CN1558756A - Pharmaceutical compositions for the treatment of urinary disorders - Google Patents
Pharmaceutical compositions for the treatment of urinary disorders Download PDFInfo
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- CN1558756A CN1558756A CNA028188764A CN02818876A CN1558756A CN 1558756 A CN1558756 A CN 1558756A CN A028188764 A CNA028188764 A CN A028188764A CN 02818876 A CN02818876 A CN 02818876A CN 1558756 A CN1558756 A CN 1558756A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The present invention concerns the field of urology. The invention provides a novel pharmaceutical composition, comprising a pharmaceutically effective combination of {i) a first compound selected from the group consisting of muscarinic receptor antagonists, 5alpha-reductase inhibitors, and alpha-adrenergic receptor antagonists, and precursors and pharmaceutically acceptable salts thereof, and {ii) a second compound selected from the group consisting of 5-HT1a receptor agonists and antagonists, and precursors and pharmaceutically acceptable salts thereof, and optionally a pharmaceutically acceptable carrier or diluent therefor. There is also provided a method of therapeutical treatment of urinary disorder in a mammal, including man, comprising administering to said mammal, including man, in need of such treatment, a therapeutically effective amount of a composition according to the invention.
Description
Technical field
The invention belongs to the urology field.More specifically, it is generally based on certain agonist that is used for the treatment of urinary disorders and/or the applied in any combination of antagonist.
Background of invention
Urinary disorders and symptom thereof comprise some or all in following: urgent micturition, frequent micturition, incontinence, urine leakage, the enuresis, dysuria, hesitate and bladder emptying difficulty.Especially, urinary disorders comprises the urinary incontinence that is for example caused by unstable or hyperactive bladder.
Term lower urinary tract spmptom (LUTS) is described a kind of medical symptom of knowing well.LUTS comprises some or all in following: obstructive urinary system disease is sewed, can not be urinated when finishing as urinating slowly, urinating and/or needs are strained and urinated with acceptable speed, perhaps irritative symptoms such as frequent micturition and/or urgent micturition.These irritative symptoms may be the hyperactive results of detrusor who takes place after being blocked by the bladder outlet that prostate increases or near-end urethral smooth muscle activity excessively causes.
Quite a few (5-10%) adult suffers from urinary incontinence, and particularly so-called urge incontinence popular increased with the age.Symptom unstable or hyperactive bladder comprise urge incontinence, urgent micturition and frequent micturition.Urge incontinence (the blended incontinence) of urge incontinence in combination with stress is that the clinician often runs into.
Unstable according to inferring or hyperactive bladder is by the smooth muscle fiber that forms bladder muscle skin (detrusor) in the filling of bladder phase bunch out of control causing of contraction.These shrink and mainly are subjected to cholinergic muscarinic receptor (muscarine receptor)) regulation and control, and the pharmacological treatment of unstable or hyperactive bladder is traditionally based on muscarinic receptor antagonist.
The reason of the inappropriate contraction of bladder muscle is unclear in many cases.For some people, it may be to cause from the nerve signal problem that brain conducts to bladder.Sometimes small nervous lesion is caused by surgical operation or childbirth.This muscle pushes or contraction more frequently and in inappropriate time than normal muscle.What the maintenance rest was different when filling bladder with urine is that detrusor shrinks when urine is filled bladder.This cause the people bladder less than the time feel to urinate suddenly and sometimes definitely urgently.
Another kind of main urinary disorders is an interstitial cystitis.Cystitis is the inflammation of a kind of bladder and dependency structure.There is not general effective treatment procedure at present.Symptoms from cystitis comprises the urgent micturition of urinating, the frequency of urinating increase and common by pain, arthritis, spastic colon, low grade fever and allergy on the pubis of emptying alleviation.The mammal of trouble cystitis is incapacitation significantly, and may need operation.For example, cystitis may be caused by infection, wound, allergy and cancer.
United States Patent (USP) 5,382,600 open 2-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl)-the 4-methylphenol, be also known as N, N-diisopropyl-3-(2-hydroxy-5-methyl base phenyl)-3-phenylpropylamine, its adopted name is a tolterodine, and other be used for the treatment of urinary incontinence replacement 3, the 3-diphenylpropylamine.People such as H Postlind, Drug Metabolism andDisposition, 26 (4): the open tolterodine of 289-293 (1998) is a kind of muscarinic receptor antagonist.At United States Patent (USP) 5,559, the active metabolite of tolterodine and 3,3 diphenylpropylamines of replacement are disclosed in 269.
United States Patent (USP) 4,377,584 open finasterides, a kind of 5 inhibitor are used for the treatment of the application of benign prostatauxe.
United States Patent (USP) 4,026,894 open terazosins, a kind of alpha-adrenergic aceptor antagonist are as the application of antihypertensive drug.The loose smooth muscle of alpha-adrenergic aceptor antagonist.
United States Patent (USP) 5,990,114 disclose certain 5-HT
1aReceptor antagonist is used for the treatment of the application of urinary incontinence.
Although there is above-mentioned development this area, the expectation exploitation further improves the new pharmaceutical composition of individual in a large number quality of life.
