CN1223575A - Treating urinary incontinence using (S)-oxybutynin and (S)-desethyloxybutynin - Google Patents

Abstract

A method for treating urinary incontinence while avoiding concomitant liability of adverse effects associated with racemic oxybutynin is disclosed. The method comprises administering from 100 mg to 1 000 mg/day of (S)-oxybutynin, (S)-desethyloxybutynin or a pharmaceutically acceptable salt thereof, substantially free of the corresponding R enantiomer. Pharmaceutical compositions in the form of tablets, soft elastic gelatin capsules and transdermal devices are also disclosed, comprising an acceptable carrier and up to 500 mg of (S)-oxybutynin or (S)-desethyloxybutynin.

Description

With (S)-oxibutynin and (S)-desethyloxybutynin treatment urinary incontinence

Invention field

The present invention relates to optical voidness (S)-oxibutynin (Oxybutynin) (S-OXY) and (S)-method and the dosage form of desethyloxybutynin (S-DEO) treatment urinary incontinence.

Background of invention

Racemic oxibutynin (OXY) is used for the treatment of enterokinesia and crosses strong and because the urinary incontinence that urgent flesh unstability causes.Racemic oxibutynin is directly bestowed the spasmolytic effect and is suppressed the effect of acetylcholine to smooth muscle smooth muscle.It is atropinic 1/5th that the cholinolytic activity that it compels flesh to rabbit has only, but the spasmolytic activity is its 4 to 10 times.It has suitable selectivity to M-ChR having in the presence of the nicotine receptor, does not consequently observe the blocking effect to skeleton MNJ or autonomic ganglion.

Raceme oxibutynin energy diastole smooth muscle of bladder, and the intravesical pressure measurement Research with imperious bladder contraction characteristic patient is shown, the raceme oxibutynin can increase the capacity of bladder, reduces the nonvoluntary contraction frequency of compeling flesh and postpones the excretory requirement of beginning.So it all is useful for treatment and prevention urinary incontinence with often arbitrarily urinating.The raceme oxibutynin is the direct spasmolytic of Antimuscarinic sample to the effectiveness of bladder and to compeling the comprehensive of flesh smooth muscle local anesthesia.Because the Antimuscarinic sample activity of racemic drugs, xerostomia (xerostomia) and platycoria (pupil diastole) are very common side effect, and these phenomenons relate to acetylcholine muscarinic receptor.In fact, to mention " inevitably platycoria, xerostomia, tachycardia etc. " be to follow people such as (, Arch.Int.Pharmacodyn.156,467-488 (1965), 481) Lish that uses that the raceme oxibutynin produces at least one researcher.The high rate of anticholinergic side effects (40 to 80%) often causes reducing dosage or therapy discontinued.

Pharmaceutical research proposition R-enantiomer to independent enantiomer is effective enantiomer.The conclusion that people such as Noronha-Blob (J.Pharmacol.Exp.Ther.256,562-567 (1991)) draw is, the cholinergic antagonism of raceme oxibutynin (external by it to M ₁, M ₂And M ₃The affinity of receptor subtype, and measuring by its various physiological reactions in vivo) can mainly ascribe the activity of (R)-enantiomer to.They find, it is similar that the intensity of all physiological reaction raceme oxibutynin and its enantiomer is put in order, promptly (R)-oxibutynin is better than or equals the raceme oxibutynin, and than (S)-oxibutynin be eager to excel many, (S)-oxibutynin is than weak 1 to 2 order of magnitude of (R)-oxibutynin.The present invention's general introduction

Find that unexpectedly optically pure in fact oxibutynin (S)-enantiomer and its go (the S)-enantiomer of ethyl metabolite to provide good therapeutical effect to the treatment urinary incontinence.

Optically pure (S)-oxibutynin (S-OXY) and (S)-desethyloxybutynin (S-DEO) provides this treatment, and lowered widely those with use the raceme oxibutynin relevant, and mainly by untoward reaction that anticholinergic activity produced.These untoward reaction include, but are not limited to, xerostomia, platycoria, sleepy, nauseating, constipation, cardiopalmus and tachycardia.Administration (S)-oxibutynin or S-DEO alleviate the cardiovascular side effects of raceme oxibutynin, and for example tachycardia and cardiopalmus are to have therapeutic value especially.

