A NON-ARRHYTHMOGENIC METABOLITE OF OXYBUTYNIN

Abstract: A method for treating and/or preventing urinary incontinence and pollakiuria while reducing concomitant liability of adverse effects associated with oxybutynin, which comprises administering to a human in need of such treatment a therapeutically effective amount of 4-ethylamino-2-butynyl cyclohexyl-phenyglycolate or a pharmaceutically acceptable salt thereof.

Description: A NON-A HYTHMOGE IC METABOLITE OF OXYBUTYNIN FIELD OF THE INVENTION. The invention relates to the racemic mono-desethyl metabolite of 4-diethylamino- 2-butynyl cyclohexylphenylglycolate. The chemical name of this metabolite is 4- ethylamino-2-butynyl cyclohexylphenylglycolate and it is also called desethyloxybutynin (DEO). The compound 4-diethylamino-2-butynyl cyclohexylphenylglycolate has the generic name oxybutynin (OXY) and is an approved drug for the management of urinary incontinence and pollakiuria. The compound DEO is now suggested to be used by individuals suffering from urinary incontinence or pollakiuria and also by patients suffering from gastrointestinal and other smooth muscle hypermotility disorders. DEO is particularly useful since this compound does not cause the cardiovascular side effects that are caused by OXY. The compound oxybutynin (OXY) and has the following chemical structure: Oxybutynin (OXY) The compound desethyloxybutynin (DEO) and has the following chemical structure: Desethyloxybutynin (DEO) BACKGROUND OF THE INVENTION. Racemic oxybutynin (OXY) is used therapeutically in the treatment of urinary incontinence due to detrusor muscle instability. The drug may also be used in patients suffering from gastrointestinal hypermotility disorders such as for example irritable bowel syndrome (IBS). OXY exerts a spasmolytic effect by inhibiting the contractions of smooth muscles with cholinergic innervation. In patients with conditions characterized by involuntary bladder contractions, clinical studies have demonstrated that OXY increases bladder 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 both incontinence and frequent voluntary urination. A secondary amine metabolite of OXY has been identified in humans after administration of OXY and is called desethyloxybutynin (DEO) (Douchamps et al. 1988). A primary amine metabolite, didesethyl-oxybutynin (DIDEO) has now been synthesized. DIDEO was found to be less potent than DEO as an antimuscarinic agent, but like DEO, DIDEO does not have the cardiac side effects of OXY and DIDEO may be useful as an antimuscarinic drug (Aberg et al. to be published.) A third metabolite, called N-oxide- oxybutynin, has been suggested but may not be chemically or metabolically stable (Lindeke et al., 1981). It has been found that the drug oxybutynin causes cardiac side effects. Example of such side effects are negative inotropic effects, negative chronotropic effects, negative dromotropic effects and prolongation of the QTc-interval of the EKG (Jones et al., 2000). The negative effects of cardiac function can be very serious, particularly in patients taking cardiodepressive drugs and in patients having existing cardiac disease. Certain of these effects are believed to be due to the fact that oxybutynin has potent membrane stabilizing ("local anesthetic") activity. Prolongation of the QTc-interval is caused by inhibition of the delayed rectifier potassium current in cardiac cells. Furthermore, it is known that a prolongation of the QTc-interval is indicative of and strongly correlated to a fatal form of cardiac arrhythmias (ventricular fibrillation) called Torsades de Pointes. Terodiline is another antimuscarinic dug for urinary incontinence and it was withdrawn from the market because it caused prolongation of the QTc interval of the ECG with concomitant and lethal Torsades de Pointes cardiac arrhythmias. It has also been described that certain types of drugs that utilize the same or similar metabolic enzymes as oxybutynin, will further increase the risk for Torsades de Pointes when combined with oxybutynin. Examples of such drugs are ketoconazole and erythromycin. Torsades de Pointes is certainly the most unwanted side effect of oxybutynin, and it is of concern to all patients given oxybutynin. In particular, patients who are of age (Hughes et al. 1992) or patients who have pre-existing cardiovascular conditions, such as for example long basal QTc interval, will therefore be at special risk for Torsades de Pointes arrhythmias. It is in this context of importance that most patients taking drugs for urinary incontinence are elderly individuals. Since the metabolism of oxybutynin to desethyl-oxybutynin is utilizing an enzyme called CYP 3A4, patients who of hereditary