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WO1998001125A2 - Isomeres dextrogyres d'oxybutynine et de desethyloxybutynine utilises dans le traitement de l'hyperactivite gastro-intestinale - Google Patents

Isomeres dextrogyres d'oxybutynine et de desethyloxybutynine utilises dans le traitement de l'hyperactivite gastro-intestinale Download PDF

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Publication number
WO1998001125A2
WO1998001125A2 PCT/US1997/012284 US9712284W WO9801125A2 WO 1998001125 A2 WO1998001125 A2 WO 1998001125A2 US 9712284 W US9712284 W US 9712284W WO 9801125 A2 WO9801125 A2 WO 9801125A2
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WO
WIPO (PCT)
Prior art keywords
glycolate
oxybutynin
pharmaceutically acceptable
acceptable salt
butynyl
Prior art date
Application number
PCT/US1997/012284
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English (en)
Other versions
WO1998001125A3 (fr
Inventor
Gunnar Aberg
Original Assignee
Sepracor, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sepracor, Inc. filed Critical Sepracor, Inc.
Priority to AU37999/97A priority Critical patent/AU3799997A/en
Publication of WO1998001125A2 publication Critical patent/WO1998001125A2/fr
Publication of WO1998001125A3 publication Critical patent/WO1998001125A3/fr