The reactive compound of these compositionss and method is the optical isomer of oxibutynin and desethyloxybutynin.The preparation of raceme oxibutynin is narrated in british patent specification 940,540.Chemically, reactive compound is (1) α-cyclohexyl-Alpha-hydroxy phenylacetic acid 4-(lignocaine)-2-butyne base ester, be also referred to as benzyl ring hexyl glycolic acid 4-(lignocaine)-2-butyne base ester, the S-enantiomer that is called oxibutynin hereinafter, (2) α-cyclohexyl-Alpha-hydroxy phenylacetic acid 4-(ethylamino)-2-butyne base ester is called the S-enantiomer of desethyloxybutynin hereinafter.By USAN committee to the raceme ditropan tablete fixed belong to oxybutynin chloride by name together, it is with trade name Ditropan ^Sell.

The isomer (registration number 119618-22-3) that oxibutynin has a S absolute stereo chemistry is for the dextrorotation photosensitiveness, shown in formula I: The S enantiomer of desethyloxybutynin is shown in formula II:

Existing people described synthetic people such as (, J.Pharmacol.Exp.Ther.247,867-872 (1988)) Kachur of (S)-oxibutynin, but (S)-oxibutynin there is no supply of commodities now.The clinical effectiveness of all reports is all obtained by racemic mixture, though having been narrated the pharmacology of Cavia porcellus and rat, independent enantiomer (saw people such as Kachur, J.Pharmacol.Exp.Ther.247, people such as 867-872 (1988) and Noronha-Blob, J.Pharmacol.Exp.Ther.256,562-567 (1991)).We have described the synthetic and pharmacology of (S)-desethyloxybutynin in PCT application WO96/23492.

An aspect that the present invention relates to is the method for the untoward reaction followed of treatment urinary incontinence and avoiding, and it comprises (the S)-oxibutynin that does not contain corresponding R-enantiomer in fact, (S)-desethyloxybutynin or their the medicinal acceptable salt of the people of this treatment of needs being given to treat effective dose.

What the present invention relates to is to comprise (S)-oxibutynin, (S)-desethyloxybutynin or their the medicinal acceptable salt and the pharmaceutical composition of medicinal acceptable carrier that does not contain corresponding R stereoisomer in fact on the other hand." do not contain its R-enantiomer in fact " and " not containing corresponding R-enantiomer in fact " means (S)-oxibutynin of containing at least 90 weight % in the compositions or (S)-desethyloxybutynin and 10 weight % or lower (R)-oxibutynin or (R)-desethyloxybutynin at this used term.In a preferred embodiment, this compositions contains S-enantiomer and 1 weight % or the R enantiomer still less of at least 99 weight %.

This optically pure in fact (S)-oxibutynin or (S)-desethyloxybutynin can be through parenteral route, rectum, intravesical, transdermal, oral or aerosol delivery.Oral and transdermal administration is preferred, and medicine-feeding rate is about 0.1mg every day about 1g extremely.

What the present invention relates to is the medicine single dose dosage form of tablet, elasticity Gelseal or transdermal delivery device form more on the one hand, and this pharmaceutical dosage form comprises (the S)-oxibutynin that does not contain corresponding R stereoisomer in fact, (S)-desethyloxybutynin or their the medicinal acceptable salt and the medicinal acceptable carrier for the treatment of effective dose.Tablet and elasticity Gelseal can prepare with conventional method known in the art, and the amount of (S)-oxibutynin, (S)-desethyloxybutynin or their medicinal acceptable salt is preferably about 0.1mg-500mg in each single dose, more preferably about 25mg-250mg most preferably is about 100mg-200mg.In transdermal delivery device, add penetration enhancer, can improve transdermal administration.

Detailed description of the present invention

The S enantiomer of oxibutynin and DEO can be split by the intermediate mandelic acid, esterification obtains then.The OXY esterification can be carried out (op.cit.) by the described method of people such as Kachur, or with improving one's methods of describing among the PCT application WO96/23492.Alternate method is that the S-enantiomer of OXY and DEO can be split with usual way by racemic oxibutynin or DEO, for example forms diastereoisomeric salt with chiral acid and obtains through fractional crystallization.The standard method for splitting that other are well known to those skilled in the art includes, but are not limited to, simple crystallization process and on chirality substrate chromatography also can use.