reasons are "slow metabolizers" will accumulate high concentrations of oxybutynin and will therefore be at risk for developing drug-induced risk for Torsades de Pointes arrhythmias. It has also been described that certain types of drugs that utilize the same or similar metabolic enzymes as oxybutynin, will further increase the risk for Torsades de Pointes when combined with oxybutynin. Examples of such drugs are ketoconazole and erythromycin. Patients with more than one risk factor, such as for example elderly patients who are "slow metabolizers" are at much higher risk for developing oxybutynin-induced arrhythmias than the general population. Examples of other drugs that have been found to cause prolongation of QTc and consequently cause Torsades de Pointes arrhythmias are the antihistaminic drugs terfenadine (Seldane®) and astemizole (Hismanal®) and the incontinence drug terodiline (Micturin®); all these drugs have been withdrawn from the market because of this side effect. One clinical study has been published where the effect of oxybutynin on QTc was investigated in 21 patients (Hussain et al., 1996). Prolongation of QTc was seen in this study in two of the patients. This was not statistically significant, but the study was a side effect study and in such studies, statistical significance of serious side effects of therapeutic doses of marketed drugs is rare. Keeping in mind that the drug oxybutynin is very commonly used, the prospect of up to 10% of the patients - as indicated by the Hussain study - developing increased QTc intervals is disturbing. While desethyl-oxybutynin is a known metabolite of oxybutynin, the therapeutic usefulness of this compound for the treatment of urinary urge incontinence or pollakiuria or other muscarinic disorders has to our knowledge not previously been described or suggested. SUMMARY OF THE INVENTION The problems of the prior art have been overcome by the present invention, which relates to a method for treating and/or preventing urinary incontinence and pollakiuria while reducing concomitant liability of adverse effects associated with oxybutynin, which comprises administering to a human in need of such treatment a therapeutically effective amount of 4-ethylamino-2-butynyl cyclohexyl-phenylglycolate or a pharmaceutically acceptable salt thereof. More specifically, the present invention relates to a method for treating and/or preventing urinary incontinence and pollakiuria while reducing concomitant liability of cardiac side effects associated with oxybutynin, which comprises administering to a human in need of such treatment a therapeutically effective amount of 4-ethylamino-2-butynyl cyclohexyl-phenylglycolate or a pharmaceutically acceptable salt thereof. In a particularly preferred embodiment, the present invention relates to a method for treating urinary incontinence and pollakiuria while reducing concomitant liability of cardiac arrhythmogenic side effects associated with oxybutynin, which comprises administering to a human in need of such treatment a therapeutically effective amount of 4-ethylamino-2-butynyl cyclohexyl-phenylglycolate or a pharmaceutically acceptable salt thereof DETAILED DESCRIPTION OF THE INVENTION It has now unexpectedly been found that the desethyl metabolite of oxybutynin (DEO) has less "local anesthetic" activity than oxybutynin and therefore less cardiodepressive activity than oxybutynin, while maintaining the therapeutic activities of oxybutynin. It has also surprisingly been found that desethyl-oxybutynin, unlike oxybutynin, does not cause a prolongation of the QTc interval of the ECG, while maintaining the therapeutic activities of oxybutynin. CHEMISTRY Oxybutynin is 4-diethylamino-2-butynyl α-cyclohexyl-α-hydroxybenzeneacetate, also known as 4-diethylamino-2-butynyl cyclohexylphenylglycolate and herein referred to as OXY. The generic name given to the hydrochloride salt of oxybutynin by the USAN Council is oxybutynin chloride; it is sold under various names, such as for example Ditropan ® and Ditropan XL ® Desethyloxybutynin is 4-ethylamino-2-butynyl cyclohexylphenyl-glycolate and is a known metabolite of oxybutynin (Hughes et al. 1992). This compound is herein referred to as DEO. No generic name is known for this compound or any of its salts. The overall process for preparing DEO involves: (a) the preparation of the side chain 4-ethylamino-2-butynyl chloride from dichlorobutyne (b) by standard esterification technique, reacting cyclohexylphenyl glycolic acid with 4-ethylamino-2-butynyl chloride to produce 4-ethylamino-2-butynyl cyclohexylphenyl-glycolate (DEO). An alternative process for preparing the compound of the invention involves the preparation of a hydroxylated