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US20060128794A1 - Treatment of interstitial cystitis using (6aR,10aR)-delta8-tetrahydrocannabinol-11-OIC acids - Google Patents

Treatment of interstitial cystitis using (6aR,10aR)-delta8-tetrahydrocannabinol-11-OIC acids Download PDF

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US20060128794A1
US20060128794A1 US11/299,688 US29968805A US2006128794A1 US 20060128794 A1 US20060128794 A1 US 20060128794A1 US 29968805 A US29968805 A US 29968805A US 2006128794 A1 US2006128794 A1 US 2006128794A1
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compound
alkyl
interstitial cystitis
bladder
administered
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Bobby Sandage
Glenn Cooper
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JB THERAEPUTICS
Indevus Pharmaceuticals Inc
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Indevus Pharmaceuticals Inc
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Priority to US11/299,688 priority Critical patent/US20060128794A1/en
Publication of US20060128794A1 publication Critical patent/US20060128794A1/en
Priority to US12/070,342 priority patent/US20080182892A1/en
Assigned to JB THERAEPUTICS reassignment JB THERAEPUTICS ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BURSTEIN, SUMNER H.
Assigned to JB THERAPEUTICS, INC. reassignment JB THERAPEUTICS, INC. CORRECTIVE ASSIGNMENT TO CORRECT THE COMPANY NAME PREVIOUSLY RECORDED ON REEL 003205 FRAME 0339. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Assignors: BURSTEIN, SUMNER H.
Priority to US12/624,313 priority patent/US8637087B2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/06—Anti-spasmodics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • 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
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to the treatment of interstitial cystitis using non-psychoactive derivatives of tetrahydrocannabinol, which exhibit anti-inflammatory and analgesic properties.
  • the present invention further relates to the use of (6aR,10aR)- ⁇ 8 -tetrahydrocannabinol-11-oic acids, and pharmaceutical compositions comprising therapeutically effective amounts of the acids, for the treatment of interstitial cystitis.
  • ⁇ 8 -tetrahydrocannabinol [6aR,7,10,10aR-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol, hereinafter referred to as ⁇ 8 -THC], which is depicted below in Formula II, has indicated that certain derivatives of this compound may prove clinically useful.
  • the bladder wall may be irritated and become scarred or stiff. Glomerulations (pinpoint bleeding caused by recurrent irritation) may appear on the bladder wall.
  • Another theory is that a bacterium may be present in bladder cells but not detectable through routine urine tests.
  • researchers are also beginning to explore the possibility that heredity may play a part in some forms of IC, but no gene has yet been implicated.
  • the inner lining of the bladder the glycosaminoglycan or GAG layer
  • GAG layer the glycosaminoglycan or GAG layer
  • Factors that influence the treatment options available typically include whether bladder capacity under anesthesia is great or small, and whether mast cells are present in the tissue of the bladder wall, which may be a sign of an allergic or autoimmune reaction. In some cases, the success or failure of a treatment helps characterize the type of IC. Some current treatments for IC include bladder distention, administration of pharmaceutical compositions by bladder instillation (also known as intravesicular instillation (IVI)), oral administration of pharmaceutical compositions, and transcutaneous electrical nerve stimulation. These treatment options will be described in greater detail below.
  • IVI intravesicular instillation
  • the bladder is filled with a solution that is held for varying periods of time, averaging 10 to 15 minutes, before being emptied.
  • IVI is typically performed using dimethyl sulfoxide (DMSO, RIMSO-50).
  • DMSO IVI treatment involves guiding a catheter up the urethra into the bladder. A measured amount of DMSO is passed through the catheter into the bladder, where it is retained for about 15 minutes before being expelled. Treatments are usually given every week or two for 6 to 8 weeks and repeated as needed. Doctors think IVI administration of DMSO works in several ways. Because it passes into the bladder wall, it may reach tissue more effectively to reduce inflammation and block pain. It may also prevent muscle contractions that cause pain, frequency, and urgency.
  • DMSO dimethyl sulfoxide
  • Pentosan polysulfate sodium was the first oral drug developed for IC to have been approved by the FDA. In clinical trials, the drug improved symptoms, but its method of action is unknown. One theory is that it may repair defects that might have developed in the lining of the bladder.
  • the FDA-recommended oral dosage of Elmiron is 100 mg, three times a day. Patients may not feel relief from IC pain for the first 2 to 4 months. A decrease in urinary frequency may take up to 6 months to achieve.