Pictorial representation system use therein raceme, two-scale and scale or enantiopure compound takes from Maehr.J.Chem.Ed.62,114-120 (1985).Wedge shape entity or dotted line (shown in formula I) is used to mark the absolute configuration of chiral element, the absolute configuration of the midbody compound of wedge-like profile and dotted line mark enantiomer-pure.

(S)-the big young pathbreaker of dosage of oxibutynin or S-DEO needs when the acute or chronic disease that prevention or treatment will be punished changes with want sanatory seriousness and character and route of administration.Dosage or administration frequency also will change with age, body weight and the reaction of individual patient.-as, (S)-oxibutynin or S-DEO are the about 1g of about 0.1mg-to disease total dose range every day described in this, be preferably the about 600mg of about 0.4mg-, the about 1g of more preferably about 100mg-, even the about 750mg of more preferably about 240mg-, and most preferably be about 300-600mg, can single dose or fractionated dose, preferably fractionated dose.When handling patient, treatment should may be about 80mg from lower dosage, and the general reaction according to patient increased to about 600mg/ days then.

Surpassed 65 years old and those kidneys and liver function diminish the patient of wound for the age, more advance-go on foot to be recommended in the low dosage of acceptance when initial, and on the basis of individual reaction and haemoconcentration, do adjustment gradually.To some case, understand as those skilled in the art, may need to exceed the dosage of this scope.More and, it is pointed out that the clinician or the treatment doctor will know the treatment of when interrupting, adjust or terminate in conjunction with the reaction of individual patient.The words and phrases of " treatment effective dose " and " enough treat urinary incontinence but be not enough to cause the dosage of untoward reaction " are included among above-mentioned dosage and the administration frequency scope.

Can be with any suitable route of administration so that (the S)-oxibutynin or the S-DEO of patient's effective dose to be provided.For example, can use oral, rectum, parenteral route (subcutaneous, intramuscular, vein), transdermal, aerosol and similar form administration.And directly per urethra is to intravesical administration, as people such as Massad to the raceme oxibutynin described [J.Urol.148,595-597 (1992)].Dosage form comprises tablet, lozenge, dispersant, suspensoid, solution, capsule, transdermal drug delivery system etc.

Pharmaceutical composition of the present invention comprises (S)-oxibutynin and S-DEO as effective composition, or the acceptable salt of its medicine, also can comprise medicine acceptable carrier and other optional therapeutic component.

Term " the acceptable salt of medicine " or " the acceptable salt of its medicine " are meant the salt that is equipped with by acceptable avirulence processed with acid on the materia medica.The suitable acceptable acid of medicine with the The compounds of this invention addition comprises acetic acid, benzenesulfonic acid (besylate), benzoic acid, camphorsulfonic acid, citric acid, ethane sulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, Loprazolam, glactaric acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulphuric acid, tartaric acid, p-methyl benzenesulfonic acid etc.Hydrochloric acid is useful especially, and in fact, below what use in the research narrated is hydrochlorate.

Compositions of the present invention comprises suspensoid, solution, elixir or solid dosage forms.Carrier such as starch, sugar and microcrystalline Cellulose, diluent, granulation agent, lubricant, bonding agent, disintegrating agent etc. are applicable to the situation (for example powder, capsule, and tablet) of oral solid formulation, and oral solid formulation than oral liquid more preferably simultaneously.Tablet and capsule will be used the solid medicinal carrier in this case because a kind of more favourable single oral dose dosage form is represented in their easy administrations.If desired, the aqueous solution of tablet available standards or non-aqueous solution method coating.