side chain in stead of the above mentioned halogenated side chain. Cyclohexylphenylglycolic acid is commercially available from SIPSY Chem Corp., 2137 Route 33, Suite 2, Hamilton Square, NJ 08690. A process for preparing the R-isomer of DEO is described in US Patent 6,123,961 and a process for preparing the S-isomer of DEO is described in US patent 5,532,278, the disclosures of which are hereby incorporated by reference. DOSING, DOSAGE FORMS, PHARMACEUTICAL COMPOSITIONS The magnitude of a prophylactic or therapeutic dose of the compound of this invention in the acute or chronic management of disease 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. In general, the total daily dose range for the compound of this invention for the conditions described herein is from about 1 mg to about 100 mg in single or divided doses, preferably in divided doses. In managing the patient, the therapy should be initiated at a lower dose, perhaps at about 0.5 mg to about 25 mg, and may be increased up to about 200 mg depending on the patient's global response. It is further recommended that patients over 65 years and those with impaired renal or hepatic function initially receive low doses and that they be titrated based on individual response(s) and plasma drug level(s). It may be necessary to use dosages outside these ranges, as will be apparent to those skilled in the art. Further, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient response. The terms "a therapeutically effective amount" and "an amount sufficient to treat urinary incontinence but insufficient to cause adverse effects" are encompassed by the above-described dosage amounts and dose frequency schedule. Any suitable route of administration may be employed for providing the patient with an effective dosage of the compound of this invention. For example, oral, sublingual, rectal, parental (subcutaneous, intramuscular, intravenous), intraocular, transdermal, aerosol and like forms of administration may be employed. Dosage forms include tablets, controlled-release tablets, troches, dispersions, suspensions, solutions, capsules, microencapsulated systems, sprays, transdermal delivery systems, and the like. The pharmaceutical compositions of the present invention comprise the compound of the present invention as the active ingredient, or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier, and optionally, other therapeutic ingredients. The terms "pharmaceutically acceptable salts" or "a pharmaceuti-cally acceptable salt thereof refer to salts prepared from pharmaceuti-cally acceptable non-toxic acids. Suitable pharmaceutically acceptable acid addition salts for the compound of the present invention include acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pathothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, and the like. The hydrochloride is particularly preferred. The 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. Because of their ease of administration, tablets and capsules represent one of the more advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Since the compound of the invention has a relatively short duration of action in the body, it may be advantageous to administer the drug in a controlled-released or slow-release formulation, thereby decreasing the frequency of drug administrations to the patient as well as reducing the side effects, including the anticholinergic side effects, of the drug. The compounds of the present invention may also be administered by controlled release means and delivery devices such as those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, and PCT application WO92/20377, the disclosures of which are hereby incorporated by reference. Various forms of controlled release or slow release transdermal administration forms and devices can also be used to improve the convenience of dosage for the patient and are hereby incorporated by reference. Pharmaceutical 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 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. Such 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. 