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Classifications

    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate

Definitions

  • the invention relates to methods for treating gastrointestinal disorders, such as gastrointestinal hyperactivity or irritable bowel syndrome. BACKGROUND OF THE INVENTION.
  • the compound 4-(diethylamino)-2-butynyl ⁇ -cyclohexyl- ⁇ - hydroxybenzeneacetate also known as 4-(diethylamino)-2-butynyl phenyicyclohexylgiycolate, has the generic name racemic oxybutynin (OXY), and its structure is as follows:
  • the US AN Council has given the hydrochloride salt of racemic oxybutynin the generic name oxybutynin chloride, which is sold under the name of DITROPAN ® , and is an approved drug for the management of urinary incontinence.
  • the preparation of racemic oxybutynin is described in British Patent Specification 940,540.
  • Racemic oxybutynin is used therapeutically in the treatment of urinary incontinence due to detrusor muscle instability.
  • OXY exerts a direct antispasmodic effect on smooth muscle and inhibits the action of acetylchohne on smooth muscle.
  • OXY is quite selective for muscarinic acetylchohne receptors over nicotinic receptors and as a result, no blocking effects are observed at skeletal neuromuscular junctions.
  • OXY relaxes urinary bladder smooth muscle and in patients with conditions characterized by involuntary bladder contractions, cystometric studies have demonstrated that OXY increases vesicle capacity, diminishes the frequency of involuntary contractions of the detrusor muscle, and delays the initial desire to void. OXY is therefore useful in the treatment and prevention of urge incontinence.
  • OXY efficacy of OXY in the bladder has been attributed to a combination of antimuscarinic, direct spasmolytic and local anesthetic effects on the detrusor muscle, but it is believed that the best therapeutic activity of OXY is seen in patients with cholinergically induced incontinence. Because of the antimuscarinic activity of the racemic drug, mydriasis (dilated pupils), xerostomia (dry mouth) and tachycardia (fast heart beats), which involve muscarinic cholinergic receptors, are common and dose-limiting side effects of oxybutynin.
  • the present invention relates to a method for treating gastrointestinal hyperactivity, or irritable syndrome, or other motility disorders involving the gastrointestinal tract, which comprises administering to a patient a therapeutically effective amount of (S)-oxybutynin, or (S)-desethyloxybutynin, or a pharmaceutically acceptable salt of either.
  • the present invention relates to methods for treating gastrointestinal hyperactivity, irritable bowel syndrome, or other motility disorders involving the gastrointestinal tract while reducing or avoiding concomitant liability of adverse effects associated with racemic oxybutynin , which comprises administering to a patient a therapeutically effective amount of (S)-oxybutynin, or (S)-desethyloxybutynin, or a pharmaceutically acceptable salt of either, substantially free of the corresponding R enantiomer.
  • the (S)-oxybutynin, or (S)-desethyloxybutynin, or a pharmaceutically acceptable salt of either, may be administered in the form of a pharmaceutical composition comprising (S)-oxybutynin, or (S)-desethyloxybutynin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising (S)-oxybutynin, or (S)-desethyloxybutynin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Non-cholinergic mechanisms include but are not limited to scars (e.g. , from surgical interventions) causing intestinal smooth muscle pacemaker activity, release of thromboxane, platelet activating factor or other non-muscarinic spasmogens, as well as uncontrolled (nonmuscarinic) release of calcium ions into the cytosol of intestinal smooth muscle cells.
  • the compounds of the present invention are (1) the S enantiomer of 4-(diethylamino)-2-butynyl- ⁇ -cyclohexyl- ⁇ - hydroxybenzeneacetate, also known as 4-(diethylamino)-2-butynyl phenyicyclohexylgiycolate, and hereinafter referred to as (S)-oxybutynin or S- OXY; and (2) the S enantiomer of 4-(ethylamino)-2-butynyl- ⁇ -cyclohexyl- ⁇ - hydroxybenzeneacetate, and hereinafter referred to as (S)-desethyloxybutynin or S-DEO.
  • the isomer of oxybutynin having the S absolute stereochemistry (Registry Number 119618-22-3) is dextrorotatory, and is shown in Formula I:
  • S-OXY and S-DEO may be obtained by resolution of the intermediate mandelic acid followed by esterification.
  • the esterification can be carried out as described by Kachur et al. (op. cit.) for OXY or by the improved method described in PCT application WO96/23492.
  • S-OXY and S-DEO can be obtained by the resolution of the corresponding racemates using conventional means such as fractional crystallization of diastereomeric salts with chiral acids.
  • Other standard methods of resolution known to those skilled in the art include, but are not limited to, simple crystallization and chromatography on a chiral substrate can also be used.
  • compositions contain at least 90% by weight of (S)-oxybutynin or (S)-desethyloxybutynin and 10% by weight or less of (R)-oxybutynin or (R)-desethyloxybutynin, respectively .
  • the compositions contain at least 99% by weight of the S enantiomer and 1% or less of the R enantiomer.
  • the magnitude of a prophylactic or therapeutic dose of S-OXY or S- DEO in the acute or chronic management of disease according to the present invention will vary with the severity and nature of the condition to be treated and the route of administration.
  • the dose and the frequency of the dosing will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose range of S-OXY or S-DEO for the conditions described herein is from about 0.1 mg to about 1000 mg, preferably from about 0.5 mg to about 750 mg, and more preferably from about 1 mg to about 200 mg, in single or divided doses, preferably in divided doses.
  • the therapy should be initiated at a lower dose of S-OXY or S-DEO, perhaps at about 0.5 mg to about 25 mg, and may be increased depending on the patient's global response, e.g., up to about 200 mg.
  • any suitable route of administration may be employed for providing the patient with an effective dosage of S-OXY or S-DEO according to the present invention.
  • oral, sublingual, rectal, parental (subcutaneous, intramuscular, intravenous), intraocular, transdermal, aerosol and like forms of administration may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, microencapsulated systems, transdermal delivery systems, and the like.
