety and tolerability of a combination of buprenorphine with Compound— 1. The study was conducted in 32 adults with major depressive disorder who had an inadequate response to antidepressant therapy. In this study, subjects received a once daily sublingual dose of placebo or Compound—1—BUP at dose ratios of 1:8 or 1:1 with corresponding escalating doses of 0.25:2mg/0.5:4mg and 4:4mg/8:8mg, respectively, for 7 days.

Among the most common adverse events were dizziness, nausea, vomiting, and on (all of which were reported more frequently by subjects in the 1:8 ratio group (Cohort A) versus subjects in the 1:1 ratio (Cohort B) or placebo groups). For example, while about 28.5% of Cohort A reported sedation or ence, only 7% of Cohort B reported sedation or somnolence. The occurrence of dizziness was also significantly higher in Cohort A (57%) compared to Cohort B (29%). A summary of the most common adverse events (i.e, those reported by 210% of subjects in any treatment group) is provided in Table A: Table A: Com arison of most common adverse events >10% in an rou n p_lacebo, Cohort A and Cohort B Adverse Event Placebo Cohort B Preferred Term (N=4) (N=14) N, % Dizziness 4 29 Nausea 3 21 Vomiting 0 4(29)* 2(14)* H oerhidrosis 1 25 2 14 Menorrhagia Pain in extremi 1 25 0 1 7 Constioation 3 21 Sedation or 1(7) ence Fatiue 0 2 14 1 7 Feeling al 0 0 2(14) Flushing 0 2(14) 0 *One subject from each active group discontinued due to vomiting.

Cohort A: 1:8 ratio of Compound 1: Buprenorphine (0.25mg:2mg for days 1 to 3 and 0.5mg:4mg for days 4 to 7) Cohort B: 1:1 ratio of Compound 1: Buprenorphine (4mg:4mg for days 1 to 3 and 8mg:8mg for days 4 to 7 Efficacy was measured by changes from baseline to Day 7 in the 17-item Hamilton Rating Scale for Depression -17) and the Montgomery-Asberg Depression Rating Scale (MADRS). For subjects treated with Compound—l—BUP at the 1:8 and 1:1 dose ratios or o, mean (standard deviation) changes from baseline to day 7 in 17 total scores were —5.0 (6.1), —6.7 (3.4), and —1.0 (4.2), respectively (p=0.032 for the 1:1 ratio versus placebo) and mean (SD) changes from baseline to day 7 in MADRS total scores were —8.5 (.4), —11.4 (6.6), and —3.5 (5.8), respectively. See Tables B and C.

TABLE B: Comparison of treatment efficacy between placebo, Cohort A and Cohort B assessed by Hamilton Depression Rating Sacle—17 (Total Score) Parameter Placebo Cohort A (1:8) Cohort B (1:1) (PBO) Baseline score # ts N=4 N=14 N=14 mean (SD) 19.0 (3.2) 17.5 (2.0) 19.4 (2.7) median 18.5 17.5 19.0 Change from # subjects N=4 N=13 N=13 baseline at Day 7 mean (SD) —1.0 (4.2) —5.0 (6.1) —6.7 (3.4) median 0 -40 —6.0 Comparison of Cohort A vs. Cohort B vs. changes from PBO PBO baseline —4 (5.78) —5.69 (3.57) 0.337 0.032 * p value from exact Wilcoxon test Cohort A: 1:8 ratio of Compound 1: Buprenorphine (0.25mg:2mg for days 1 to 3 and 0.5mg:4mg for days 4 to 7) Cohort B: 1:1 ratio of Compound 1: Buprenorphine (4mg:4mg for days 1 to 3 and 8mg:8mg for days 4 to 7 TABLE C: Comparison of treatment efficacy between placebo, Cohort A and Cohort B assessed by Montgomem—Asberg Depression Rating Scale (Total Score) Parameter Placebo Cohort A Cohort B (1:8) (1:1) ne score # subjects N=4 N=14 N=14 mean (SD) 24.5 (7.9) 23.3 (4.1) 26.4 (4.4) Median 26.0 23.5 26.0 Change from # subjects N=4 N=13 N=13 e at Day 7 mean (SD) —3.5 (5.8) -8.5 (7.4) —11.4 (6.6) median —2.5 —9.0 —13.0 ison of Cohort A vs. Cohort B vs. changes from PBO PBO baseline mean (SD) —4.96 (7.10) —7.88 (6.41) P value* 0.256 0.054 Cohort A: 1:8 ratio of Compound 1: Buprenorphine (0.25mg:2mg for days 1 to 3 and 0.5mg:4mg for days 4 to 7) Cohort B: 1:1 ratio of Compound 1: Buprenorphine (4mg:4mg for days 1 to 3 and 8mg:8mg for days 4 to 7 Visual analog scales (VAS) were used to assess drug liking and other subjective drug effects. Subjects on active drug at the 1:8 ratio enced greater subjective experiences of “Feeling High” (Table D) and ng Sedated” (Table E) compared to the 1:1 ratio. The VAS results are reported as predose and postdose scores showing the magnitude of difference in the subjective experiences. For example, on Day 7, the predose Cohort A VAS score for “Feeling High” was 5.8 and postdose score was 32.9, showing a difference of 27.1 score before and after dosing. In case of Cohort B, the predosing VAS score was 14.5 and postdosing was 19.6 showing only an increase of 5.1. The comparison between the two cohorts shows that Cohort A experienced a significant increase in “Feeling High” after the dosing compared to Cohort B.