  • narcotic analgesics such as acetaminophen with codeine or longer acting narcotics may be necessary.
  • U.S. Pat. No. 5,338,753 discloses (3R,4R)- ⁇ 6 -THC-7-oic acids (which correspond to (6aR,10aR)- ⁇ 8 -THC-11-oic acids, but were named using an alternative numbering system) that are useful as anti-inflammatory agents and analgesics, as well as methods of synthesizing them, but does not disclose compositions or methods for treating patients suffering from IC.
  • the present invention may control the symptoms and improve the quality of life for patients suffering from IC and may also reduce the urgency and frequency associated with urination.
  • compositions and methods for treating a patient suffering from interstitial cystitis whereby the (6aR, 10aR)- ⁇ 8-THC-11-oic acids according to the present invention are advantageously administered to said patient.
  • unique methods are provided for the treatment of interstitial cystitis in a mammal using a compound having Formula II wherein R 1 is hydrogen, —COCH 3 or —COCH 2 CH 3 ; and R 2 is a branched C 5 -C 12 alkyl compound which may optionally have a terminal aromatic ring, or optionally a branched —OCHCH 3 (CH 2 ) m alkyl compound which may have a terminal aromatic ring, wherein m is 0 to 7.
  • the method comprises the steps of identifying a mammal suffering from or suspected of suffering from interstitial cystitis; and administering to the mammal an effective amount of the compound of formula II, or a pharmaceutically acceptable salt, ester, or solvate thereof.
  • compositions and methods are provided for a pharmaceutical composition for use in treating interstitial cystitis in a mammal, particularly humans, including a therapeutically effective amount of a compound having Formula II wherein R 1 is hydrogen, —COCH 3 or —COCH 2 CH 3 ; and R 2 is a branched C 5 -C 12 alkyl compound, which may optionally have a terminal aromatic ring, or optionally a branched —OCHCH 3 (CH 2 ) m alkyl compound, which may have a terminal aromatic ring, wherein m is 0 to 7, or a pharmaceutically acceptable salt, ester or solvate thereof.
  • R 1 is hydrogen, —COCH 3 or —COCH 2 CH 3
  • R 2 is a branched C 5 -C 12 alkyl compound, which may optionally have a terminal aromatic ring, or optionally a branched —OCHCH 3 (CH 2 ) m alkyl compound, which may have a terminal aromatic ring, wherein m is
  • compositions and methods are provided for pharmaceutical composition for use in treating interstitial cystitis in a mammal, including an effective amount of a compound having Formula III or a pharmaceutically acceptable salt, ester or solvate thereof.
  • FIG. 1 is a synthetic scheme for the (6aR,10aR)- ⁇ 8 -THC-11-oic acids of the present invention.
  • FIG. 2 shows cystometrograms relating to Example i.
  • FIG. 5 is a summary of the numerical results of Example i.
  • FIG. 6 shows cystometrograms relating to Example j.
  • FIG. 7 is a summary of results of Example j.
  • FIG. 8 is a summary of the numerical results of Example j.
  • FIGS. 9A-9C show a preliminary dose-response curve, response to acetic acid 24 hours post drug treatment, and response to acetic acid 48 hours post drug treatment.
  • the present invention relates to (6aR,10aR)- ⁇ 8 -THC-11-oic acids, pharmaceutical compositions comprising therapeutically effective amounts of these compounds, and methods of treating IC in a mammal by administering such compounds or pharmaceutical compositions.
  • the THC derivatives of the present invention have reduced or no psychoactivity and do not bind to the CB1 receptor.
  • a particularly preferred ⁇ 8 -THC-11-oic acid analog in accordance with the present invention is 1′,1′-dimethylheptyl- ⁇ 8 -THC-11-oic acid (also known as CT3 or ajulemic acid), shown below in Formula III,
  • THC derivatives in the treatment of IC are specifically envisioned by the present invention.
  • compositions and pharmaceuticals useful in relieving symptoms of IC which comprise ⁇ 8 -THC-11-oic acids and derivatives and analogs thereof, as depicted below in Formula II: wherein R 1 is hydrogen, —COCH 3 or —COCH 2 CH 3 ; R 2 is a branched C 5 -C 12 alkyl compound, which may optionally have a terminal aromatic ring, or optionally a branched —OCHCH 3 (CH 2 ) m alkyl compound, which may have a terminal aromatic ring, wherein m is 0 to 7.
  • R 1 is hydrogen
  • R 2 is 1′,1′-dimethylheptyl (IP-751).