In preferred embodiments, can use conventional method known in the art (to see Ebert, Pharm.Tech., 1 (5): 44-50 (1977)) pharmaceutical composition of the present invention is shaped to elasticity Perle single dose dosage form.The elasticity Perle has soft, globular gelatin shell, and the thickness of this shell is thicker than hard gelatin capsule, wherein, adds glycerol, sorbitol or similar polyhydric alcohol and can make the gelatin plasticizing.The hardness of capsule shells changes according to the type of gelatin and the consumption of plasticizer and water.Soft gelatin shell can comprise antiseptic such as methyl butex and propylparaben and sorbic acid, to prevent the growth of mycete.Active component solubilized or be suspended in the liquid carrier, as vegetable oil or mineral oil, dihydroxylic alcohols such as Polyethylene Glycol and propylene glycol, triglyceride, surfactant such as Spheron MD 30/70, the perhaps combination of above material.In the present invention's elasticity Perle single dose of drug dosage form, (S)-amount of oxibutynin or S-desethyloxybutynin is preferably the about 500mg of about 0.1mg-, the about 250mg of more preferably about 25mg-, and most preferably be about 100mg-200mg.

Except that above-mentioned regular dosage form, The compounds of this invention also can be by other controlled release method well known by persons skilled in the art and doser administration.

The pharmaceutical composition of the present invention that is applicable to oral administration can be the single dose form of simple grain such as capsule, cachet, tablet, all contain the effective ingredient of measured quantity in advance in every, as powder or granule, perhaps wherein active component is dissolved or suspended in elasticity Gelseal in the liquid carrier, perhaps solution in waterborne liquid or non-aqueous liquid or suspension, or oil-in-water Emulsion or water in oil liquid emulsion.These compositionss can prepare with any method of pharmacy, but all methods all comprise active component and the associating step of carrier that constitutes one or more neccessary compositions.Generally speaking, this compositions is prepared as follows: the solid carrier of active component and aqueous carrier or fine dispersion or both all had equably and closely mixes, then, if desired, product is made the shape that needs, as known racemic mixture.

The surprising practicality of S enantiomer of OXY and DEO is to be established by following research.

Oxibutynin enantiomer (R)-and (S)-oxibutynin and people M ₁, M ₂, M ₃And M ₄The conjugated protein source of M-ChR hypotype

Experiment be by the SF9 cell of baculovirus infection with the expressing human M that recombinates ₁, M ₂, M ₃And M ₄Muscarine hypotype and carry out on the film for preparing.Binding analysis

Table 1

Receptor	Radioligand	Concentration	Non-specific	Incubation	Reference compound
						????M 1H	???[ 3H] pirenzepine	???2nM	Atropine (1 μ M)	?60min ??27℃	Pirenzepine
????M 2H	???[ 3H]AF-DX?384	???2nM	Atropine (1 μ M)	?60min ??27℃	Aesthstic he bright (methoctramine)
						????M 3H	???[ 3H]4-DAMP	???0.8nM	Atropine (1 μ M)	?60min ??27℃	?????4-DAMP
????M 4H	???[ 3H]4-DAMP	???0.3nM	Atropine (1 μ M)	?60min ??27℃	?????4-DAMP

Behind the incubation, analyte filters fast through GF/B glass fiber filter (Whatman) under vacuum, and washs with the Brandel cell harvestor with ice-cold buffer.(LS6000 Beckman) measures with liquid scintillation cocktail (Formula99, Dupont NEN) bonded radioactivity with liquid scintillation counter.Experimental program

Chemical compound obtains competition curve with 10 kinds of concentration as duplicate determination to every kind of receptor.In the experiment, the receptor reference compound of research also confirms this experiment with 8 kinds of concentration duplicate determinations to obtain competition curve simultaneously each time.Analysis and result's expression

The combination of the specificity radioligand of every kind of receptor is to determine with total binding and in the difference that the non-specific binding of measuring in the presence of the excessive unlabelled part is arranged.Measure IC with the competition curve that nonlinear regression analysis obtains ₅₀Value (suppressing specificity) in conjunction with 50% o'clock needed concentration.These parameters are for using Sigmaplot ^TMSoftware does that curve fitting obtains.The IC of R-and S-OXY ₅₀See Table 2.

