TW200918048A - Drug combinations for the treatment of sialorrhoea - Google Patents

Abstract

A combination comprises an α 2-adrenoceptor agonist and an anti-muscarinic agent for the treatment or prevention of sialorrhoea, for example clozapine-induced sialorrhoea, in a patient subgroup selected from: (I) those suffering from, or at risk of suffering from: (a) a pathological confused mental state; (b) hallucinations; (c) dementia, for example Lewy body dementia; (d) cognitive disturbances; (e) bladder outflow obstruction; (f) prostatism, for example benign prostatic hypertrophy or prostate cancer; (g) glaucoma; (h) hypotension; (i) somnolence; (j) ocular hypertension and (k) needle phobia; or (II) (a) individuals with cortical Lewy bodies; (b) males with an enlarged prostate; (c) individuals with a tendency to presyncope or syncope; (d) individuals with a score ≥ 1 on questions I. 1 and I. 2 on the UPDRS or < 88/100 on the Cambridge ACE (Addenbrooke's cognitive assessment); (e) individuals with a score ≥ 1 on American Urology Association symptom index; (f) individuals with an intraocular pressure of > 20mmHg or taking medication to lower previously raised intraocular pressure; (g) individuals with needle phobia; (h) individuals with a score 1 on Q42 on section C of the UPDRS (unified Parkinson's disease rating scale); (i) individuals with a score 1 on Q41 on section C of the UPDRS; (j) individuals with an ESS (Epworth sleepiness score) of > 10; (k) individuals with a leaky blood brain barrier.

Description

200918048 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to a pharmaceutical composition and its use for treating Sialorhoea. [Prior Art]

患有. Suffering from serious neurological disorders such as dyskinesia (such as cerebral palsy, peripheral neuromuscular disease, facial nerve itching, Parkins〇n, s disease, severe mental retardation, and other conditions such as stroke and esophagus Cancer) Patients with Sialorrhoea (or drooling) whose saliva and his oral contents will unconsciously flow out of π. Drooling (4) (10) (4) is common in individuals with neurological disorders. For example, about 1% of people with cerebral itching in the society often have obvious "water symptoms. Continuous drooling over 3 or 4 years old is considered to be incorrect. ^ ^ ^ 疋 + hanging flow Saliva. The case of Salojo is derived from the excessive secretion of saliva or the impaired sputum of Atari. The latter is a special problem for patients with dyskinesia. The drooling causes speech, 咭&gt; $ ^ ^ Impaired problems such as sputum and swallowing and increase the risk of aspiration into the lungs, accompanied by cyanosis and mortality. Control of drooling to prevent the occurrence of eight patients with posterior drooling Suffocation and suffocation are important. People with impaired movements can use the new electronic aids on the eve of the day to communicate, manipulate and provide more in the daily life, greater integration and self-sufficiency. Unfortunately, the people are allowed to control through mouth or face manipulation. The drooling can be applied to the device of 5丨±, b. Social isolation and the inability to use the new 200918048 drooling not only Bringing trouble and restrictions to people suffering from Salouho disease And also cause problems for the caregiver. The responsible caregiver must clean and control the drooling, and remove the saliva from the drooler's body, clothes and surrounding equipment. In addition, the caregiver must be very careful not to be exposed to such as saliva. Therefore, it is recognized that Sarroh's disease requires medical treatment. Current treatments include anticholinergic agents such as glycopyirolate and scopolamine, and botulinum toxin injection. Injection) and surgery. In the case where an anti-Saroho disease effect (reducing salivation) is required, it is appropriate to not completely damage secretion or prevent saliva production due to response to food, etc. Anticholinergic agents to reduce the amount of saliva produced, such as the positive effects of stomach Changning (tablets) and scopolamine (skin patch). Although Yuechangning is a seasonal compound that has limited access to the CNS, it is not About 20-25% of patients are well tolerated. Similarly, although scopolamine can be moderately tolerated for several days, it will touch There are many kinds of systemic effects. The saliva produced after administration of stomach Changning or scopolamine may be extremely thick and thus unpleasant. This is because the parasympathetic tone of the salivary glands is blocked. It mainly maintains the aqueous component of saliva, making the sympathetic innervation of the salivary glands responsible for the more viscous mucus/proteinaceous components unaffected. Clonidine is an α2-adrenergic receptor agonist and is clinically It is mainly used for antihypertensive drugs. In addition to lowering blood pressure and heart rhythm, clonidine also causes significant sedation and dry mouth. Clinidine (cl〇nidine) has been shown to be effective in reducing the sarois disease induced by cl〇zapine 200918048 (Grabowski, 1992, J. Clin. Psychopharmacol., 12, 69-70;

Praharaj et al., 2005, J. Psychopharmacol., 19, 426-428). Coronol (0.15 mg) was administered orally (per 08) to 7 Parkinson's patients and was found to significantly reduce Sarowo's disease. Four of the 17 patients experienced side effects.