  • IP-751 1′,1′-dimethylheptyl
  • the preferred compounds are also similarly preferred when used in pharmaceutical compositions and for methods of treating IC by administration of the compounds or pharmaceutical compositions according to the invention.
  • terapéuticaally effective amount means that amount of the pharmaceutical composition that provides a therapeutic benefit in the treatment, prevention, or management of interstitial cystitis.
  • Dosage amounts for the (6aR,10aR)- ⁇ 8 -THC-11-oic acids according to the present invention when administered orally for the relief of symptoms of IC, are generally between about 1 mg and about 200 mg, preferably between about 10 mg and about 100 mg per day, and more preferably between about 20 mg and about 60 mg per day, administered about 2 to about 4 times daily.
  • the dose, and dose frequency will vary according to the patient's age, body weight, and therapeutic response, as well as the severity of the condition.
  • the orally administered compounds and pharmaceutical compositions according to the present invention may be optionally administered in conjunction with other existing oral treatments for IC, including, but not limited to, sodium pentosanpolysulfate (Elmiron®), preferably administered as about 100 mg three times a day; antihistamines such as hydroxizine (Atarax® Vistaril®); antidepressants (for their direct effect on bladder pain fibers) such as amitriptyline HCL (Elavil®, Triavil®), preferably administered as from about 25 mg to about 75 mg daily, or doxepin HCL (Sinequan®), preferably administered as about 75 mg at bedtime; imipramine (Trazodone®), preferably administered as about 25 mg three times a day; antispasmodics (Anaspaz®, Cystospaz®, Ditropan®, Levsin®, Levsinex®, Urispas®, Urised®)); urinary anesthetics such as phenazopyridine (P
  • the orally administered compounds and pharmaceutical compositions according to the present invention may be optionally administered in conjunction with existing treatments for IC that are administered via IVI.
  • the compounds and pharmaceutical compositions according to the present invention may also be beneficially administered as formulations for use in bladder instillation or intravesicular instillation (IVI).
  • Dosage amounts for the (6aR,10aR)- ⁇ 8 -THC-11-oic acids according to the present invention when administered via IVI, are generally between about 12.5 and about 3500 ng/ml exposure within the bladder per administration, preferably between about 20 ng/ml exposure to about 2,000 ng/ml exposure within the bladder per administration. More preferably, the amount of exposure of the patient to the compounds of interest within the bladder per administration ranges from about 50 ng/ml to less than about 1,000 ng/ml.
  • the dose would be less than about 1 mcg to about 100 mcg per administration, preferably less than about 10 mcg to about 50 mcg, more preferably less than about 20 mcg to about 40 mcg, administered twice, once or fewer times daily.
  • the dose, and dose frequency will vary according to the patient's age, body weight, and therapeutic response, as well as the severity of the condition.
  • the compounds and pharmaceutical compositions according to the present invention may be administered via IVI, optionally in conjunction with other existing IVI treatments for the side effects of IC, including, but not limited to, dimethyl sulfoxide (DMSO), heparin, hyaluronic acid, Cystitat, silver nitrate, chlorpactin, and Bacillus Calmette Guerin (BCG).
  • DMSO dimethyl sulfoxide
  • BCG Bacillus Calmette Guerin
  • Other compositions suitable for administration via IVI may also be combined with the compositions and pharmaceuticals of the present invention. Preferably, they are administered in a manner consistent with their present use in the treatment of IC.
  • the compounds and pharmaceutical compositions according to the present invention may be administered via IVI, optionally in conjunction with other existing orally administered treatments for the side effects of IC.
  • the compounds and pharmaceutical compositions may optionally be administered in conjunction with an anticholinergic agent.
  • the anticholinergic agent is preferably administered orally or via IVI, although other routes of administration are contemplated in accordance with the present invention.
  • Such anticholinergic agents may be selected from anisotropine, aprophen, artane, atropine, belladonna, benactyzine, benztropine, clidinium, dicyclomine, glycopyrrolate, homatropine, hyoscyamine, isopropamide, mepenzolate, methantheline, methscopolamine, oxybutynin, oxyphencyclimine, propantheline, scopolamine, terodiline, tridihexethyl, trihexyphenidyl, and trospium.
  • the anticholinergic agents are administered in a manner consistent with their present use in the treatment of IC.
  • compositions of the present invention may include the active ingredients described above, and may also contain pharmaceutically acceptable carriers, excipients and the like, and optionally, other therapeutic ingredients.