Table 2

R-oxibutynin and S-oxibutynin are to the combination of people's M-ChR hypotype M1-M4

Receptor	???R-OXY?IC 50(nM)	???S-OXY?IC 50(nM)	Reference compound IC 50(nM)
				???M 1	??????0.99	??????47.6	Pirenzepine 11.9
???M 2	??????9.9	??????178	Aesthstic he bright 14.6
				???M 3	??????1.8	??????149	????4-DAMP?1.6
???M 4	??????1.2	??????100	????4-DAMP?0.87

A little less than these results show that S-OXY is than the affinity of R-OXY to the M-ChR hypotype.(R)-and (S)-oxibutynin to calcium channel in conjunction with binding analysis

Binding analysis carries out with following method:

Table 3

Receptor	Film	Reference compound	List of references
				Calcium channel (T+L, diltiazem position)	Rat cerebral cortex	Diltiazem	Schoemakor?and Langer(1985)
Calcium channel (T+L, verapamil position)	Rat cerebral cortex	????D600	Reynolds?et?al (1986)

Experiment condition is:

Table 4

Receptor	Part	Concentration	Non-specific	Hatch
					Ca passage (T+L, diltiazem position)	[ 3H] diltiazem	???5nM	Diltiazem (10 μ M)	??120min ???25℃
Ca passage (T+L, verapamil position)	[ 3H]D?888	???0.5nM	??D600 ??(10μM)	???60min ????22℃

Behind incubation, analyte filters fast through GF/B or GF/C glass fiber filter (Whatman) under vacuum, and washs with ice-cold buffer with the Brandel cell harvestor.(LS6000 Beckman) measures with liquid scintillation cocktail (Formula 989, Dupont NEN) bonded radioactivity with liquid scintillation counter.Experimental program

Chemical compound is 10 ^-5M concentration is to twice of every kind of receptor determination.Each experiment, reference compound also confirms this experiment with two parts of 8 kinds of concentration determinations to obtain competition curve simultaneously to the receptor of research.Analysis and result's expression

The combination of the specificity radioligand of every kind of receptor is to determine with total binding and in the difference that the non-specific binding of measuring in the presence of the excessive unlabelled part is arranged.What provide in the table 5 is that specificity is in conjunction with the meansigma methods that suppresses percent.IC ₅₀Value (suppressing specificity in conjunction with 50% required concentration) is to be measured by the nonlinear regression analysis of their competition curve.These parameters are for using Sigmaplot ^TMSoftware does that the curve match obtains.

Table 5

R-oxibutynin and S-oxibutynin combining to calcium channel

[diltiazem and verapamil suppress (representing with %) to the combination of calcium channel receptor]

Receptor	?????R-OXY ????(10 -5M)	?????S-OXY ????(10 -5M)	Reference compound IC 50(nM)
				Calcium (diltiazem)	??????86	??????59	Diltiazem 55.8
Calcium (verapamil)	??????86	??????68	?????D600 ?????36.4

These results show that S-OXY is similar to R-OXY to the blocking activity that calcium enters.

The desethyloxybutynin enantiomer

The major metabolite of raceme oxibutynin is RS-desethyloxybutynin (DEO).The R of DEO and S enantiomer were not narrated before our research, and the spasmolytic of R-and the independent enantiomer of S-DEO and calcium to enter blocking activity also be unknown.We have synthesized these enantiomer, and studied with receptors bind model and bladder function these enantiomer antimuscarinic, spasmolytic enter retardance effectiveness with calcium.We find that the metabolite of every kind of enantiomer has all kept the relevant pharmacology situation of their " parent " oxibutynin enantiomer.The combination of M-ChR hypotype

Inhibition percent by three kinds of inductive specificity radioligands of concentration of every kind of chemical compound (R-, S-and RS-DEO) is the people's M-ChR hypotype (M with the clone ₁-M ₄) measure with the method for aforesaid oxibutynin enantiomer description.Following table (table 6 and table 7) provides the inhibition percent to every kind of hypotype.And, people's receptor subtype M of mensuration ₁And M ₂IC ₅₀Value provides in table 6.