Summary of the invention
For these and other objects, the purpose of this invention is to provide a kind of new pharmaceutical composition that is used for the treatment of mammal, comprises people's urinary disorders, described compositions suppresses or prevents unstable bladder to shrink, and eliminates and the incomplete relevant problem of bladder emptying.
Another object of the present invention provides a kind of new method for the treatment of mammal, comprising people's urinary disorders, and described method suppresses effectively or prevents unsettled bladder contraction, and eliminates and the incomplete relevant problem of bladder emptying.
To obviously find out these and other objects from following content, and the invention provides a kind of new pharmaceutical composition, the pharmacy that described compositions comprises following material effectively makes up:
(i) be selected from muscarinic receptor antagonist, 5 inhibitor, alpha-adrenergic aceptor antagonist, their precursor and pharmaceutically acceptable salt first chemical compound and
(ii) be selected from 5-HT
1aSecond chemical compound of receptor stimulating agent and antagonist, their precursor and pharmaceutically acceptable salt,
And the pharmaceutically acceptable carrier or the diluent of optional they.
The present invention is based on and recognize at least a chemical compound and the 5-HT that is selected from muscarinic receptor antagonist, 5 inhibitor and alpha-adrenergic aceptor antagonist
1aThe combination of receptor stimulating agent and antagonist produces favourable stimulation to bladder contraction and bladder storage, and this will describe more following.5-HT for example
1a-agonist can be a kind of reverse agonist, and 5-HT
1a-antagonist can be a kind of neutral 5-HT
1aReceptor antagonist.
In an embodiment preferred according to compositions of the present invention, this first chemical compound is muscarinic receptor antagonist or their precursor or pharmaceutically acceptable salt.
In a preferred embodiment according to compositions of the present invention, this muscarinic receptor antagonist is 3 of replacement, the 3-diphenylpropylamine.Have 3 of the active replacement of muscarinic receptor antagonist, the 3-diphenylpropylamine is meant in the background of invention technology alleged 3, the 3-diphenylpropylamine.
In a further preferred embodiment according to compositions of the present invention, 3 of this replacement, the 3-diphenylpropylamine is selected from tolterodine and hydroxyl tolterodine.
Preferably be somebody's turn to do 3 of replacement, the 3-diphenylpropylamine is a tolterodine.In the most preferred embodiment according to compositions of the present invention, this first chemical compound is a tolterodine L-tartrate.
In another embodiment preferred according to compositions of the present invention, this muscarinic receptor antagonist is selected from oxibutynin and reactive derivative thereof.Its reactive derivative is its active metabolite N-desethyloxybutynin.Preferred this muscarinic receptor antagonist is an oxibutynin.
In another embodiment preferred according to compositions of the present invention, this muscarinic receptor antagonist is selected from darifenacin and reactive derivative thereof.Its reactive derivative be it activity 3 '-the hydroxy metabolite thing.Preferred this muscarinic receptor antagonist is a darifenacin.
In an embodiment preferred according to compositions of the present invention, the quantity that this first chemical compound exists is that about 0.1mg is to about 100mg.
In embodiment preferred of compositions according to the present invention, this second chemical compound is neutral 5-HT
1aReceptor antagonist.
In an embodiment preferred according to compositions of the present invention, the quantity that this second chemical compound exists is that about 0.1mg is to about 1g.
In another embodiment preferred according to compositions of the present invention, this first chemical compound remains on identical sending in the excipient with this second chemical compound.
In another embodiment preferred according to compositions of the present invention, this first chemical compound remains on different sending in the excipient with this second chemical compound.
In an embodiment according to compositions of the present invention, said composition is used for the treatment of mammal, people particularly, but also comprise the urinary disorders of animal such as house pet such as pig and cat.
In preferred embodiment of chemical compound according to the present invention, this disease is selected from lower urinary tract spmptom, instability or hyperactive bladder, bladder flows out obstruction, urinary incontinence, particularly stress incontinence and interstitial cystitis.
In another embodiment preferred of chemical compound according to the present invention, said composition is used for the treatment of this mammiferous depression, the described depression described urinary disorders that occurs together.
And, the invention provides compositions according to the present invention is used to prepare the treatment mammal, comprises the application of medicine of people's urinary disorders.In an embodiment preferred according to application of the present invention, described medicine is used for the treatment of this mammiferous depression, the described depression described urinary disorders that occurs together.
And, the invention provides a kind of method for the treatment of mammal, comprising people's urinary disorders, described method comprises this mammal to this treatment of needs, comprise people's administering therapeutic effective dose according to compositions of the present invention.
In an embodiment preferred of the method according to this invention, this disease is selected from lower urinary tract spmptom, instability or hyperactive bladder, bladder flows out obstruction, urinary incontinence, particularly stress incontinence and interstitial cystitis.
In another embodiment preferred of the method according to this invention, this method also is used for the treatment of this mammiferous depression, described depression this urinary disorders that occurs together.
In an embodiment preferred of the method according to this invention, said composition rectum, intravaginal, part, mouth, Sublingual, intranasal, transdermal or parenteral.
In another embodiment preferred of the method according to this invention, first chemical compound of this in the said composition and the administration simultaneously of this second chemical compound.
In another embodiment preferred of the method according to this invention, the administration of accompanying of first chemical compound of this in the said composition and this second chemical compound.