  • the drug may be suspended in a vegetable oil, such as olive oil or peanut oil, and, optionally encapsulated in a gelatin capsule.
  • the compounds or pharmaceutical compositions are preferably administered orally, in the form of a gelatin capsule, or by IVI in the form of a suspension or solution.
  • pharmaceutically acceptable salt refers to a salt prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic or organic acids.
  • inorganic acids are hydrochloric, hydrobromic, hydroiodic, sulfuric, and phosphoric.
  • Appropriate organic acids may be selected, for example, from aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic, stearic, sulfanilic, algenic, and galacturonic.
  • organic acids may be selected, for example, from aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic
  • inorganic bases for potential salt formation with sulfate or phosphate compounds of the invention, include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc.
  • Appropriate organic bases may be selected, for example, from N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), and procaine.
  • the compounds and pharmaceutical compositions of the present invention may be administered in the form of such pharmaceutically acceptable salts.
  • the compounds of interest may also be administered in the form of esters, e.g., methyl, ethyl and the like. Solvates of the compounds of interest may also be useful, including hydrates and the like.
  • the compounds and pharmaceutical compositions of the present invention may also be included in formulations such as suspensions, solutions and elixirs; aerosols; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like, in the case of oral solid preparations (such as powders, capsules, and tablets), with oral solid preparations being preferred over oral liquid preparations.
  • oral solid preparations such as powders, capsules, and tablets
  • the most preferred oral solid preparations are capsules.
  • tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Because of the benefits of IVI for relieving symptoms of IC, IVI formulations are another particularly preferred dosage form, in which case the compounds and pharmaceutical compositions of the present invention are provided dissolved or suspended in a pharmaceutically acceptable solvent or diluent.
  • the compounds and pharmaceuticals of the present invention may also be administered by controlled release means and/or delivery devices such as those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, the disclosures of which are hereby incorporated by reference.
  • the compounds and pharmaceutical compositions of the present invention can be used in methods of treating mammals suffering from IC, in both veterinary medicine and human therapy contexts.
  • the method of administering the compounds and pharmaceutical compositions in the acute or chronic management of IC will vary with the severity of the condition and the route of administration.
  • the dose, and perhaps the dose frequency will also vary according to the age, body weight, and response of the individual patient.
  • the actual preferred amounts of the active ingredients administered will vary with each case, according to the species of mammal, the nature and severity of affliction being treated, and the method of administration.
  • the compounds and pharmaceutical compositions of the present invention are periodically administered to an individual patient as necessary to improve symptoms associated with IC.
  • the length of time during which the compounds and pharmaceutical compositions are administered and the total dosage will necessarily vary with each case, according to the nature and severity of the IC with which the patient is afflicted, and the physical condition of the subject.
  • the compounds and pharmaceutical compositions may be administered via any appropriate route, e.g. intravenously, intraarterially, topically, by injection, intraperitoneally, intrapleurally, orally, subcutaneously, intramuscularly, sublingually, intraepidermally, or rectally.
  • the preferred methods of administration are orally and via IVI.
  • the oral formulations may be solutions, suspensions, suppositories, tablets, granules, powders, capsules, ointments, or creams.
  • the IVI formulations may be solutions or suspensions, including compositions comprising liposomes.
  • a solvent e.g., water or physiological saline
  • solubilizing agent e.g., ethanol, Polysorbates, or Cremophor EL7
  • agent for making isotonicity preservative, antioxidizing agent, excipient (e.g., lactose, starch, crystalline cellulose, mannitol, maltose, calcium hydrogen phosphate, light silicic acid anhydride, or calcium carbonate)
  • binder e.g., starch, polyvinylpyrrolidone, hydroxypropyl cellulose, ethyl cellulose, carboxy methyl cellulose, or gum arabic
  • lubricant e.g., magnesium stearate, talc, or hardened oils
  • stabilizer e.g., lactose, mannitol, maltose, polysorbates, macrogols, or polyoxyethylene hardened castor oils
  • glycerin dimethylacetarnide, 70% sodium lactate, a surfactant, or a basic substance such as sodium hydroxide, ethylenediamine, ethanolamine, sodium bicarbonate, arginine, meglumine, or trisaminomethane is added.
  • Pharmaceutical preparations such as solutions, tablets granules or capsules can be formed with these components.
  • Compositions for slow release of the compound can be formed as described in U.S. Pat. No. 4,880,830.