TABLE D: Visual analog scale {VAS) results for “feeling high” Timepoint Placebo Cohort A (1:8) Cohort B (1:1) (mean[SD]) (mean[SD]) (mean[SD]) Day 1 Predose 18.0 (20.98) 8.6 (19.58) 9.1 (13.70) Postdose 48.0 (32.04) 54.4 ) 29.4 (30.87) Day 2 Predose 6.8 (4.65) 14.8 (16.97) 22.5 (23.63) Postdose 9.0 (8.76) 39.3 (29.40) 31.5 (29.02) Day 3 Predose 7.3 (2.63) 7.2 (11.35) 22.7 (27.21) Postdose 6.3 (8.66) 41.8 (30.31) 35.5 (32.42) Day 4 e 6.3 (4.92) 10.2 (9.94) 17.5 (22.92) Postdose 7.8 (10.97) 57.1 (30.21) 19.1 (23.19) Day 5 Predose 7.3 (10.59) 6.3 (4.52) 15.7 (20.68) Postdose 23.8 (33.05) 35.1 (34.95) 19.5 (27.58) Day 6 Predose 22.8 (25.68) 4.6 (3.29) 15.5 (21.99) se 29.3 (32.35) 43.7 (30.21) 22.1 (30.36) Day 7 e 24.5 (26.85) 5.8 (5.37) 14.5 (23.57) Postdose 9.0 (8.76) 32.9 (30.14) 19.6 (29.51) TABLE E: Visual analog scale {VAS) s for ng sedated” Timepoint Placebo Cohort A (1 :8) Cohort B (1:1) SD]) SD]) (mean[SD]) Day 1 Predose 5.3 (9.24) 17.5 (26.98) 3.0 (4.96) Postdose 36.5 (38.73) 60.4 (28.73) 34.3 (31.51) Day 2 Predose 5.5 (6.61) 11.5 (12.80) 13.8 (15.42) Postdose 6.3 (6.75) 48.9 (28.69) 37.8 (31.21) WO 88242 Day3Predose 5.5 (5.32) 8.2(8.64) 21.6(27.76) Postdose 4.5 (3.87) 49.0(32.63) 31.2 (29.48) Day 4 Predose 5.8 (6.02) 12.2 (15.80) 22.4 (25.55) Postdose 2.8 (2.22) 38.4 (34.01) 22.2 (24.54) Day5Predose 4.0(3.56) 9.5(13.69) 13.9(18.05) se 30 004.55) 37.0(31.65) 20.2 (23.79) Day6Predose 9.8(14.93) 68) 10.6(14.65) Postdose 21.3 ) 44.8 (31.26) 19.5 (24.77) Day 7 Predose 10.8 (10.53) 17.0 (21.21) 9.7 (12.91) Postdose 5.3 (3.77) 30.3 (25.12) 14.5 (24.22) Bioanalytical method used for determining the Cmax for Compound—1: A method was validated for measuring Compound-1 in human plasma A). Samples were analyzed using a 50 uL aliquot volume and a protein-precipitation extraction procedure followed by liquid chromatography/tandem mass spectrometry (LC/MS/MS). nd— 1 trations were calculated with a l/x2 linear regression over a concentration range of 0.250 to 100 ng/mL using naltrexone-d3 as an internal standard. Ten-fold dilution was successfully tested at 400 ng/mL for both analytes. The API 5000 was operated in the Selected Reaction Monitoring (SRM) mode under optimized conditions for detection of Compound—1, naltrexone—d3 positive ions formed by electrospray ionization.