At last, the invention provides a kind of treatment mammal, comprise the medicinal reagent box of people's urinary disorders, described test kit comprises
(i) comprise first container of the first above-mentioned chemical compound,
Second container that (ii) comprises the second above-mentioned chemical compound,
Operation instructions with the (iii) test kit of choosing wantonly.
Invention is described
In describing embodiment preferred, for clarity sake use some term.These terms are intended to comprise that described embodiment and all operate the technical equivalents thing with the similar purpose that is used to realize similar results in a similar fashion.Open about any pharmaceutically active compound or require degree, obviously be intended to comprise the active metabolite that produces in all bodies, and obviously be intended to comprise all enantiomer, isomer or tautomer, wherein said chemical compound can exist with its enantiomer, isomer or tautomeric forms.
The invention provides a kind of new pharmaceutical composition, described compositions is at least a muscarinic receptor antagonist or 5 inhibitor or alpha-adrenergic aceptor antagonist or norepinephrine and/or serotonin reuptake inhibitor and 5-HT
1aThe combination of receptor stimulating agent and antagonist.
Compositions of the present invention is used for the treatment of urinary disorders.
The particularly preferred compositions that is used for the treatment of urinary disorders is anti-muscarinic agents and neutral 5-HT
1aThe combination of-antagonist.
According to the present invention, now wondrous and creative discovery anti-muscarinic agents and neutral 5-HT
1aThe treatment of the combination of-antagonist is stored generation effect simultaneously to bladder contraction and bladder.
Anti-muscarinic treatment will be by suppressing to act on effector organ to spreading out of of central nervous system is swollen towards the reaction of making.Therefore, particularly under higher dosage, anti-muscarinic treatment suppresses filling period unstable bladder contraction, but also suppresses the contraction that ejection time causes, thereby the pressure that causes urinating reduces, and finally causes the negative results of incomplete bladder emptying.But this effect has limited the probability of this reagent of other acceptable dose.And anti-muscarinic treatment causes the main side effect of being blocked by the muscarinic receptor among other tissue such as salivary gland, internal organs and the CNS outside the genitourinary system that causes, and causes side effect such as xerostomia, constipation and confusion respectively.To a certain extent, these side effect can have optionally newer anti-muscarinic agents such as tolterodine reduces to smooth muscle of bladder by introducing.But, even the effect that bladder-selective anti-muscarinic agents is also always shunk urinating owing to above-mentioned they is restricted to the treatment to the hyperkinesia bladder.
The effect of research anti-muscarinic agents in many animal models, and they always show as the amplitude or contractions of urinating that reduces emptying, and bladder capacity is not directly acted on.For these reagent, the effect of bladder capacity has been shown as generation after the pressure of urinating significantly reduces.
The storage function of bladder do not had direct acting reagent clinically.But, have recognized that 5-HT
1a-agonist or-antagonist, particularly neutral 5-HT
1aThe combination of-antagonist and anti-muscarinic agents or 5 inhibitor or alpha-adrenergic aceptor antagonist or norepinephrine and/or serotonin reuptake inhibitor, particularly anti-muscarinic agents can increase bladder capacity, and bladder contraction is not had negative consequences.
Importantly, in estimating the model of anti-muscarinic agents, use neutral 5-HT-antagonist and Antimuscarinic simultaneously and do not weaken the effect of anti-muscarinic agents bladder contraction to the effect of bladder contraction.
And, be used to estimate neutral 5-HT
1aIn the model of antagonist to the effect that suppresses with micturition reflex of bladder capacity, use anti-muscarinic agents and neutral 5-HT simultaneously
1a-antagonist does not weaken 5-HT
1a-antagonist is to the effect and its effect to micturition reflex of bladder capacity.
The muscarinic receptor antagonist or the anti-muscarinic agents that are used for pharmaceutical composition of the present invention include but not limited to non-selective reagent, bladder selective reagent and muscarinic M 3 receptors selective reagent.
The example of muscarinic receptor antagonist includes but not limited to tolterodine and its active metabolite, as hydroxyl tolterodine, YM905, propiverine, oxibutynin, trospium chloride (trospium), Propantheline, darifenacin, temiverine and ipratropium and pharmaceutically acceptable salt thereof.YM905 is a succinic acid, chemical compound (1S)-(3R)-1-azabicyclo [2.2.2] oct-3-yl 3, and 4-dihydro-1-phenyl-2 (1H)-isoquinolin formic acid esters (1: 1) is (9CI).Propiverine is 1-methyl-4-piperidyl α, α-diphenyl-α-(positive propoxy) acetas, and be disclosed among DRP 106,643 and the CAS82155841S (1975).Oxibutynin is 4-(diethylamino)-2-butyne base α-Phenylcyclohexane ethyl glycolate and is disclosed in the UK patent 940,540.Trospium chloride be 3 Alpha-hydroxy spiral shells [1 α H, 5 α H-nortropines-8,1 '-pyrrolidine] chloride henzylate thing and be disclosed in United States Patent (USP) 3,480, in 623.Darifenacin is (S)-2-{1-[2-(2,3-Dihydrobenzofuranes-5-yl) ethyl]-the 3-pyrrolidinyl }-2,2-diphenyl-acetamide also is disclosed in the US patent 5,096,890.Temiverine is a phenylacetic acid, α-cyclohexyl-Alpha-hydroxy-4-(diethylamino)-1, and 1-dimethyl-2-butyne ester also is disclosed in United States Patent (USP) 5,036, in 098.Ipratropium is a 8-isopropyl noratropine Methobromide, and is disclosed in United States Patent (USP) 3,505, in 337.