  • Pharmaceutical compositions administered according to the present invention comprise S-OXY or S-DEO as the active ingredient, or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier, and optionally, other therapeutic ingredients.
  • Suitable pharmaceutically acceptable acid addition salts for S- OXY or S-DEO include acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pathothenic, phosphoric, p-toluenesulfonic, succinic, sulfuric, tartaric, and the like.
  • compositions of the present invention include suspensions, solutions, elixirs or solid dosage forms.
  • Carriers such as starches, sugars, and microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like are suitable in the case of oral solid preparations (such as powders, capsules, and tablets), and oral solid preparations are preferred over the oral liquid preparations.
  • oral solid preparations such as powders, capsules, and tablets
  • oral solid preparations are preferred over the oral liquid preparations.
  • tablets and capsules represent one of the more advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are employed.
  • tablets may be coated by standard aqueous or nonaqueous techniques.
  • the pharmaceutical compositions of the present invention may be formulated in a soft elastic gelatin capsule unit dosage form by using conventional methods, well-known in the art (see, e.g., Ebert, Pharm. Tech.. U5):44-50(1977 ⁇ ).
  • Soft elastic gelatin capsules have a soft, globular, gelatin shell somewhat thicker than that of hard gelatin capsules, wherein a gelatin is plasticized by the addition of glycerin, sorbitol, or a similar polyol.
  • the hardness of the capsule shell may be changed by varying the type of gelatin and the amounts of plasticizer and water.
  • the soft gelatin shells may contain a preservative to prevent the growth of fungi, such as methyl- and propylparabens and sorbic acid.
  • the active ingredient may be dissolved or suspended in a liquid vehicle or carrier, including, but not limited to, vegetable or mineral oils, glycols such as polyethylene glycol and propylene glycol, triglycerides, surfactants such as polysorbates, or a combination thereof.
  • S-OXY or S-DEO is preferably present in an amount of about 0.1 mg to about 250 mg, more preferably in an amount of about 0.25 mg to about 100 mg, and even more preferably in an amount of about 0.5 mg to about 50 mg.
  • compositions of the present invention suitable for oral administration may be presented as discrete unit dosage forms such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient, as a powder or granules, or as soft elastic gelatin capsules wherein the active ingredient is dissolved or suspended in a liquid carrier, 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.
  • compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients.
  • 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, just as is known for the racemic mixture.
  • 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, which has been milled or granulated to a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active agent 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. All of the foregoing techniques are well know to persons of skill in the pharmaceutical art.
  • Each tablet may contain from about 0.1 mg to about 250 mg, more preferably about 0.25 mg to about 100 mg, and even more preferably about 0.5 mg to about 25 mg, of the active ingredient.
  • the assays were rapidly filtered under vacuum through GF/B glass fiber filters (Whatman) and washed with an ice-cold buffer using a Brandel Cell Harvester. Bound radioactivity was determined with a liquid scintillation counter (LS 6000, Beckman) using a liquid scintillation cocktail (Formula 99, DuPont NEN). The compounds were tested on each receptor at 10 concentrations in duplicate to obtain competition curves. In each experiment, the reference compound for the receptor under investigation was simultaneously tested at 8 concentrations in duplicate to obtain a competition curve in order to validate this experiment.
  • the specific radioligand binding of each receptor was defined as the difference between total binding and nonspecific binding determined in the presence of an excess of unlabeled ligand.
  • IC 50 values concentration required to inhibit 50% of specific binding
  • IC 50 for R- and S-OXY are given in Table 2.
  • the assays were performed using the following methods:
  • the experimental conditions were:
  • the compounds were tested in duplicate on each receptor at a concentration of 10 5 M.
  • the reference compound for the receptor under investigation was simultaneously tested at 8 concentrations in duplicate to obtain a competition curve in order to validate this experiment.
  • the specific radioligand binding of each receptor was defined as the difference between total binding and nonspecific binding determined in the presence of an excess of unlabeled ligand. Mean values, expressed as a percentage of inhibition of specific binding, are presented in Table 5. IC 50 values (concentration required to inhibit 50% of specific binding) were determined by non linear regression analysis of their competition curves. These parameters were obtained by curve fitting using SigmaplotTM software.
  • the resultant data are analyzed for treatment-related differences by one-way analysis of variance (ANOVA). Since only one concentration of antagonist is studied in each strip of intestinal tissue, a modified procedure is used to estimate the pA2 and slope of the Schild regression.
  • ANOVA one-way analysis of variance
  • the concentrations of agonist producing a half-maximal response (the EC 50 ) is estimated for each strip from the second set of concentration-effect data.
  • the EC 50 is obtained from linear regression lines fit to the logarithm of the concentration of drug and the responses bracketing the half maximum level of response.
  • a "concentration ratio" (CR) is calculated as the ratio of the EC 50 of the treated tissue divided by the EC 50 of the untreated tissue.
  • a pKD is calculated as (concentration of antagonist)/(CR-l) and the negative logarithm of the KD is then pooled with the pA2 values to yield an expanded set of pA2 values.
  • the S-DEO is blended with the lactose and cellulose until a uniform blend is formed.
  • the lake is added and further blended.
  • the calcium stearate is blended in, and the resulting mixture is compressed into tablets using a 9/32 inch (7 mm) shallow concave punch.
  • the active ingredient may be milled or granulated prior to blending. Tablets of other strengths may be prepared by altering the ratio of active ingredient to the excipients or to the final weight of the tablet.

