Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2002-01-30
2003-12-09
O'Sullivan, Peter (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C564S099000
Reexamination Certificate
active
06660772
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to medicaments containing 2-amino-1-(4-hydroxy-3-methanesulfonamidophenyl)ethanol, one of the two optical isomers thereof, and/or the pharmacologically acceptable salts thereof, particularly for treating urinary incontinence.
The compound according to the invention has the following structure (Formula (I)).
By incontinence is meant an involuntary release of urine, i.e., weakness of the bladder. The various manifestations of urinary incontinence include urge incontinence, reflex incontinence, overflow incontinence, and stress incontinence. The most common form of urinary incontinence is stress incontinence. Women, in particular, are affected by this after more or less difficult childbirth. The reason for this is that pregnancy and labor easily lead to a weakening of the pelvic floor. Other causes of incontinence may lie, for example, in damage to the nerves of the pelvic floor, a congenitally short urethra, or damage to the sphincter muscle.
According to WO 96/32939 it is beneficial to use alpha-1L-agonists in the treatment of urinary incontinence, as they act selectively on the adrenoreceptors of the bladder and thus have a crucial effect on the tonicity of the urethra, without significantly affecting the cardiac circulatory system.
EP 0 538 469 describes 2-amino-1-(2-fluoro-5-methanesulfonamidophenyl)ethanol and the use thereof for treating urinary incontinence.
SUMMARY OF THE INVENTION
Surprisingly, it has now been found that the compound of Formula (I) has an outstanding agonistic effect on alpha-1L-receptors. The substance acts highly selectively on the bladder and inhibits urinary urgency.
The aim is therefore to develop a medicament with which urinary incontinence can be treated in a controlled manner.
A further objective is to develop medicaments which act selectively on the contractile mechanisms of the bladder without seriously affecting other organs such as, e.g., peripheral blood vessels.
Another objective is to develop a medicament for treating urinary incontinence, in particular stress urinary incontinence, which has a relatively long-lasting effect.
Another objective is to develop a method of treating urinary incontinence, in particular stress urinary incontinence.
Preferably, a drug which can be administered orally should be developed.
A further aim is to develop a non-toxic drug with few side-effects.
The overall aim of the present invention is therefore to find an active substance having the profiles described above and to develop a suitable medicament therefrom.
DETAILED DESCRIPTION OF THE INVENTION
The racemate of the compound according to the invention has been known since the 1960s. It is described, for example, in U.S. Pat. No. 3,341,584 and GB 933,584. These publications mention that the racemate has a stimulant effect on alpha- and/or beta-receptors. The Journal of Medicinal Chemistry 1967, 10, page 467, describes an alpha-adrenergic effect.
The enantiomerically pure forms of the compound, i.e., the R- or S-form, are not known as pharmaceutical substances. Furthermore, the use of the compound as a racemate or in enantiomerically pure form, i.e., in the R- or S-form, in a pharmaceutical composition for treating urinary incontinence, in particular stress urinary incontinence, is not known.
The compound is used in a pharmaceutical composition in the form of the racemate or one of the pure enantiomers.
The substance may be used both as a free base and as an acid addition salt. Examples of such salts are salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid, or organic acids such as acetic acid, citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, lactic acid, ascorbic acid, etc. The hydrochloride is preferably used.
The compound according to the invention may be administered as a medicament by inhalation, orally, intranasally, intravenously, subcutaneously, intramuscularly, transdermally, or vaginally, or as a suppository. Oral administration is preferred.
The compound may be administered on its own or in conjunction with other appropriate active substances.
To determine the optimum dose of the active substance for urinary incontinence, various parameters have to be taken into consideration, such as the age and body weight of the patient, and the nature and stage of the complaint.
The preferred dose for humans is between 0.001 mg and 1 g per day, preferably between 0.001 mg and 500 mg, more preferably between 0.01 mg and 100 mg, and most preferably between 0.01 mg and 10 mg.
In some cases a smaller amount may be sufficient, whereas in other cases a larger total amount may be needed.
The total daily dose may be taken in one go or in several portions depending on the treatment regimen. The treatment regimen may also prescribe intervals of more than one day between doses of the drug.
The active substance according to the invention may be administered orally in various formulations, e.g., as a solid, in liquid form, as a powder, in the form of tablets, as a coated tablet, sugar-coated tablets, as an oral disintegrating tablet, as a sublingual tablet, in a capsule, in granulated form, as a suspension, solution, emulsion, elixir, or syrup, in the form of drops or in other forms.
Capsules may be produced, starting from a powder of the kind mentioned above or other powders, which are packed into a capsule, preferably a gelatine capsule.
It is also possible to introduce lubricants known from the prior art into the capsule or to use them to seal the two halves of the capsule. The dissolution rate of a capsule can be increased by the addition of disintegrant or solubilizing substances, such as, for example, carboxymethylcellulose, carboxymethylcellulose calcium, lowly-substituted hydroxypropylcellulose, calcium carbonate, sodium carbonate, sodium carboxymethyl starch, crospovidone, croscarmellose sodium and other substances. The active substance may be contained in the capsule not only as a solid but also in solution or in suspension, e.g., in vegetable oil, polyethyleneglycol, or glycerol, using surfactants, etc.
Tablets (including vaginal tablets) may be prepared in which the powdered mixture is processed to form granules, mixed with other substances if necessary, and then further compressed, for example. The tablets may contain various excipients, e.g., starches, lactose, sucrose, glucose, sodium chloride, urea for soluble or injectable tablets, amylose, various types of cellulose as described above, etc. Glycerol or starch may be added, for example, as moisture retaining agents.
Starch, alginic acid, calcium alginate, pectic acid, powdered agar—agar, formaldehyde gelatine, calcium carbonate, sodium bicarbonate, magnesium peroxide, and amylose, for example, may be used as disintegrants.
Sucrose, stearin, solid paraffin (preferably with a melting point in the range from 50° C.-52° C.), cocoa butter, and hydrogenated fats may be used as anti-disintegrants or solution retardants.
Suitable resorption accelerators include, inter alia, quaternary ammonium compounds, sodium lauryl sulfate, saponins.
Ether may be used as a binder distributor, for example, and cetyl alcohol, glycerol monostearate, starch, lactose, wetting agents (e.g., Aerosol OT, Pluronics, Tweens), etc. may be used as hydrophilizers or breakdown accelerators
Moreover, the following may be considered as tablet-making excipients in general: Aerosil, Aerosol OT ethylcellulose, Amberlite resin, XE-88, Amijel, Amisterol, amylose, Avicel microcrystalline-cellulose, bentonite, calcium sulfate, Carbowax 4000 and 6000, carrageenin, castor wax, cellulose, microcrystalline cellulose, dextran, dextrin, base for pharmaceutical tablets, kaolin, spray dried lactose (USP), lactosil, magnesium stearate, mannitol, mannitol granular N.F. methylcellulose, Miglyol 812 neutral oil, powdered milk, lactose, nal-tab, Nepol-amylose, Pöfizer crystalline sorbitol, plasdone, polyethyleneglycols, polyvinylpyrrolidone, Précirol, calves' foo
Esser Franz
Ishiguro Naoki
Kitagawa Hisato
Muramatsu Ikunobu
Pouzet Pascale
Boehringer Ingelheim Pharma KG
O'Sullivan Peter
Raymond R. P.
Witkowski T. X.
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