Preferred muscarinic receptor antagonist can be selected from 3 of replacement with antimuscarinic activity, 3-diphenylpropylamine (as being disclosed in United States Patent (USP) 5,382,3 in 600,3-diphenylpropylamine), and pharmaceutically acceptable salt.Preferred muscarinic receptor antagonist includes but not limited to tolterodine and hydroxyl tolterodine, oxibutynin and reactive derivative thereof such as N-desethyloxybutynin and darifenacin and reactive derivative thereof, as its 3 '-the hydroxy metabolite thing, and its pharmaceutically acceptable salt.
The 5 inhibitor that is used for pharmaceutical composition of the present invention comprises but is not limited to finasteride (United States Patent (USP) 4,377,584), dutasteride's (United States Patent (USP) 5,565,467), epristeride (United States Patent (USP) 5,017,568) and turosteride (United States Patent (USP) 5,155,107) and pharmaceutically acceptable salt.
The alpha-adrenergic aceptor antagonist that is used for pharmaceutical composition of the present invention includes but not limited to terazosin (United States Patent (USP) 4,026,894), doxazosin (United States Patent (USP) 4,188,390), prazosin (United States Patent (USP) 3,511,836), bunazosin (United States Patent (USP) 3,920,636), indoramine (United States Patent (USP) 3,527,761), alfuzosin (United States Patent (USP) 4,315,007), abanoquil (United States Patent (USP) 4,686,228), naftopidil (United States Patent (USP) 3,997,666), phentolamine, tamsulosin (United States Patent (USP) 4,703,063), trazodone, dapiprazole, phenoxybenzamine, idazoxan (United States Patent (USP) 4,818,764), efaroxan (United States Patent (USP) 4,411,908), yohimbine, dibenzamide, trimazosin, tolazoline, corynthanine, rauwolscine (rauwolscine), tamsulosin, with piperoxan and pharmaceutically acceptable salt thereof.
The norepinephrine and/or the serotonin reuptake inhibitor that are used for pharmaceutical composition of the present invention include but not limited to duloxetine (United States Patent (USP) 4,956,388), the racemate (Zoloft) of reboxetine, [S, S]-reboxetine succinate and reboxetine and Sertraline.
The selection dosage of first chemical compound be can reduction of patient dosage.The dosage of known this chemical compound and dosage regimen (being every day one, two, three or more times administration) depend on effectiveness, administering mode, patient's age and the body weight of multiple factor such as selected specific compound, order of severity of symptom to be treated or the like.
This is within the scope that those skilled in the art consider, and it can consider that existing document about component is to determine optimal dose.
When first chemical compound was anti-muscarinic agents, average Coming-of-Age Day dosage of preferred first chemical compound was about 0.05mg to about 5mg/ kg body weight, with one or more dosed administrations, for example comprised about 0.05mg to about 250mg at every turn.
When first chemical compound was the 5 inhibitor, the quantitative range that preferred first chemical compound exists was that about 2mg is to about 20mg, preferably approximately 5mg/ dosage.
When first chemical compound was alpha-adrenergic aceptor antagonist, the quantitative range that preferred first chemical compound exists was that about 1mg is to about 25mg, preferably approximately 10mg/ dosage.
The 5-HT that is used for pharmaceutical composition of the present invention
1aReceptor stimulating agent and antagonist include but not limited to by with 5-HT
1aThe 5-HT receptors bind of hypotype and act on central nervous system's chemical compound.5-HT
1aThe limiting examples of receptor antagonist is WAY-100,635, i.e. and cyclohexane carboxamide, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-the N-2-pyridine radicals-, tri hydrochloride; Robalzotan, i.e. (3R)-3-(two cyclobutyl amino)-8-fluoro-3,4-dihydro-2H-l-.alpha.-5:6-benzopyran-5-Methanamide; And LY426965, promptly [(2S)-(+)-and 1-cyclohexyl-4-[4-(2-methoxyphenyl)-1-piperazinyl] 2-methyl-2-phenyl-1-butanone one hydrochlorate].Usually, chemical compound and 5-HT
1aThe bonded degree of the receptor-selective of hypotype is greatly greater than them and other receptor such as α
1And D
2The degree of receptors bind.And they show as 5-HT in pharmacology test
1aThe activity of-agonist or antagonist.5-HT of the present invention
1aReceptor stimulating agent and antagonist can be used for the treatment of mammal, particularly people's CNS disease such as anxiety.They can also be used as antidepressants, hypotensor, as the reagent of regulating sleep/clear-headed cycle, feedback performance and/or sexual function, be used for the treatment of cognitive illnesses, and be used for the treatment of the disorder of lower urinary tract neuromuscular function, particularly relate to the lower urinary tract neuromuscular function disorder of urinate (piss), as dysuria, incontinence and the enuresis.