Bioanalytical method used for determining the Cmax for buprenorphine: A method was validated for measuring buprenorphine in human plasma (K2EDTA). Samples were analyzed using a 400 uL t volume and a solid-phase extraction procedure followed by liquid chromatography/tandem mass spectrometry (LC/MS/MS). Buprenorphine concentrations were calculated with a l/x2 linear regression over a concentration range of 0.250 to 100 ng/mL. The API 5000 was operated in the Selected Reaction Monitoring (SRM) mode under optimized conditions for detection of buprenorphine and buprenorphine—d4 ve ions formed by electrospray ionization.

The [35S]GTPyS assay measures the functional ties of a compound by quantifying the level of G-protein activation following t binding in studies using stably ected cells, and is considered to be a measure of the efficacy of a compound.

Membranes from CHO (Chinese Hamster Ovary) cells that stably expressed the cloned human u opioid receptor were used in the experiments. In a final volume of 0.5 mL, 12 different concentrations of Compound—1 were incubated with 7.5 ug of CHO cell membranes that stably expressed the human u opioid receptor. The assay buffer consisted of 50mM Tris-HCl, pH 7.4, 3 mM MgC12, 0.2 mM EGTA, 3 uM GDP, and 100 mM NaCl.

The final concentration of [35$]GTPyS was 0.080 nM. cific binding was measured by inclusion of 10 uM GTPyS. Binding was initiated by the addition of the membranes.

After an incubation of 60 min at 30°C, the s were ed through cher & Schuell No. 32 glass fiber filters. The filters were washed three times with cold 50 mM Tris—HCl, pH 7.5, and were counted in 2 mL of Ecoscint scintillation fluid. Data are the mean Emax and EC50 values :: S.E.M. For calculation of the Emax values, the basal [35$]GTPyS g was set at 0%, and the 100% [35$]GTPyS binding level was set at the maximum binding achieved with DAMGO.

Example 2. Experiments were ted in rats to assess the y of opioid antagonists to modulate buprenorphine—induced dopamine efflux in the Nucleus Accumbens shell (NAc—sh) region of the mesolimbic region of the brain. Male rats weighing 300—400 grams were used for all studies. To measure the efflux of dopamine in the NAc—sh an in vivo microdialysis method was utilized in free-moving rats. This method allows the sampling of extracellular cerebrospinal fluid (CSF) from specific brain regions of interest and measurement of neurotransmitter concentrations following the analysis of sampled dialysate with HPLC—EC.