  • the oral administration methods and formulations of the present invention provide between about 1 mg and about 200 mg per day, preferably between about 10 mg and about 100 mg per day, and more preferably between about 20 mg and about 60 mg per day, administered about 2 to about 4 times daily, of the (6aR,10aR)- ⁇ 8 -THC-11-oic acids (i.e., excluding excipients, carriers, and any of the optional additional active ingredients described herein).
  • the daily dose may include two or more unit doses, i.e., tablets, cachets or capsules, to be administered each day.
  • Dosage amounts for the IVI methods of administration and formulation of the present invention are generally between about 12.5 and about 3500 ng/ml exposure within the bladder per administration, preferably between about 20 ng/ml exposure to about 2,000 ng/ml exposure within the bladder per administration. More preferably, the amount of exposure of the patient to the compounds of interest within the bladder per administration ranges from about 50 ng/ml to less than about 1,000 ng/ml.
  • the dose would be less than about 1 mcg to about 100 mcg per administration, preferably less than about 10 mcg to about 50 mcg, more preferably less than about 20 mcg to about 40 mcg, administered twice, once or fewer times daily.
  • the dose, and dose frequency will vary according to the patient's age, body weight, and therapeutic response, as well as the severity of the condition.
  • the methods of the present invention envision the optional inclusion of existing treatments for IC in conjunction with the methods of administration and formulation of compounds and pharmaceutical compositions comprising the (6aR,10aR)- ⁇ 8 -THC-11-oic acids of the present invention.
  • the methods of administration and formulation include the administration and formulation of compounds and pharmaceutical compositions comprising the (6aR,10aR)- ⁇ 8 -THC-11-oic acids in accordance with the present invention, in conjunction with both anticholinergic agents and existing treatments for IC.
  • the existing IC treatments and/or anticholinergic agents are formulated or co-administered with the (6aR,10aR)- ⁇ 8 -THC-11-oic acids in accordance with the present invention in a manner that is consistent with their present use in the treatment of IC.
  • the optional addition of existing treatments for IC to the methods of the present invention may include oral administration of sodium pentosanpolysulfate (Elmiron®), preferably administered as about 100 mg three times a day; antihistamines such as hydroxizine (Atarax® Vistaril ®); antidepressants (for their direct effect on bladder pain fibers) such as amitriptyline HCL (Elavil®, Triavil®), preferably administered as from about 25 mg to about 75 mg daily, or doxepin HCL (Sinequan®), preferably administered as about 75 mg at bedtime; imipramine (Trazodone®), preferably administered as about 25 mg three times a day; antispasmodics (Anaspaz®, Cystospaz®, Ditropan®, Levsin®, Levsinex®, Urispas®, Urised®); urinary anesthetics such as phenazopyridine (Pyridium®, Uristat®); and capsaicin.
  • IC treatments suitable for oral administration may also be combined with the compounds and pharmaceutical compositions of the present invention. Where appropriate, these oral IC treatments may be formulated as a single unit dose with the compounds and pharmaceutical compositions of the present invention. When such formulations are not possible or desirable, these oral IC treatments may be beneficially co-administered with the compounds and pharmaceutical compositions of the present invention.
  • IVI treatments for IC may include administration of IVI formulations of dimethyl sulfoxide (DMSO), heparin, hyaluronic acid, Cystitat, silver nitrate, chlorpactin, and Bacillus Calmefte Guerin (BCG).
  • DMSO dimethyl sulfoxide
  • BCG Bacillus Calmefte Guerin
  • Other IC treatments suitable for administration via IVI may also be combined with the compounds and pharmaceutical compositions of the present invention.
  • Other IC treatments suitable for oral administration may also be combined with the compounds and pharmaceutical compositions of the present invention.
  • these IVI formulated IC treatments may be formulated as a single solution or suspension with the compounds and pharmaceutical compositions of the present invention. When such formulations are not possible or desirable, these IVI formulated IC treatments may be beneficially co-administered with the compounds and pharmaceutical compositions of the present invention.
  • the oral and IVI administration and formulation methods of the present invention may optionally include providing an anticholinergic agent in the formulation, where feasible, or coadministering the anticholinergic agent with the compounds and pharmaceutical compositions of the present invention.
  • Such anticholinergic agents may be selected from anisotropine, aprophen, artane, atropine, belladonna, benactyzine, benztropine, clidinium, dicyclomine, glycopyrrolate, homatropine, hyoscyamine, isopropamide, mepenzolate, methantheline, methscopolamine, oxybutynin, oxyphencyclimine, propantheline, scopolamine, terodiline, tridihexethyl, trihexyphenidyl, and trospium.