Neutral antagonist is a kind of and chemical compound receptors bind, and receptor is not had intrinsic activity, but the receptor-mediated functional activity that blocking-up is caused by agonist.In this respect, agonist is defined as the chemical compound of the functional response that mediates with receptors bind and activated receptor, such as but not limited to 5-HT
1aThe active inhibition of adenylyl cyclase of-mediation or the activation of potassium channel.
The dosage of known second chemical compound and dosage regimen (being every day one, two, three or more times administration) depend on about the dosage of first chemical compound selects mentioned factor.Average Coming-of-Age Day dosage of second chemical compound is about 1 μ g to about 10mg/ kg body weight, with one or more dosed administration, for example contains about 50 μ g to about 1g at every turn.Child dose can be less.
Be used for including but not limited to acetate according to the example of the pharmaceutically acceptable salt of compositions of the present invention, benzoate, hydroxybutyric acid salt, disulfate, bisulfites, bromide, butine-1, the 4-diacid salt, carpoate, chloride, chloro benzoate, citrate, dihydric phosphate, dinitro-benzoate, fumarate, glycollate, enanthate, hexin-1, the 6-diacid salt, hydroxy benzoate, iodide, lactate, maleate, malonate, mandelate, metaphosphate, mesylate, methoxybenzoic acid salt, ar-Toluic acid salt, dibasic alkaliine, naphthalene-1-sulfonate, naphthalene-2-sulfonic acid salt, oxalates, phenylbutyric acid salt, phenylpropionic acid salt, phosphate, phthalate, phenylacetate, propane sulfonic acid salt, propiolate, propionate, pyrophosphate, pyrosulfate, sebacate, suberate, succinate, sulfate, sulphite, sulfonate, tartrate, xylenesulfonate etc.
Compositions of the present invention can be easily to contain the pharmaceutical composition administration with the suitable bonded reactive compound of excipient.This pharmaceutical composition can prepare by method as known in the art, and contains excipient as known in the art.The common outline of these methods and composition is the Remington ' s Pharmaceutical Sciences of E.W.Martin (Mark Publ.Co., 15th Ed., 1975).Therefore fully quote this reference material as a reference here.Compositions of the present invention can parenteral (for example by intravenous, intraperitoneal, subcutaneous or intramuscular injection), topical, oral, sublingual administration, transdermal administration, intranasal administration, intravaginal administration or rectally, special preferred oral.
For oral medication, compositions of the present invention can with one or more excipient composition, and use with forms such as absorbable tablet, Sublingual tablet, tablet, capsule, elixir, suspension, syrup, thin slice, chewing gum, foods.These compositionss and preparation preferably comprise at least 0.1% reactive compound.The percentage rate of compositions and preparation certainly changes, and can be easily given dosage form units weight about 0.1 to about 100%.The quantity of the reactive compound in the useful compositions of this treatment is the quantity that obtains the effective dose level.
Tablet, tablet, pill, capsule etc. can also comprise following: binding agent such as Tragacanth, arabic gum, corn starch or gelatin; Excipient such as dicalcium phosphate; Disintegrating agent such as corn starch, potato starch, alginic acid etc.; Lubricant such as magnesium stearate; With sweeting agent such as sucrose, fructose, lactose or aspartame or flavoring agent such as Mentha arvensis L. syn.M.haplocalyxBrig, oil of wintergreen or Fructus Pruni pseudocerasi flavoring agent.More than tabulation only is representative, and those skilled in the art it is contemplated that other binding agent, excipient, sweeting agent etc.When unit dosage form was capsule, it comprised liquid-carrier such as vegetable oil or Polyethylene Glycol except the material of above type.Can there be the physical form of various other materials as coating or change solid unit dosage form.For example, tablet, pill or capsule can be used coatings such as gelatin, wax, lacca or sugar.Syrup or elixir can comprise reactive compound, sucrose or fructose as sweeting agent, and methyl parahydroxybenzoate and propyl p-hydroxybenzoate be as antiseptic, dyestuff and regulator such as Fructus Pruni pseudocerasi or orange flavoring agent.Certainly, any material that is used to prepare any unit dosage form should be pharmaceutically acceptable and nontoxic basically under used quantity.In addition, active component can be added to sustained release formulation and device, include but not limited to depend on that osmotic pressure is to obtain the preparation and the device of target release profiles.Preparation once a day particularly including each active component.
Contain physical form that the compositions of the present invention of two kinds or more kinds of reactive compounds can be identical or according to the administration of accompanying of above-mentioned dosage, and be in above-mentioned sending in the excipient.The dosage of each reactive compound can be measured respectively, and the dosage as single unitized dose or difference administration can be provided.They can be simultaneously or not administration simultaneously, as long as the two has activity to the patient in 24 hours time.Together or administration simultaneously mean the patient and in taking a kind of about 5 minutes scopes of medicine, take another kind of medicine.
The present invention also comprises the medicinal reagent box that is used for the treatment of mammal, comprises people's urinary disorders.Similar to compositions, this test kit comprises first container that contains above-mentioned first chemical compound, contains second container of above-mentioned second chemical compound and the operation instructions of test kit.
" pharmaceutically acceptable " refer to aspect composition, preparation, stability, patient's acceptance level and bioavailability, is acceptable to the patient and is acceptable performance and/or material from the physical/chemical viewpoint to the pharmaceutical chemistry worker from pharmacology/toxicology viewpoint.