Each rat underwent surgical implantation of microdialysis guide cannula (CMA 12, CMA Microdialysis) to guide the insertion of the microdialysis probe later on. Rats were anesthetized with a mixture of ne/xylazine (80/6 mg/kg IP) and placed in a stereotaxic apparatus. Using bregma and skull as reference points, final coordinates were determined by The Rat Brain in Stereotaxic Coordinates (Paxinos and Watson, 2006) for the s accumbens shell (+1.7 A/P, +—0.80 M/L, —7.8 D/V) and the guide cannula were lowered vertically into position (D/V = -5.8 from the skull) and fixed to the skull with glass-ionomer dental acrylic. Guide cannula were capped with dummy probes until microdialysis probe insertion. On the day prior to experimentation (3 -4 days post surgery), animals were weighed to determine appropriate dose for test articles. A microdialysis probe (CMA 12, 2mm membrane, CMA microdialysis) was then inserted through the guide cannula. Microdialysis probes were connected to a tether system ng free movement and sterile artificial CSF (aCSF) (CMA microdialysis) was pumped via yringe pumps at a rate of 0.25 uL/min through the probe overnight for approximately 16 hours prior to experimentation. On the day following probe insertion, e aCSF perfusion was increased to 2.0ul/min and a pre-baseline equilibration period was established for at least 1.5 hours prior to initiating continuous collection of CSF.

After the equilibration period a baseline neurotransmitter levels were determined for each animal over 1.75 hours. Following this baseline period, antagonist plus buprenonorphine (0.1mg/kg, SC) were administered and uous sampling of the microdialysate conducted for an additional 4.25 hours. While uously collected, the CSF was automatically fractioned into 15 minute s using a chilled microfraction collector for the entire 6.0 hours collection period (1.75 baseline phase and 4.25 hour treatment phase).

Each sample was analyzed via HPLC—EC to determine neurotransmitter concentration of dopamine based upon a six—point standard curve. The average dopamine per sample over the 4.25 treatment phase was used in all isons among treatment groups.

In rats orphrine resulted in a dose dependent increases in NAc—sh dopamine efflux between doses of 0.01 and 1 mg per kg (Figures 1 and 2). At doses of 0.1 and 1.0 mg per kg behavioral effects of buprenorphine were observed, including initial sedation followed by hyperactivity. Consequently all additional experiments with u opioid antagonist used a dose of 0.1 mg per kg of buprenorphine since it represented the lowest dose associated with clear behavioral effects. As shown in Figure 3 each of the four antagonists evaluated resulted in linear dose—dependent decreases in NAc—sh dopamine efflux.

Example 3. Due to the inherent minor stress ated with PK sampling, and the sensitivity of neural chemistry to this stress, different groups of animals were ed to establish circulating concentrations of buprenorphine and the antagonists at each dose level evaluated Male rats ng between 300 — 400 grams, the same weight range used in the microdialysis studies, were used for . Since all animals ed a fixed dose of buprenorphine, a cial formulation of buprenorphine (Buprenex (Reckitt Benckiser)) was diluted to 0.1 mg/ml with sterile saline and then used as the vehicle for the required doses of compound 1, Compound—10, naltrexone and nalmefene. This approached ensured that at each dose of the antagonist studied the concomitant dose of orphrine would be 0.1 mg per kg. All injections were made by the aneous route at the doses indicated in Table G. Sterile solutions of the test formulations (combination of antagonist with 0.1 mg/kg buprenorphine) were given subcutaneously (designated as time 0). Sample of blood were collected at 5, 15, 30, 60 and 120 minutes post dosing. For each blood sampling time point, rats were lightly anesthetized using (3%) isoflourane anesthesia and approximately 200pl of blood was withdrawn from the lateral tail vein using a 27.5 gauge needle and placed into chilled K2 EDTA tubes. The tion tubes were inverted 10—15 times and then held on ice prior to centrifugation.

Plasma was obtained by centrifuging samples for 2 s at 14,000 X g (11,500 RPM using Eppendorf 5417R centrifuge rotor) at 40 C. The harvested samples of plasma were frozen at -80° C until assayed for buprenorphine and the nists (Compound 1, Compound 10, xone or nalmefene). The Cmax values for each nist at the doses evaluated are shown in Table F.