  • Use of other compounds including an anticholinergic action is specifically envisioned by the present invention.
  • compositions for use in the methods of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, or aerosol sprays, each containing a predetermined amount of the active ingredient, as a powder or granules, as creams, pastes, gels, or ointments, or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion.
  • Formulations that include micelles are also contemplated.
  • Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association the carrier with the active ingredient which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet may be prepared by compression or molding, optionally, with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as powder or granules, optionally mixed with a binder (e.g., carboxymethylcellulose, gum arabic, gelatin), filler (e.g., lactose), adjuvant, flavoring agent, coloring agent, lubricant, inert diluent, coating material (e.g., wax or plasticizer), and a surface active or dispersing agent.
  • Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • compositions and pharmaceuticals according to the present invention are administered using the IVI method, it is preferred that they be provided as dispersions, suspensions, or solutions.
  • the methods of the present invention may comprise administering to an afflicted individual a compound or pharmaceutical composition comprising an effective amount of the (6aR,10aR)- ⁇ 8 -THC-11-oic acids of the present invention for use in treating IC, where the compositions are provided in a pharmacologically acceptable carrier, for example, a gelatin capsule, or edible oil (e.g., a vegetable oil) for oral administration; or a pharmaceutical composition comprising an effective amount of the (6aR,10aR)- ⁇ 8 -THC-11-oic acids of the present invention, which may be optionally provided in liposomes and suspended in a sterile saline solution for IVI administration.
  • a pharmacologically acceptable carrier for example, a gelatin capsule, or edible oil (e.g., a vegetable oil) for oral administration
  • a pharmaceutical composition comprising an effective amount of the (6aR,10aR)- ⁇ 8 -THC-11-oic acids of the present invention, which may be optionally provided in lip
  • the invention is further defined by reference to the following examples describing in detail the preparation of the compound and the compositions used in the methods for treating IC according to the present invention, as well as their utility.
  • the examples are representative, and they should not be construed to limit the scope of the invention.
  • the compounds of the present invention may be prepared according to the synthetic scheme depicted in FIG. 1 .
  • melting points were taken in glass capillary tubes with a Thomas-Hoover Uni-Melt apparatus. Infrared spectra were recorded on a JASCO A-200 spectrophotometer. Rotations were determined on a Perkin-Elmer Model 141 polarimeter in chloroform. Chromatographic separations were performed on silica gel columns (Woelm TSC silica, for dry chromatography, activity III/30 mm, No. 04530). The high-resolution mass spectrometry (HRMS was performed on a Varian 711 instrument.
  • the primary allylic hydroxy compound 4a (1.8 g, 3.6 mmol) in methylene chloride-DMF (4:1) (7.2 mL) was added, and the reaction mixture was stirred at room temperature for one (1) hour. Ethanol (1.8 mL) was added, and the mixture was stirred for an additional ten (10) minutes and was then diluted with ethyl acetate (180 mL). The resulting mixture was filtered through a sintered-glass funnel, packed with silica (3 cm), with a layer of anhydrous sodium sulfate on top, and eluted with ethyl acetate (ca 600 mL).
  • Tetrabutylammonium fluoride (0.6 mmol from a 1.0M solution in THF, Aldrich,) was added by injection under a nitrogen atmosphere to a cold solution (ice bath) of the acid 3b (280 mg, 0.54 mmol) in tetrahydrofuran (THF) (3 mL). The resulting solution was stirred at 0.degree. C. for fifteen (15) minutes. Water was added, and the mixture was extracted several times with ether. The ether layer was dried and evaporated to give the crude product. The product was further purified by silica gel column with ether-petroleum ether (1:1) as eluent.
  • a large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with the desired amount of the powdered active ingredient as described above, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
  • the capsules may also be prepared to include existing compounds useful in treating interstitial cystitis, and/or anticholinergic agents.
  • a mixture of active ingredient in a digestible oil such as soybean oil, lecithin, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing the desired amount of the active ingredient.
  • the capsules are washed and dried for packaging.
  • the soft gelatin capsules may also be prepared to include existing compounds useful in treating interstitial cystitis, and/or anticholinergic agents.
  • a formulation suitable for administration via intravesicular instillation is prepared by dissolving the desired amount of the active ingredient as described above in a suitable volume of saline.
  • the formulation may also be prepared to include existing compounds useful in treating interstitial cystitis, and/or anticholineric agents.
  • the active ingredient may be relatively insoluble in water, it may be advantageously incorporated into liposomes.