Compositions of the present invention is intended to be used for the treatment of urinary disorders.Particularly, described compositions is used for the treatment of the LUTS or the incontinence of any kind, for example stress incontinence, pure stress incontinence and blended incontinence.Stress incontinence be a kind of when being engaged in any raising intraabdominal pressure as cough or sneeze movable the urine symptom of forfeiture unconsciously.Stress incontinence still is a kind of clinical symptoms, and it is that the viewed patient of care-giver urine when cough or tension is sprayed the symptom of overflowing from urethra (opening).Pure stress incontinence (urging incontinence) is the pathological diagnosis by the sphincter of urethra incapability of Urodynamic test diagnosis.Blended incontinence is that stress incontinence is followed and urged incontinence.The latter is the compound part of the symptom of hyperkinesia bladder.Reservation may be blocked (as high urethra pressure) by flowing out, detrusor (bladder muscle) shrinks to lack between bad or detrusor contractions and the urethra diastole and coordinates to cause.Drug regimen of the present invention can be used for stress incontinence, urge incontinence or blended incontinence.
Also be used for the treatment of interstitial cystitis according to compositions of the present invention.
When the anti-muscarinic treatment of urinary disorders is influenced by remaining urine increase, can be by adding neutral 5-HT
1aAntagonist and increase treatment.Especially may occur in this case since the bladder that causes of prostate hyperplasia flow out block after on one's body the hyperactive patient of bladder of secondary.
In other situation, side effect such as xerostomia that anti-muscarinic treatment may be subjected to tolerate limit.In this case, Antimuscarinic dosage can reduce, but by adding neutral 5-HT
1aAntagonist keeps rendeing a service.These reagent be more preferred than other reagent, have more bladder optionally under the situation of reagent, this combination allows to use the anti-muscarinic agents to the bladder non-selectivity.
In another case, neutral 5-HT
1aThe treatment of antagonist may be owing to any effect that lacks bladder contraction is restricted.In this case, the adding of anti-muscarinic agents brings extra effectiveness.This situation may be that vesical reflex is hyperfunction, and the patient of relevant symptom is shunk in a kind of known and vesical reflex.
In another case, neutral 5-HT
1aThe effectiveness of antagonist may be subjected to the restriction of side effect.In this case, can consider to regulate the dosage and the effectiveness therefore of 5-HT antagonist by adding anti-muscarinic agents.
Think that new compositions of the present invention alleviates the experimenter who suffers from above disease or disease apace, and have the harmful side effect of minimum.
By following non-limiting example the present invention is described in more detail.
Embodiment
Embodiment 1
By with tolterodine and neutral 5-HT
1aReceptor antagonist is combined in the pharmaceutically acceptable carrier and pharmaceutical compositions.Compositions comprises the tolterodine/kg of patient body weight (for example the people for heavy 60kg is the 3mg-240mg tolterodine) of the extremely about 4mg of about 0.05mg and the neutral 5-HT of the extremely about 1mg of about 0.01mg
1aReceptor antagonist/kg of patient body weight.Use compositions to treat incontinence, particularly stress incontinence, to urge incontinence or blended incontinence to the patient.
Embodiment 2
By with 5-HT
1aReceptor antagonist is combined in the pharmaceutically acceptable carrier and prepares first pharmaceutical composition, so that can send about 0.5mg its every day to about 50mg.By being combined in, tolterodine prepares second pharmaceutical composition in the pharmaceutically acceptable carrier, so that can send about 0.05mg its every day to about 4mg tolterodine/kg of patient body weight.
Use once for every day the patient of the incontinence of one or more forms of patient, first compositions of secondary, three times, four times or six times so that daily dose is about 0.5mg to about 50mg.Any time of every day within the time identical with the administration of first compositions or the first compositions administration 24 hours give that identical patient uses once, secondary, three times, four times or six times second compositionss, so that daily dose is about 0.05mg to about 4mg tolterodine/kg of patient body weight.
Selectively, second compositions can first administration, then as disclosed simultaneously or use first compositions in 24 hours of its administration.
Embodiment 3
By with 5 inhibitor and neutral 5-HT
1aReceptor antagonist is combined in the pharmaceutically acceptable carrier and pharmaceutical compositions.Described compositions comprises about 2mg extremely approximately 20mg5 alpha-reductase inhibitors and the neutral 5-HT of the extremely about 50mg of about 0.5mg
1aReceptor antagonist.Use compositions with the treatment urinary disorders to the patient.
Embodiment 4
By with alpha-adrenergic aceptor antagonist and neutral 5-HT
1aReceptor antagonist is combined in the pharmaceutically acceptable carrier and pharmaceutical compositions.Said composition comprises about 1mg extremely approximately 25mg alpha-adrenergic aceptor antagonist and the neutral 5-HT of about 0.5mg to about 50mg
1aReceptor antagonist.Use said composition with the treatment urinary disorders to the patient.
Describe the present invention in detail with reference to embodiment preferred, but be apparent that it is possible making amendment and changing under the situation of the scope that does not deviate from appended claim.