Table 6

	???????????????????????M 1H				??????????????????M 2H
										10 -9M	10 -7M	10 -5M	IC 50(nM)	10 -9M	10 -7M	10 -5M	IC 50(nM)
??R-DEO	???63	???100	??100	?????1.2	???21	????97	???102	????14.7
									??S-DE0	???-	????82	??101	?????25.4	???-	????36	???101	????177
??RS-DEO	???43	???100	??100	?????1.8	???-	????94	???99	????7.0

Table 7

	??????????????M 3H			?????????????M 4H
								10 -9M	10 -7M	10 -5M	10 -9M	10 -7M	10 -5M
???R-DEO	???58	???100	???100	????58	????100	???99
							???S-DEO	???-	????63	???99	????-	????43	???99
???RS-DEO	???36	????99	???101	????34	????99	???95

These results show that S-DEO is weaker than the DEO of R-or racemization to the affinity of M-ChR hypotype.The calcium channel combination

By the bonded inhibition percent of the inductive specificity radioligand of all cpds (R-, S-and RS-DEO) is to measure with the diltiazem and the verapamil position of L-type calcium channel.The results are shown in table 8.

Table 8

Receptor	?R-DEO ?10 -5M	?S-DEO ?10 -5M	????SR-DEO ????10 -5M
				Calcium (diltiazem)	???86	???72	????88
Calcium (verapamil)	???96	???76	????89

These results show that calcium that S-DEO has enters blocking activity and revolves the similar of DEO to R-with export trade.The active functional characteristic of Antimuscarinic/spasmolytic

The external effect of research R-, S-and RS-oxibutynin (OXY) and R-, S-and RS-DEO to the bladder function model.As described below, the bladder bar of isolated Cavia porcellus smooth muscle of bladder is positioned in the tissue bath, and makes its contraction with muscarinic agonist carbachol or the concentration that increases inner potassium.

The bladder bar.The method that experiment is to use people such as being similar to Kachur (1988) and Noronha Blob and Kachur (1991) to be narrated is carried out.(Elm Hill multiply test chamber, Chelmsford MA) isolates in the body strip of tissue (about 10mm is long, 1.5mm is wide) from the Hartley Cavia porcellus of male body weight 400-600g.Tissue suspension is in the buffer with following composition and logical oxygen: mM:NaCl, 133; KCl, 4.7; CaCl ₂, 2.5; MgSO ₄, 0.6; NaH ₂PO ₄, 1.3; NaHCO ₃, 16.3; And glucose, 7.7.They maintain 37.5 ℃.Shrink with waiting and hold transducer (FT-10 type) and ink polygraph (7 type) (Astro-Med, Inc.Grass Instrument Div., West Warwick, RI) record.Each in a organized way resting tension all maintain 0.5g.

In each experiment, isolate 7 of as many as, be suspended in the tissue compartments separately from a bladder, and experimentizing before in bath solution balance one hour.

The inductive contraction of hydrogen chloride Carbamoylcholine.A series of experiment concentrates on the cholinolytic effect of oxibutynin.In these experiments, for the feasibility of estimating each tissue and as the structure of reference, each strip of tissue organizes replying all at first in the medium to be recorded to being exposed to, and the NaCl in this tissue medium replaces with KCl, makes the medium of 137.7mM KCl concentration.Then be put back into then in the medium of standard, be exposed to then in the medium of carbachol of progressive increase concentration, only be exposed in the concentration at every turn, reply until recording peak value.Then one is not processed and/or one be exposed in the 17mM ethanol as control tissue, remaining flesh bar is exposed in a kind of antagonist of concentration one hour at every turn.Not good when the dissolubility of measured matter, when stock solution need be prepared with ethanol, then use alcoholic acid contrast, the ethanol of 17mM as a result of tissue bath's test is effective concentration.At last, record is exposed to replying of 137.7mM KCl subsequently to the carbachol that increases concentration for the second time.

The inductive contraction of potassium.The second series experiment concentrates on the spasmolysis of tested material.Being recorded in the contraction that increases potassium concn in the medium in proper order replys.