TABLE F: Cmax values for Compound-1, Compound-10, naltrexone and nalmefene with Buprenorphine (0.1 mg/kg) Dose of Antaonist m oer k Anta-0nist 0-03 Comma-1 —-- Compound—10 2.24 18.1 29.5 —— Naltrexone ——— 19.27 76.9 169 Nalmefene --- 14.13 162 Example 4. In the “forced swim test” (FST) rats are placed in a tank of water, from which they cannot escape, on two successive days; 15 minutes on the first day and 5 minutes on the second day. While in the water they will swim, attempt to climb the container wall or become “immobile” floating in the water. The total time rats are immobility increases between the first and second day. Drugs that have antidepressant effects in humans reduce lity time on day 2 and this model is frequently used to evaluate potential anti-depressive like activity of drugs. Strain of rat can also affect total lity time, with the Wistar-Kyoto (WKY) strain showing high immobility times.

The WKY rat is spontaneously hypertensive and displays hormonal and depressive—like behavioral abnormalities. Rats received three separate subcutaneous injections of either vehicle alone or a combination of orphine (0.1 mg/kg) and Compound—1 (0.3 or 3.0 mg/kg) at 1, 19, and 23 h after the first exposure to the swim tanks. At 24 h after the first swim, rats were retested for 5 minutes. Videos were scored manually for immobility time (in seconds) using a manual stop watch in 60 second intervals by a rater blinded to the WO 88242 treatment groups. A rat was judged to be immobile if it was making only movements necessary to keep its head above water. Results for this study are shown in Figure 5.

Immobility time was significantly lower (p<0.05) in rats given the combination of buprenorphine and Compound 1 at 0.3 mg/kg, indicating an anti-depressive like action.

While this invention has been particularly shown and described with references to preferred ments thereof, it will be understood by those d in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims (37)

CLAIMS What is claimed is:

1. A composition comprising a pharmaceutically effective amount of an opioid agonist and Compound-1: O OH O wherein the molar ratio of Compound-1:agonist is about 0.5-5.0:1.0.

2. The composition of claim 1, wherein said opioid agonist is selected from alfentanil, allylprodine, rodine, anileridine, benzylmorphine, bezitramide, 10 brifentanil, buprenorphine, carfentanil, clonitazene, codeine, dextromoramide, desomorphine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, ylthiambutene, dioxaphetyl butyrate, none, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, ine, fentanyl, , hydrocodone, hydrocodeine, 15 hydromorphone, hydroxypethidine, hadone, ketobemidone, levorphanol, levallorphan, levomethadone, levophenacylmorphan, lofentanil , meperidine dine), metazocine, methadone, metopon, 4-methoxymethylfentanyl, 3- methylfentanil, mirfentanil , acetylmorphine, morphine, morphine glucuronide, ohmefentanyl , oxycodone, oxymorphone, propoxyphene, 20 pentazocine, propiram, propoxyphene, racemorphan, sufentanil, tapentadol, tramadol, tilidine.

3. The composition according to claim 2, wherein said opioid agonist is selected from morphine, codeine, hydromorphone, hydrocodone, oxycodone, oxymorphone, 25 dihydrocodeine, dihydromorphine and tramadol.

4. The composition according to any one of claims 1-3, wherein the molar ratio of Compound-1:agonist is about 0.75-1.5:1.0.

5 5. A controlled release formulation sing a composition according to any one of claims 1-4.

6. The composition according to any of claims 1-5, wherein said agonist is buprenorphine.

7. The composition according to any one of claims 1-6, further comprising an additional agent for the treatment of depression selected from a ive nin re-uptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), monoamine oxidase inhibitor (MAOIs) and tricyclic antidepressants, or an 15 antidepressant compound belonging to the heterocyclic class.

8. The composition of claim 6, n said additional anti-depressant is ed from fluoxetine, norfluoxetine, paroxetine, line, fluvoxamine, citalopram, escitalopram, bupropion, done, mirtazapine, venlafaxine, duloxetine, 20 milnacipran, reboxetine, zimelidine, indalpine, gepirone, femoxetine and alaproclate.

9. A unit dosage form sing a composition according to any one of claims 1-8. 25

10. The composition according to any one of claims 1-8, wherein the molar ratio of Compound-1:agonist is about 0.9-1.3:1.0.