Claims (43)
1. the effective pharmaceutical composition of combination of a pharmacy that comprises following material:
(i) be selected from muscarinic receptor antagonist, 5 inhibitor, alpha-adrenergic aceptor antagonist, their precursor and pharmaceutically acceptable salt first chemical compound and
(ii) be selected from 5-HT
1aSecond chemical compound of receptor stimulating agent and antagonist, their precursor and pharmaceutically acceptable salt,
And the pharmaceutically acceptable carrier or the diluent that randomly are used for it.
2. according to the pharmaceutical composition of claim 1, wherein this first chemical compound is a muscarinic receptor antagonist, perhaps their precursor or pharmaceutically acceptable salt.
3. according to the compositions of claim 2, wherein this muscarinic receptor antagonist is 3 of replacement, the 3-diphenylpropylamine.
4. according to the compositions of claim 3, wherein be somebody's turn to do 3 of replacement, the 3-diphenylpropylamine is selected from tolterodine and hydroxyl tolterodine.
5. according to the compositions of claim 4, wherein be somebody's turn to do 3 of replacement, the 3-diphenylpropylamine is a tolterodine.
6. according to the compositions of claim 5, wherein this first chemical compound is a tolterodine L-tartrate.
7. according to the compositions of claim 2, wherein this muscarinic receptor antagonist is selected from oxibutynin and reactive derivative thereof, as the N-desethyloxybutynin.
8. according to the compositions of claim 7, wherein this muscarinic receptor antagonist is an oxibutynin.
9. according to the compositions of claim 2, wherein this muscarinic receptor antagonist is selected from darifenacin and reactive derivative thereof, as its 3 '-the hydroxy metabolite thing.
10. according to the compositions of claim 9, wherein this muscarinic receptor antagonist is a darifenacin.
11. according to each the compositions of claim 1-10, wherein the quantity that exists of this first chemical compound is about 0.1mg to about 100mg.
12. according to each the compositions of claim 1-11, wherein this second chemical compound is neutral 5-HT
LaReceptor antagonist.
13. according to each the compositions of claim 1-12, wherein the quantity that exists of this second chemical compound is about 0.1mg to about 1g.
14. according to each the compositions of claim 1-13, wherein this first chemical compound remains on identical sending in the excipient with this second chemical compound.
15. according to each the compositions of claim 1-13, wherein this first chemical compound remains on different sending in the excipient with this second chemical compound.
16. according to each the compositions of claim 1-15, described compositions is used for the treatment of mammal, comprises people's urinary disorders.
17. according to the compositions of claim 16, wherein this disease is a lower urinary tract spmptom.
18. according to the compositions of claim 16, wherein this disease is unstable or hyperactive bladder.
19. according to the compositions of claim 16, wherein this disease is that bladder flows out obstruction.
20. according to the compositions of claim 16, wherein this disease is a urinary incontinence.
21. according to the compositions of claim 20, wherein this disease is a stress incontinence.
22. according to the compositions of claim 16, wherein this disease is an interstitial cystitis.
23. according to each the compositions of claim 16-22, described compositions is used for the treatment of this mammiferous depression, described urinary disorders is followed in described inhibition.
24. each the pharmaceutical composition according to claim 1-15 is used to prepare the treatment mammal, comprise the application of medicine of people's urinary disorders.
25. according to the application of the compositions of claim 24, wherein this disease is a lower urinary tract spmptom.
26. according to the application of the pharmaceutical composition of claim 24, wherein this disease is unstable or hyperactive bladder.
27. according to the application of the pharmaceutical composition of claim 24, wherein this disease is that bladder flows out and blocks.
28. according to the application of the pharmaceutical composition of claim 24, wherein this disease is a urinary incontinence.
29. according to the application of the pharmaceutical composition of claim 28, wherein this disease is a stress incontinence.
30. according to the application of the pharmaceutical composition of claim 24, wherein this disease is an interstitial cystitis.
31. according to each the application of pharmaceutical composition of claim 24-30, wherein this medicine is used for the treatment of this mammiferous depression, described depression is followed described urinary disorders.
32. the method for the treatment of mammal, comprising people's urinary disorders, described method comprise this mammal to this treatment of needs, comprise each the compositions according to claim 1-15 of people's administering therapeutic effective dose.
33. according to the Therapeutic Method of claim 32, wherein this disease is a lower urinary tract spmptom.
34. according to the Therapeutic Method of claim 32, wherein this disease is unstable or hyperactive bladder.
35. according to the Therapeutic Method of claim 32, wherein this disease is that bladder flows out obstruction.
36. according to the Therapeutic Method of claim 32, wherein this disease is a urinary incontinence.
37. according to the Therapeutic Method of claim 36, wherein this disease is a stress incontinence.
38. according to the Therapeutic Method of claim 32, wherein this disease is an interstitial cystitis.
39. according to each Therapeutic Method of claim 32-38, described method also is used for the treatment of this mammiferous depression, described depression is followed described urinary disorders.
40. according to each Therapeutic Method of claim 32-39, wherein said composition per rectum, intravaginal, part, mouth, Sublingual, intranasal, transdermal or parenteral.
41. according to each the Therapeutic Method of claim 32-40, wherein this of said composition first chemical compound and the administration simultaneously of this second chemical compound.
42. according to each the Therapeutic Method of claim 32-40, wherein this of said composition first chemical compound and this second chemical compound administration of accompanying.