Coke, etc. are clinically used to treat conditions such as hypertension, as an adjuvant to anesthesia, sedation (before treatment), muscle spasm (spasticity), and many signs of withdrawal from opium and alcohol abuse. One of the imidazole-type compounds. Examples of other such compounds are rUmenidine, dexmedetomidine, tizanidine, moxonidine and iftfexidine. Sarroco may be a side effect of certain drugs. For example, clozapine-induced seroholism uses a non-selective muscarinic receptor antagonist, ipratropium, a solution of a quaternary derivative of atropine, via the sublingual or meridian Nasal administration, and some successful treatment #(〇. Freudenreich et al., 2004, J. Clin. PsychopharmacoL, 24, 98-100; J. Calder〇n et al, 2_, plus

Psychopharmacol·, 15, 49_52). Freudenreich et al. (2〇〇4) administered isopropylamine nasal spray (0·03_0.06%) sublingually to 8 patients who received clozapine and had excessive drooling. After several weeks of use, the two patients were reported to have a complete response and five patients had partial responses (the symptoms were controlled for 2-8 hours), while i patients were non-responders. The use of ipratropium dissolution = the term defect is a bitter taste. In addition, sublingual administration of atropine ophthalmic solution has been found to reduce sevoflurane-induced Salouho disease (A shama Μ ^, 200918048 2004, Ann. Pharmacother., 38, 1538). In a small case study, patients with Parkinson's disease underwent sublingual ophthalmic atropine solution and recorded a significant reduction in saliva production. However, 2 of the 7 patients had hallucinations (H, C. Hyson et al., 2002, Mov. Disorders, 17, 1 3 1 8-1 320). Atropine is a non-selective muscarinic antagonist that exhibits a significant side effect of the central nervous system. The use of non-selective muscarinic antagonists that can enter the brain extensively and produce undesirable side effects must be avoided, especially in patients with Parkinson's disease (PD). A new generation of anticholinergic muscarinic antagonists has been developed for use in indications such as urinary incontinence, overactive bladder, irritating bowel syndrome or C〇pD. Such compounds include tolterdine (d〇lter〇dine), dafinenacin, s〇lifenacin, zamifenacin^ Ro-3202904 (PSD-506) (trospium) ^ revatropate and ti〇tropium. Patients with PD are more prone to confusion and hallucinations, especially with their disease. There is evidence that blood-brain barriers in these patients are impeded by altered penetration and are therefore more "leak" than healthy individuals. Patients with pD are therefore more prone to spoilage and illusion when taking anticholinergic agents. Sleep problems are also extremely common in PD. β α2_adrenergic receptor agonists promote sleep and are therefore unsuitable for deduction. Furthermore, in older people, cardiovascular problems, like bladder outlet obstruction, are generally more common, especially among men. The α2 adrenergic receptor agonist is not suitable for the former and the anti-muscarinic drug is not suitable for both. To date, the cholinergic muscarinic receptor has been described as phenotypically and genetically as five subtypes. The major muscarinic receptor subtypes from the knockout study (kn〇ck _ _ called '200918048') that affect salivary (salivati〇n) are M3 receptor subtypes, but Μ1, M4 and M5 receptor stimulation It also has a small contribution to the overall parasympathetic effects of hooliganism. Weichangning and East berberine are older generations of antimuscarinic drugs and block all five muscarinic receptor subtypes. Significantly reduced but not completely inhibited, there is a need for an antagonist that selectively or preferentially blocks the M3 receptor.