  • Cystometrograms were performed under urethane anesthesia (1 g/kg s.c.) using a catheter inserted into the bladder through the bladder dome via a midline abdominal incision. Saline was infused at a rate of 0.04 ml/min to elicit repetitive bladder contractions. Effects of intravenous (i.v.) injection of Compound 3a on bladder overactivity induced by either intravesical administration of acetic acid solution or one day treatment with cyclophosphamide were investigated.
  • cyclophosphamide CYP, 150 mg/kg
  • control CMGs were recorded for 1 to 2 hour prior to i.v. administration of Compound 3a or vehicle. See, example i, above.
  • changes in cystometric parameters such as ICIs, MVP, PT and BP were recorded to evaluate the effects of Compound 3a on cyclophosphamide-induced bladder overactivity.
  • instillation of liposomal-Compound 3a was first conducted. Then, 24 hours and 48 hours after instillation, under urethane anesthesia, bladder hyperactivity was induced by infusing acetic acid at the concentration of 0.125% and 0.25%. Prior to acetic acid infusion, baseline CMG was conducted by saline infusion (0.04 ml/min) to measure intercontraction interval (ICI). A percentage reduction in ICI was measured following acetic acid infusion as an indicator of bladder irritation.
  • ICI reductions in the treatment groups were approximately 50% lower then those of the control groups (saline and empty liposome), suggesting an effective response at both the 24-hour and 48-hour time points. See, FIGS. 9B and 9C , respectively.
  • Each group consisted of a minimum of seven subjects, except for those of a preliminary dose response study, where two subjects were used in each group.
  • the preliminary dose response study indicated an optimal Compound 3a dose of 0.8 mg/ml. See, FIG. 9A .
  • 1.6 mg/ml was highest concentration of Compound 3a encapsulated into liposomes; higher concentrations apparently compromised formulation stability.
  • Comparable results are obtained using any of the compounds of the invention including, but not limited to, Compounds 3a, 3b, 3c, 3d, 3e, their prodrugs (e.g., esters) and pharmaceutically acceptable salts or solvates thereof. Comparable results are also obtained using other models of bladder overactivity using irritants including, but not limited to, nerve growth factor and protamine sulfate.

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8637087B2 (en) 2004-12-13 2014-01-28 Jb Therapeutics Inc. Treatment of interstitial cystitis using (6aR, 10aR)-Δ8-tetrahydrocannabinol-11-OIC acids
WO2019232413A1 (fr) * 2018-05-31 2019-12-05 Corbus Pharmaceuticals Inc. Cannabinoïdes et leurs utilisations
WO2021113656A1 (fr) * 2019-12-04 2021-06-10 Corbus Pharmaceuticals, Inc. Cannabinoïdes et leurs utilisations
WO2021113669A1 (fr) * 2019-12-04 2021-06-10 Corbus Pharmaceuticals, Inc. Cannabinoïdes et utilisations associées
EP3980007A1 (fr) * 2019-06-07 2022-04-13 Selectimmune Pharma AB Méthode pour traiter les problèmes inflammatoires chroniques dans le tractus urinaire inférieur

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9849086B2 (en) * 2012-03-19 2017-12-26 Nanologix Research, Inc. Method and composition for treating cystitis
WO2021067834A1 (fr) * 2019-10-03 2021-04-08 Corbus Pharmaceuticals, Inc. Cannabinoïdes et utilisations associées

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4876276A (en) * 1986-10-24 1989-10-24 Yissum Research Development Co. Of The Hebrew University Of Jerusalem (3S-4S)-7-hydroxy-Δ6 -tetrahydrocannabinols
US4973603A (en) * 1988-06-16 1990-11-27 Sumner Burstein Platelet activating factor antagonist and methods of use therefor
US5338753A (en) * 1992-07-14 1994-08-16 Sumner H. Burstein (3R,4R)-Δ6 -tetrahydrocannabinol-7-oic acids useful as antiinflammatory agents and analgesics
US6162829A (en) * 1997-10-17 2000-12-19 Atlantic Pharmaceuticals, Inc. (3R,4R)-Δ8 -tetrahydrocannabinol-11-oic acids useful as antiinflammatory agents and analgesics