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, just as is known for the racemic mixture. For example, 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, 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 0.5 mg to about 25 mg of the active ingredient. Example 1 ORAL UNIT DOSAGE FORMULATION Tablets: Ingredients per tablet per batch of 10,000 tablets DEO 5 mg 50 g Microcrystalline cellulose 30 mg 300 g Lactose 70 mg 700 g Calcium stearate 2 mg 20 g FD&C Blue #1 Lake 0.03 mg 300 mg The compound of the present invention is blended with the lactose and cellulose until a uniform blend is formed. The lake is added and further blended. Finally, the calcium stearate is blended in, and the resulting mixture is compressed into tablets using a 9/32 inch (7 mm) shallow concave punch. Tablets of other strengths may be prepared by altering the ration of active ingredient to the excipients or to the final weight of the tablet. The surprising utility of the compound of the present invention has been established by the following studies. PHARMACOLOGICAL STUDIES 1. Ligand Binding Studies: Muscarinic Receptors. The experiments are carried out on membranes prepared from SF9 cells infected with baculo virus to express human recombinant muscarinic receptor subtypes. After incubation with the test article and the proper radioligand and washing, bound radioactivity is determined with a liquid scintillation counter, using a commercial scintillation cocktail. The specific radioligand binding to each receptor is defined as the difference between total binding and nonspecific binding determined in the presence of an excess of unlabelled ligand. IC 50 values (concentrations required to inhibit 50% of specific binding) were determined by non linear regression analysis of the competition curves. Results: Binding of oxybutynin (OXY) and desethyl-oxybutynin (DEO) to human Ml -M4 muscarinic receptors. OXY DEO Ref. Compound Receptor IC 50 (nM) IC 50 (nM) IC 50 (nM) Mlh 2.9 1.8 Pirenzepine 11.9 M2h 14.7 7.0 Methoctramine 14.6 M3h 6.8 3.4 4-DAMP 1.6 M4h 4.0 2.0 4-DAMP 0.87 Conclusions: Both oxybutynin and desethyl-oxybutynin had high affinity for the human Ml - M4 receptors. Desethyl-oxybutynin was approximately twice as active as oxybutynin. 2. Functional Characterization of Antimuscarinic/ Antispasmodic Activity. Strips of urinary bladder muscle tissue are removed from the body of male Hartley guinea pigs weighing 400-600 g. The strips are suspended in an oxygenated buffer of the following composition, in mM: NaCl, 133; KCl, 4.7; CaCl 2 , 2.5; MgSO 4 , 0.6; NaH 2 PO 4 , 1.3; NaHCO 3 , 16.3; and glucose, 7.7, or a similar balanced physiological solution. They are maintained at constant temperature. Contractions are recorded with isometric transducers (Model FT- 10) on an ink- writing polygraph. The strips allowed to equilibrate with the bathing solution for one hour before proceeding with the experiment. In order to assess the viability of each tissue and to serve as a frame of reference, contractions of each strip of tissue are recorded initially in response to exposure to a tissue medium in which the NaCl was replaced by KCl to yield a concentration of 137.7 mM KCl in the medium. This is followed by return to the standard medium, and then by exposures to progressively creasing concentrations of carbachol, with separate exposures to each concentration only until the peak response has been recorded. Then, leaving one strip untreated and/or one strip exposed to the test solution to serve as control tissue(s), the remaining strips each are exposed for one hour to one concentration of an antagonist. Finally, the responses to increasing concentrations of carbachol followed by exposure to 137.7 mM KCl are recorded a second time. To determine whether antagonists decrease the peak response to agonists, the peak tension developed by each strip during the second set of determinations is expressed as a percent of the peak tension developed during the first concentration-effect determination. Then, for each antagonist the resultant data are analyzed using standard statistical methodology. Results: Inhibition by oxybutynin and desethyl-oxybutynin of carbachol-induced contractions of isolated strips of guinea pig bladder. Summary of Schild analysis pA2 Slope Compound (mean±SE) (mean±SE) Oxybutynin 8.9 ± 0.2 1.18 ± 0.1 Desethyl-oxybutynin 8.6 ± 0.3 1.35 ± 0.3 pA 2 = the negative logarithm of the concentration of an antagonist that doubles EC 50 of an agonist. Conclusions: Both oxybutynin and desethyl-oxybutynin potently inhibited cholinergically induced contractions of the isolated guinea pig detrusor muscle. There was no statistically significant difference in spasmolytic activity between the two compounds in this study. The slopes were not different from unity, which is consistent with the interaction of each compound with only one receptor type (M-3.) 