Data analysis.Whether the mensuration antagonist can reduce the peak value of agonist is replied, and the tensile expansion in peak in measuring for the second time of each flesh bar is to represent with the percent that peak tension force during concentration-effect is measured is for the first time expanded.Then, the data that every kind of antagonist is obtained are all used unidirectional variation analysis (ANOVA) method analyzing and processing-relevant difference.Because each bladder bar is only studied a kind of antagonist of concentration, Arunlakshana and Schild (1959) method is used to estimate pA2 and Schild regression slope with improved form.At first estimate that by second cover concentration-effect data each bar bladder muscle agonist produces the concentration (EC that the half maximum is replied ₅₀).EC ₅₀Be by the logarithm of drug level with comprise the half maximum and reply replying of level, the linear regression of linear fit obtains.Flesh bar to each bar drug treating will calculate " concentration ratio " (CR), and its algorithm is the EC of the tissue handled ₅₀EC divided by untreated tissue ₅₀To each experiment, wherein two or more flesh bar are exposed to medicine of the same race but in the different concentration, this ratio subtracts 1 logarithm, and [Log (CR-1) just] is figure with the concentration logarithm of antagonist, and this antagonist is that the flesh bar once exposed wherein generation " Schild point ".The slope of the pA2 and the regression line is estimated in the regression analysis of Log (CR-1) and antagonist concentration logarithm.At last, the meansigma methods ± S.E. of medicine grouping and calculating pA2 and slope is pressed in experiment.With 95% confidence limit (CL) of standard method by its S.E. estimation slope.Have only a flesh bar to be exposed to experiment in the given medicine for the sort of, then calculate pKD with (concentration of antagonist)/CR-1), the negative logarithm of KD and pA2 value are united the expanded set of generation pA2 value simultaneously.

Raceme oxibutynin and DEO and they enantiomer separately is summarized in the following table 9 effectiveness of the inductive contraction of carbachol.The value that provides is the summary that Schild analyzes, and it provides pA2 value [meansigma methods ± SE] and slope [meansigma methods ± SE]

Table 9

Antagonist	The experiment number	????????pA2	Slope
				????R-OXY	????4	????8.80±0.27	????1.28±0.26
????S-OXY	????4	????7.09±0.13	????1.13±0.17
				????RS-OXY	????5	????8.81±0.29	????1.34±0.15
????R-DEO	????4	????9.04±0.32	????1.16±0.11
				????S-DEO	????4	????7.31±0.35	????0.87±0.11
????RS-DEO	????4	????8.55±0.32	????1.35±0.25

These results show that S-OXY and S-DEO are than the bladder muscarinic receptor antagonist a little less than R-and raceme OXY and R-and the raceme DEO.

Raceme oxibutynin and its enantiomer are summarized in down to the inductive contraction effectiveness of potassium and tabulate in 10 that (numerical value that provides is for being exposed in the chemical compound behind the 60min by 137.7mMK ⁺Inductive contraction size is divided by inductive contraction size before being exposed in the medicine)

Table 10

Antagonist	Before average % handles ± SE (n=3)
		????R-OXY	??????32±8*
????S-OXY	??????26±9*
		????RS-OXY	??????20±1*
????R-DEO	??????36±5*
		????S-DEO	??????42±5*
????RS-DEO	??????47±8*

* with the untreated analog value significant difference (P＜0.01) of organizing

These results show that the enantiomer of oxibutynin and it and desethyloxybutynin and its enantiomer are equicohesive smooth muscle of bladder spasmolytic.

The emptying of known bladder is to be regulated and control by cholinergic mechanism, and shrinks relevant in the bladder instability of suffering from seen in the uracratia patients with non-cholinergic.People such as Andersson [Neurourol.Urodyn.5,579-586 (1986)] show that in animal it is extremely sensitive to calcium antagonist that anti-atropine is compeled flesh.

Above-mentioned (R)-and (S)-oxibutynin can be reached a conclusion with receptors bind affinity research of calcium antagonist diltiazem and verapamil acceptor site, promptly (S)-oxibutynin and (S)-desethyloxybutynin has the therapeutical effect to involuntary urination, and (unlike R-isomer and racemic modification) is very little to normal effect of draining mechanism simultaneously.When comparing with corresponding R-isomer and racemic modification, S-OXY and S-DEO also have significantly low anticholinergic side effects.Avoid gazing at especially by the cardiovascular side effects that raceme oxibutynin anticholinergic effect produces.Our conclusion is, S-oxibutynin and S-desethyloxybutynin are effective medicines to treatment people urinary incontinence, reduces greatly than the side effect of racemic modification or pure R-enantiomer.