11. Use of Compound-1 in combination with a partial opioid agonist in the manufacture of a medicament for treating a depressive disorder: O OH O Compound-1; wherein the molar ratio of Compound-1:agonist is about 0:1.0. 5

12. The use according to claim 11, wherein said depressive disorder is selected from major depressive disorder, chronic depression, severe unipolar recurrent major depressive episodes, dysthymic disorder, depressive neurosis and neurotic depression, melancholic sion, atypical depression, reactive depression, treatment resistant depression, seasonal ive disorder and pediatric depression; 10 premenstrual me, premenstrual dysphoric disorder, hot flashes, bipolar disorders or manic depression, bipolar I disorder, bipolar II disorder and hymic disorder.

13. The use according to claim 11, wherein said depressive disorder is major depressive 15 er.

14. The use according to claim 12, n said major depressive disorder is resistant to two or more antidepressants. 20

15. The use according to claim 13, wherein the antidepressants are selected from the group comprising selective serotonin reuptake inhibitors (SSRIs), Serotoninnorepinephrine ke inhibitors (SNRIs), Monoamine oxidase inhibitors (MAOIs) and Tricyclic antidepressants.

16. The use according to claim 12, wherein said depressive disorder is treatment resistant depression.

17. The use according to any of claims 11-16, wherein said subject exhibits one or more 5 depressive symptoms ed from irritability, feelings of hopelessness and helplessness, inability to concentrate, sadness, insomnia, appetite loss, lack of interest in life’s activities, thoughts of suicide, dizziness, nausea, ng, idrosis, hagia, pain in extremity, constipation, sedation, fatigue, feeling abnormal, flushing and somnolence.

18. The use according to any one of claims 11-17, wherein the molar ratio of Compound-1:agonist is about 0.75-1.5:1.0.

19. The use according to claim 18, wherein the opioid agonist is buprenorphine. 15

20. Use of Compound-1 in ation with an opioid agonist in the manufacture of a medicament for treating an opioid receptor mediated disease or disorder: O OH O Compound-1; n the molar ratio of Compound-1:agonist is about 0.5-5.0:1.0.

21. The use according to claim 20, n the opioid agonist is buprenorphine.

22. The composition according to any one of claims 1-8 or 10, further comprising a pharmaceutically acceptable carrier.

23. The composition according to any one of claims 1-8, wherein the molar ratio of Compound-1:agonist is about 0.5-4.0:1.0.

24. The ition according to any one of claims 1-8, wherein the molar ratio of 5 Compound-1:agonist is about 0.5-3.0:1.0.

25. The composition according to any one of claims 1-8, wherein the molar ratio of Compound-1:agonist is about 0.5-2.5:1.0. 10

26. The ition according to any one of claims 1-8, wherein the molar ratio of Compound-1:agonist is about 75:1.0.

27. The use according to any one of claims 11-17, wherein the molar ratio of Compound-1:agonist is about 0.5-4.0:1.0.

28. The use according to any one of claims 11-17, wherein the molar ratio of Compound-1:agonist is about 0.5-3.0:1.0.

29. The use ing to any one of claims 11-17, wherein the molar ratio of 20 Compound-1:agonist is about 0.5-2.5:1.0.

30. The use according to any one of claims 11-17, wherein the molar ratio of Compound-1:agonist is about 0.5-1.75:1.0. 25

31. The use according to any one of claims 11-17, wherein the molar ratio of Compound-1:agonist is about 0.9-1.3:1.0.

32. The use according to claim 20, wherein the molar ratio of Compound-1:agonist is about 0.5-4.0:1.0.

33. The use according to claim 20, wherein the molar ratio of Compound-1:agonist is about 0.5-3.0:1.0. 5

34. The use according to claim 20, wherein the molar ratio of Compound-1:agonist is about 0.5-2.5:1.0.

35. The use ing to claim 20, wherein the molar ratio of Compound-1:agonist is about 0.5-1.75:1.0.

36. The use according to claim 20, wherein the molar ratio of Compound-1:agonist is about 0.75-1.5:1.0.

37. The use according to claim 20, n the molar ratio of Compound-1:agonist is 15 about 0.9-1.3:1.0.