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  • Pharmacology & Pharmacy (AREA)
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  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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Abstract

Cette invention concerne un procédé permettant de traiter l'hyperactivité gastro-intestinale, le syndrome du côlon irrité, ainsi que d'autres troubles de motilité liés aux voies gastro-intestinales. Ce procédé consiste à administrer une quantité efficace sur le plan thérapeutique de (S)-oxybutynine, de (S)-déséthyloxybutynine ou d'un de leurs sels acceptable sur le plan pharmaceutique, ces éléments ne comprenant quasiment pas d'énantiomère R correspondant.
PCT/US1997/012284 1996-07-09 1997-07-09 Isomeres dextrogyres d'oxybutynine et de desethyloxybutynine utilises dans le traitement de l'hyperactivite gastro-intestinale WO1998001125A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU37999/97A AU3799997A (en) 1996-07-09 1997-07-09 Dextrorotatory isomers of oxybutynin and desethyloxybutynin in the treatment of gastrointestinal hyperactivity

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US2140296P 1996-07-09 1996-07-09
US60/021,402 1996-07-09

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WO1998001125A2 true WO1998001125A2 (fr) 1998-01-15
WO1998001125A3 WO1998001125A3 (fr) 1998-05-07

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000071108A2 (fr) * 1999-05-20 2000-11-30 Sepracor Inc. Procedes de traitement de l'asthme a l'aide de s-oxybutynine

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB940540A (en) * 1960-07-26 1963-10-30 Mead Johnson & Co Aminoacetylenes and process for preparing the same
WO1996012477A1 (fr) * 1994-10-21 1996-05-02 Leiras Oy Systeme d'administration orale a liberation lente contenant de l'oxybutynine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB940540A (en) * 1960-07-26 1963-10-30 Mead Johnson & Co Aminoacetylenes and process for preparing the same
WO1996012477A1 (fr) * 1994-10-21 1996-05-02 Leiras Oy Systeme d'administration orale a liberation lente contenant de l'oxybutynine

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HUGHES, K.M. ET AL: "Measurement of oxybutynin and its N-desethyl metabolite in plasma, and its application to pharmacokinetic studies in young, elderly and frail elderly volunteers" XENOBIOTICA, vol. 7, July 1992, pages 859-869, XP000572170 cited in the application *
KACHUR, J.F. ET AL: "R and S enantiomers of Oxybutynin: Pharmacological effects in guinea pig bladder and intestine" THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 247, no. 3, 1988, pages 867-872, XP000200584 cited in the application *
NORONHA-BLOB, L. ET AL: "Enantiomers of Oxybutynin: In vitro pharmacological characterization at M1, M2 and M3 muscarinic receptors and in vivo effects on urinary bladder contraction, mydriasis and salivary secretion in guinea pigs" THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 256, no. 2, 1991, pages 562-67, XP000572006 cited in the application *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000071108A2 (fr) * 1999-05-20 2000-11-30 Sepracor Inc. Procedes de traitement de l'asthme a l'aide de s-oxybutynine
WO2000071108A3 (fr) * 1999-05-20 2001-05-17 Sepracor Inc Procedes de traitement de l'asthme a l'aide de s-oxybutynine
US6294582B1 (en) 1999-05-20 2001-09-25 Sepracor Inc. Methods for treatment of asthma using S-oxybutynin

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WO1998001125A3 (fr) 1998-05-07
AU3799997A (en) 1998-02-02

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