3. Cardiac arrhythmogenic side effects. Male guinea pigs (450-600 g) are anesthetized with freshly prepared dialurethane sodium. The jugular vein is catheterized for iv administration of test drugs and the trachea is exposed and cannulated. Subdermal electrodes are positioned for Lead II electrocardiogram recording, monitored on a Grass Polygraph recorder, set at a paper speed of 50 mm/sec. The animals are allowed to stabilize for 30 minute after completion of surgery, and three baseline EKG recordings are then made at 10-minute intervals. The animals are then given 5 mg/kg of a test compound or vehicle as an intravenous infusion over 30 min. EKG recordings are used to determine QT intervals and heart rates. To compensate for variations in heart rates, QTc intervals are calculated from QT- and RR- intervals as known to those skilled in the art (Bazett's formula). Prolongation of QTc is indicative of a prolonged action potential, caused by an inhibition of the delayed rectifier potassium channel. Prolongation of QTc is the known cause of Torsades de Pointes ventricular fibrillation by drugs such as terfenadine, astemizole and terodiline (now withdrawn from the market). Results: Effects of oxybutynin (OXY) and desethyl-oxybutynin (DEO) on QTc and heart rate (HR) Compound N ΔQTc (%) ΔHR (bpm) OXY 7 + 12 ± 2.0 — 5 ± 12 DEO 8 — 4 ± 1.0 + 8 ± 5 Vehicle 8 — 3 ± 1.0 — 0.4 ± 3 Conclusions: Oxybutynin caused a statistically significant increase in QTc interval, while there were no such effects of desethyl-oxybutynin. The effects on heart rate were not significant since there was a highly variability within the oxybutynin group of animals. EQUIVALENTS Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents include numerous pharmaceutically acceptable salt forms e.g. sulfate, fumarate, hydrobromide, hydrochloride, dihydrochloride, methanesulphonate, hydroxynaphthoate, chlorotheophylline or where appropriate one or other of the hydrate forms thereof, see Merck Index 11th edition (1989) items 9089, 209, 3927, 4628, 8223, 5053, 5836, 8142, 2347, 7765, 1840, 9720, 7461, 1317,4159, and 963 and references cited therein and Am. Rev. Resp. Dis. 1988, 137: (4;2/2) 32. Such equivalents also include the simultaneous administration of the compound of the present invention with any other drug that is used to combat diseases in mammals, mentioned in this document. Such equivalents also include the co-administration of the compound of the present invention with any other compound or drug that may be used in combination with medication for urinary incontinence or intestinal hyperactivity or other forms of smooth muscle, such as for example renal, biliary and respiratory/bronchial hyperactivity or hyperreactivity. Those skilled in the art of medicine will also realize that higher or lower doses than those indicated here may be preferred and the doses may be given more or less frequently than suggested here. The didesethyl metabolite of oxybutynin has pharmacological activities that are similar to those of des-ethyl oxybutynin, although the didesethyl metabolite has somewhat lower affinity for muscarinic receptors than the des-ethyl metabolite. Since the didesethyl metabolite does not prolong the QTc interval of the ECG, this metabolite and its optically active isomers and the salt forms thereof are of therapeutic use and are intended to be included into the present invention. The compound desethyl-oxybutynin is an antimuscarinic drug that is useful also for other therapeutic indications than urinary incontinence, pollakiuria and intestinal hyperactivity. Thus, desethyl-oxybutynin may decrease the contractile activity of other smooth muscles with muscarinic (cholinergic) innervation, as for example biliary smooth muscle, renal smooth muscle and respiratory/ bronchial smooth muscle. The drug can also effectively inhibit muscarinic innervation to various glands, such as for example sweat glands and may therefore be used for the treatment of excessive sweat production. Desethyl-oxybutynin can also be used for treatment of acute pancreatitis. Des-ethyl oxybutynin may be particularly useful for these therapeutic indications since desethyloxybutynin does not carry the risk for prolonged QTc and Torsades de Pointes cardiac arrhythmias. These therapeutic indications for desethyl-oxybutynin are also included in the present invention Those skilled in the art will realize that the terms intestinal hyperactivity disorders and intestinal hypermotility disorders include irritable bowel syndromes (IBS). Those skilled in the art of pharmacology will realize that the compounds of the invention, having certain pharmacological properties (such as antimuscarinic activity on various receptor types, calcium antagonistic activity, spasmolytic activity on various types of smooth muscle etc.), while not causing cardiac side effects, such as for example Torsades de Pointes arrhythmias, may be useful for other indications than those listed here. Such indications are equivalents to the specific embodiments of the invention described herein. All equivalents are intended to be included in this present invention.