Embodiment

Embodiment 1

Formula of oral capsule: the amount in the composition capsule (mg)

A B CS-DEO 50 100 200 lactose 230 280 330 corn starchs 65 65 65 magnesium stearate 555 compressing weights 350 450 600

S-DEO, lactose and corn starch are mixed to evenly, in the gained powder, add magnesium stearate then, sieve, then use conventional machine to insert in two hard gelatin capsules of suitable dimension.Change filling weight and change capsule size in case of necessity, can prepare other dosage thus.

Because at least a crystal form of The compounds of this invention is acicular,,, free-pouring powder is used in flakes or encapsulate so that being provided so when using the dry powder technology, be necessary to grind or the granulation active component.

Embodiment 2

Formula of oral tablet: the amount (mg) in every of the composition

A B CS-OXY 50 100 200 lactose, 205 245 245 corn starchs, 30 50 50 water (per thousand) ^*300ml 500ml 500ml corn starch 60 100 100 magnesium stearate 555 compressing weights 350 500 600* are the water evaporation in manufacture process.

S-OXY and lactose are mixed to the formation homogeneous mixture.A spot of corn starch mixes with water, to form corn starch paste.This gelatinized corn starch and above-mentioned homogeneous mixture are mixed together, until forming uniformly wet material.In the wet material of gained, add remaining corn starch, and be mixed to and obtain homogeneous granules.By passing through in the suitable grinding machine, use 1/4 inch stainless steel mesh that granule is sieved then.Dry granule through grinding in suitable drying oven is until reaching desirable water content.In suitable grinding machine, grind the granule of drying, sneak into magnesium stearate, then the gained mixture is pressed into the tablet of desired shape, thickness, hardness and disintegration.The tablet of other intensity can be prepared by the final weight of ratio that changes active component and excipient or tablet.

Claims (10)

1, a kind of method of the ill effect for the treatment of urinary incontinence and avoiding supervening, it comprises the following chemical compound of the about 1g of mammal administration about 100mg-every day to this treatment of needs: (the S)-oxibutynin, (S)-desethyloxybutynin or the acceptable salt of their medicine that do not contain its R enantiomer in fact.

2, the method for claim 1, wherein the dosage of (S)-oxibutynin, (S)-desethyloxybutynin or their the acceptable salt of medicine is about 240mg-every day about 750mg/ days.

3, method as claimed in claim 2, wherein, (S)-dosage of oxibutynin, (S)-desethyloxybutynin or their the acceptable salt of medicine is about 300mg-every day about 600mg/ days.

4, the method for claim 1, wherein (S)-oxibutynin, (S)-desethyloxybutynin or the acceptable salt of their medicine are with non-intestinal, transdermal, rectum, oral or inhalation.

5, method as claimed in claim 4, wherein, (S)-oxibutynin, (S)-desethyloxybutynin or the acceptable salt of their medicine are with transdermal or oral administration.

6, the medicine single dose dosage form of a kind of tablet or elasticity Gelseal, it comprises the following chemical compound of medicine acceptable carrier and 0.1-500mg: (the S)-oxibutynin, (S)-desethyloxybutynin or the acceptable salt of their medicine that do not contain its R enantiomer in fact.

7, medicine single dose dosage form as claimed in claim 6, wherein, (S)-amount of oxibutynin, (S)-desethyloxybutynin or their the acceptable salt of medicine is about 25mg-250mg.

8, medicine single dose dosage form as claimed in claim 7, wherein, (S)-amount of oxibutynin, (S)-desethyloxybutynin or their the acceptable salt of medicine is about 100mg-200mg.

9, a kind of drug dose dosage form of transdermal delivery device form, it comprises the following chemical compound of medicine acceptable carrier and 0.1-500mg: (the S)-oxibutynin, (S)-desethyloxybutynin or the acceptable salt of their medicine that do not contain its R enantiomer in fact.

10, drug dose dosage form as claimed in claim 9, wherein, described drug acceptable carrier comprises penetration enhancer.