US6335650B1 (en) * 2000-09-28 2002-01-01 International Business Machines Corporation Method and apparatus for adjusting time delays in circuits with multiple operating supply voltages
US6448288B1 (en) * 2000-05-17 2002-09-10 University Of Massachusetts Cannabinoid drugs
US20040048910A1 (en) * 2002-08-22 2004-03-11 Bove Susan Elizabeth Method of treating osteoarthritis
US20040054007A1 (en) * 2000-05-17 2004-03-18 Burstein Summer H Methods for decreasing cell proliferation based on (3r,4r)-delta8-tetrahydrocannabinol-11-oic acids
US20040225001A1 (en) * 2001-01-26 2004-11-11 Vrudhula Vivekananda M. Imidazolyl derivatives as corticotropin releasing factor inhibitors

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US448910A (en) * 1891-03-24 Electric street-car driving-gear
US3536809A (en) 1969-02-17 1970-10-27 Alza Corp Medication method
US3598123A (en) 1969-04-01 1971-08-10 Alza Corp Bandage for administering drugs
US3845770A (en) 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent
US3916899A (en) 1973-04-25 1975-11-04 Alza Corp Osmotic dispensing device with maximum and minimum sizes for the passageway
US4008719A (en) 1976-02-02 1977-02-22 Alza Corporation Osmotic system having laminar arrangement for programming delivery of active agent
US4054007A (en) * 1976-04-15 1977-10-18 Sprayrite Manufacturing Company Row-crop tillage and treating device
US4225011A (en) * 1978-11-27 1980-09-30 Moriyuki Taguchi Method and device for silencing the exhaust noise of internal combustion engines
GB2186485B (en) 1986-02-13 1988-09-07 Ethical Pharma Ltd Slow release formulation
US7313430B2 (en) 2003-08-28 2007-12-25 Medtronic Navigation, Inc. Method and apparatus for performing stereotactic surgery
WO2006065793A2 (fr) 2004-12-13 2006-06-22 Indevus Pharmaceuticals, Inc. Traitement de la cystite interstitielle au moyen d'acides (6ar,10ar)-?8-tetrahydrocannabinol-11-oiques

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4876276A (en) * 1986-10-24 1989-10-24 Yissum Research Development Co. Of The Hebrew University Of Jerusalem (3S-4S)-7-hydroxy-Δ6 -tetrahydrocannabinols
US4973603A (en) * 1988-06-16 1990-11-27 Sumner Burstein Platelet activating factor antagonist and methods of use therefor
US5338753A (en) * 1992-07-14 1994-08-16 Sumner H. Burstein (3R,4R)-Δ6 -tetrahydrocannabinol-7-oic acids useful as antiinflammatory agents and analgesics
US6162829A (en) * 1997-10-17 2000-12-19 Atlantic Pharmaceuticals, Inc. (3R,4R)-Δ8 -tetrahydrocannabinol-11-oic acids useful as antiinflammatory agents and analgesics
US6448288B1 (en) * 2000-05-17 2002-09-10 University Of Massachusetts Cannabinoid drugs
US20040054007A1 (en) * 2000-05-17 2004-03-18 Burstein Summer H Methods for decreasing cell proliferation based on (3r,4r)-delta8-tetrahydrocannabinol-11-oic acids
US6335650B1 (en) * 2000-09-28 2002-01-01 International Business Machines Corporation Method and apparatus for adjusting time delays in circuits with multiple operating supply voltages
US20040225001A1 (en) * 2001-01-26 2004-11-11 Vrudhula Vivekananda M. Imidazolyl derivatives as corticotropin releasing factor inhibitors
US20040048910A1 (en) * 2002-08-22 2004-03-11 Bove Susan Elizabeth Method of treating osteoarthritis

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8637087B2 (en) 2004-12-13 2014-01-28 Jb Therapeutics Inc. Treatment of interstitial cystitis using (6aR, 10aR)-Δ8-tetrahydrocannabinol-11-OIC acids
WO2019232413A1 (fr) * 2018-05-31 2019-12-05 Corbus Pharmaceuticals Inc. Cannabinoïdes et leurs utilisations
CN112739346A (zh) * 2018-05-31 2021-04-30 柯巴斯医药有限公司 大麻素及其用途
EP3980007A1 (fr) * 2019-06-07 2022-04-13 Selectimmune Pharma AB Méthode pour traiter les problèmes inflammatoires chroniques dans le tractus urinaire inférieur
WO2021113656A1 (fr) * 2019-12-04 2021-06-10 Corbus Pharmaceuticals, Inc. Cannabinoïdes et leurs utilisations
WO2021113669A1 (fr) * 2019-12-04 2021-06-10 Corbus Pharmaceuticals, Inc. Cannabinoïdes et utilisations associées

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