Claims: CLAIMS 1. A method for treating urinary incontinence and pollakiuria while reducing concomitant liability of adverse effects associated with oxybutynin, which comprises administering to a human in need of such treatment a therapeutically effective amount of 4-ethylamino-2-butynyl cyclohexyl-phenylglycolate or a pharmaceutically acceptable salt thereof. 2. A method for treating urinary incontinence and pollakiuria while reducing concomitant liability of cardiac side effects associated with oxybutynin, which comprises administering to a human in need of such treatment a therapeutically effective amount of 4-ethylamino-2-butynyl cyclohexyl-phenylglycolate or a pharmaceutically acceptable salt thereof. 3. A method for treating urinary incontinence and pollakiuria while reducing concomitant liability of cardiac arrhythmogenic side effects associated with oxybutynin, which comprises administering to a human in need of such treatment a therapeutically effective amount of 4-ethylamino-2-butynyl cyclohexyl-phenylglycolate or a pharmaceutically acceptable salt thereof. 4. The method of claim 1, wherein 4-ethylamino-2-butynyl cyclohexylphenylglycolate or a pharmaceutically acceptable salt thereof is administered by inhalation or by parenteral, transdermal, rectal, sublingual or oral administration. 5. The method of claim 2, wherein 4-ethylamino-2-butynyl cyclohexylphenylglycolate or a pharmaceutically acceptable salt thereof is administered by inhalation or by parenteral, transdermal, rectal, sublingual or oral administration. 6. The method of claim 3, wherein 4-ethylamino-2-butynyl cyclohexylphenylglycolate or a pharmaceutically acceptable salt thereof is administered by inhalation or by parenteral, transdermal, rectal, sublingual or oral administration. 7. The method of claim 1, wherein 4-ethylamino-2-butynyl cyclohexylphenylglycolate or a pharmaceutically acceptable salt thereof is administered orally in an extended release or controlled release formulation. 8. The method of claim 2, wherein 4-ethylamino-2-butynyl cyclohexylphenylglycolate or a pharmaceutically acceptable salt thereof is administered orally in an extended release or controlled release formulation. 9. The method of claim 3, wherein 4-ethylamino-2-butynyl cyclohexylphenylglycolate or a pharmaceutically acceptable salt thereof is administered orally in an extended release or controlled release formulation. 10. The method of claim 1, wherein 4-ethylamino-2-butynyl cyclohexylphenylglycolate or a pharmaceutically acceptable salt thereof is admimstered transdermally. 11. The method of claim 2, wherein 4-ethylamino-2-butynyl cyclohexylphenylglycolate or a pharmaceutically acceptable salt thereof is administered transdermally. 12. The method of claim 3, wherein 4-ethylamino-2-butynyl cyclohexylphenylglycolate or a pharmaceutically acceptable salt thereof is administered transdermally. 13. The method of claim 1 wherein 4-ethylamino-2-butynyl cyclohexylphenylglycolate or a pharmaceutically acceptable salt thereof is administered from about 0.5 mg to about 200 mg per day. 14. The method of claim 2 wherein 4-ethylamino-2-butynyl cyclohexylphenylglycolate or a pharmaceutically acceptable salt thereof is administered from about 0.5 mg to about 200 mg per day. 15. The method of claim 3 wherein 4-ethylamino-2-butynyl cyclohexylphenylglycolate or a pharmaceutically acceptable salt thereof is administered from about 0.5 mg to about 200 mg per day.

Inventors: ABERG A K GUNNAR, ABERG, A., K, GUNNAR
Applicants: BRIDGE PHARMA INC, BRIDGE PHARMA, INC.
Application year: 2001
Main classification: A61K31
IPC codes: A61K31