43. the medicinal reagent box for the treatment of mammal, comprising people's urinary disorders, described test kit comprises
(i) comprise each first container of first chemical compound according to claim 1-10,
(ii) comprise according to second container of second chemical compound of claim 1 or 12 and optional
The (iii) operation instructions of test kit.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US09/965,556 US20030060513A1 (en) | 2001-09-27 | 2001-09-27 | Pharmaceutical composition |
| US09/965,556 | 2001-09-27 | ||
| SE01038587 | 2001-11-20 | ||
| SE0103858A SE0103858D0 (en) | 2001-09-27 | 2001-11-20 | Pharmaceutical composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1558756A true CN1558756A (en) | 2004-12-29 |
Family
ID=26655594
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA028188764A Pending CN1558756A (en) | 2001-09-27 | 2002-09-26 | Pharmaceutical compositions for the treatment of urinary disorders |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP1438035A2 (en) |
| JP (1) | JP2005503424A (en) |
| KR (1) | KR20040039436A (en) |
| CN (1) | CN1558756A (en) |
| BR (1) | BR0212824A (en) |
| CA (1) | CA2461731A1 (en) |
| IL (1) | IL160852A0 (en) |
| MX (1) | MXPA04002496A (en) |
| WO (1) | WO2003026564A2 (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0957073A1 (en) | 1998-05-12 | 1999-11-17 | Schwarz Pharma Ag | Novel derivatives of 3,3-diphenylpropylamines |
| FR2843303B1 (en) * | 2002-08-07 | 2006-01-21 | R & D Pharma | NOVEL PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF URINARY INCONTINENCE |
| DE10315917A1 (en) * | 2003-04-08 | 2004-11-18 | Schwarz Pharma Ag | Highly pure bases of 3,3-diphenylpropylamine monoesters |
| CN100382794C (en) * | 2004-08-30 | 2008-04-23 | 鲁南制药集团股份有限公司 | Dispersed tablet of tartaric acid tolterodine tartrate |
| WO2009151613A1 (en) * | 2008-06-13 | 2009-12-17 | Concert Pharmaceuticals, Inc. | Oxybutynin derivatives |
| US20110262566A1 (en) * | 2008-11-07 | 2011-10-27 | Dainippon Sumitomo Pharma Co., Ltd. | Novel useful therapeutic agent for lower urinary tract symptom |
| GB2571696B (en) | 2017-10-09 | 2020-05-27 | Compass Pathways Ltd | Large scale method for the preparation of Psilocybin and formulations of Psilocybin so produced |
| WO2020212948A1 (en) | 2019-04-17 | 2020-10-22 | Compass Pathfinder Limited | Methods of treating neurocognitive disorders, chronic pain and reducing inflammation |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9417135D0 (en) * | 1994-08-23 | 1994-10-12 | Medinnova S F | Method |
| IT1282705B1 (en) * | 1996-02-28 | 1998-03-31 | Recordati Chem Pharm | USE OF 5-HT | A SEROTONINERGIC RECEPTOR ANTAGONISTS FOR THE TREATMENT OF URINARY INCONTINENCE |
| PE92198A1 (en) * | 1996-08-01 | 1999-01-09 | Banyu Pharma Co Ltd | DERIVATIVES OF FLUORINE-CONTAINED 1,4-PIPERIDINE |
| US5942519A (en) * | 1997-10-28 | 1999-08-24 | Merck & Co., Inc. | Prevention of precipitated acute urinary retention |
| WO2001021167A1 (en) * | 1999-09-22 | 2001-03-29 | Merck & Co., Inc. | Treatment of lower urinary tract symptoms and pharmaceutical compositions for use therein |
| IT1314192B1 (en) * | 1999-10-18 | 2002-12-06 | Recordati Chem Pharm | BENZOPYRANIC DERIVATIVES |
-
2002
- 2002-09-26 KR KR10-2004-7004529A patent/KR20040039436A/en not_active Application Discontinuation
- 2002-09-26 JP JP2003530203A patent/JP2005503424A/en not_active Withdrawn
- 2002-09-26 EP EP02775633A patent/EP1438035A2/en not_active Withdrawn
- 2002-09-26 CA CA002461731A patent/CA2461731A1/en not_active Abandoned
- 2002-09-26 MX MXPA04002496A patent/MXPA04002496A/en unknown
- 2002-09-26 BR BR0212824-1A patent/BR0212824A/en not_active IP Right Cessation
- 2002-09-26 CN CNA028188764A patent/CN1558756A/en active Pending
- 2002-09-26 IL IL16085202A patent/IL160852A0/en unknown
- 2002-09-26 WO PCT/SE2002/001748 patent/WO2003026564A2/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| WO2003026564A9 (en) | 2004-06-17 |
| WO2003026564A3 (en) | 2003-12-11 |
| CA2461731A1 (en) | 2003-04-03 |
| WO2003026564A2 (en) | 2003-04-03 |
| IL160852A0 (en) | 2004-08-31 |
| JP2005503424A (en) | 2005-02-03 |
| KR20040039436A (en) | 2004-05-10 |
| BR0212824A (en) | 2004-10-13 |
| MXPA04002496A (en) | 2004-05-31 |
| EP1438035A2 (en) | 2004-07-21 |
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