The present invention is based on the discovery that a combination of an anti-scorpion venom test and an alpha2-adrenergic agonist can be used in the treatment of Sarroh's disease. The composition may have improved utility and/or reduced side effects. The two agents can be administered together in a single composition, or simultaneously, or sequentially. In addition, if the agonist does not cross the blood-brain barrier or its system is not easily administered in the manner of CNS or its concentration is not seen in the unwanted, political 'is expected to be stimulated The α2·adrenergic receptors reduce the salivary flow by supporting the negative feedback of cholinergic and sympathetic nerves in saliva without producing negative effects of central media such as hypertension and sedation. Therefore, the Α-receptor agonist is at least preferably administered via a tongue (pa-called, ancient or buccal route. Dan 3r, if the combination of α2-kidney is such that they are agonists or The concentration of antimuscarinic drugs or their concentrations in the concentrated gland and/or para-salivary glands in the systemic circulation is higher than that of the system (which is also used in a non-existent manner, which may also help to reduce the effect of the bladder of the present invention. And anti-scorpion venom test, / σ substance 'which contains α2·Β 受体 receptor agonism, used to treat or prevent 选自 发 罗 罗 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 Symptoms: (a) Saurohu disease in the subgroup of the broad-spectrum disease group, such as clozapine-inducing mental state such as Lewy body (4); (b) hallucinations; (4) cancerous, glandular syndrome, such as reed (4) cognitive impairment (4) bladder outlet obstruction; (7) pre-(j) south eye pressure, and (k) needle phobia. On the other hand, 士&αα,, 4 gland sin~ "species composition, which contains α2 _ 上 脉 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京 京Symptoms: (a) individuals with a Lewy body; (8) men with prostatic hypertrophy; (c) individuals with a tendency to faint or faint; (4) scores with & 1 on the questionnaire li ^ 2 on UpDRs Individuals with a score of &lt;88/1GG on Cambridge ACE (Addenbrooke, °'&quot;Knowledge#); (4) on the American Urology Ass〇ciati〇n syndrome index Individuals with a scalpel, (f) individuals with intraocular pressure of > 2〇mmHg or medication to reduce previously elevated intraocular pressure; (g) individuals with needle phobia; κ (8) in UPDRS "Unified parkinson, s disease rating scale", the individual with score 1 on Q42 of section c; (1) the individual with score on Q41 of section C of UPDRS; (1) has &gt; ι〇 An individual of the ESS (Epw〇rth sieepiness sc〇re), (k) an individual having a leaky brain barrier. In another aspect, the invention encompasses a composition comprising α2_ Adrenergic receptor agonists and anti-muscarinic drugs for the treatment or prevention of sa Huo disease, such as nitrozapine-induced sauroxosis, wherein the α2_adrenergic receptor agonist and the anti-muscarinic agent are in the form of a unit of measure, wherein the α2-adrenalin is subjected to the unit of measurement The concentration of the body agonist and the anti-muscarinic agent is 200918048. The inter-d〇se coefficient of variation is less than 5〇0/〇. [Embodiment] It is preferred that the composition of the present invention is administered separately. In the case of individual compounds, an efficacious medical effect can be produced when the compositions of the invention are administered. The term "efficacious" includes advantageous effects such as additivity (four) mountain kisses, synergy (synergism), reduced side effects, reduced toxicity, time to disease progression, a drug $, Dingchuan 3 A force of sensitization or rensitizati〇n), or improved response rate. Advantageously, the efficacy of the assay can contribute to the lower dose of each component or ingredients to be administered to the patient, thereby reducing toxicity/side effects, while producing "promoting, maintaining the same therapeutic effect". In this paper, it is said that the therapeutic effect produced by the 5 hai composition is greater than the sum of the therapeutic effects of the components contained in the composition of δ W W 〇 成 成 生效 生效 生效 生效 生效 生效 生效 生效The therapeutic utility produced by the composition is greater than the therapeutic utility of any of the ingredients contained in the composition when presented individually. "Pharmaceutical composition (10) coffee aceuticaIc〇mp〇siti〇n)" is a solid or liquid composition, its form,, itching, concentration, and purity are suitable for administration to patients (such as human or animal diseases) Suffering), after; * secret _ after giving it's can induce the desired physiological changes. "Pharmaceutical" is typically sterile and/or non-heating (n〇n_Pyr〇geniC). The term "non-heating," is defined in the administration of the pharmaceutical composition of the invention. Severe π± Λ J patients do not cause adverse inflammatory response to the composition. As used herein, the term "combination," is intended to define two or more compounds and/or agents (also referred to herein as ingredients) in the context of 12 200918048. There are materials in which the two or more compounds/agents are combined. The term "combined" and "combining" are used herein to describe two or more compounds/agents in combination. The combination may be physical or non-physical. Examples of physically combined combination compounds/agents include: 组成 • Compositions (eg, single blends), including those that are mixed with one another (eg, within the same single agent) Two or more compounds/agents; • Compositions comprising two or more compounds/agents chemically/physically linked (eg via cross-linking, molecular agglomeration or binding to a common medium) a group (a material of vehicie _丨; • a composition comprising two or more compounds/agents chemistry/physicochemically co-constructed (c〇_packaged) (eg, configured in a liquid medium)

Body, particles (such as microparticles or nanoparticles) or emulsion droplets above materials; β pharmaceutical kits, pharmaceutical packs or patient packs, two or more of them A variety of compounds/agents are presented in a total of _packaged or co-presented (as part of). Examples of non-, physically combined combination compounds/agents include: - a material (eg, a non-single blend), comprising at least one of two or more compounds / = plus instructions to indicate the at least one An ad hoc combination of a compound/agent to form a physical knot of the two or more compounds/agents 13 2009 18048; • a material (eg, a non-single blend) containing two or more compounds / Combination instructions for indicating combination therapy of the two or more compounds/agents; materials comprising at least one of two or more compounds/agents to indicate a vote for the patient population Where the patient family has taken (or is taking) the other of the two or more compounds/agents (others); '2 materials containing two or more compounds/agents At least one, in or a form is specifically adapted for combination with the other of the two or more compounds/agents (others). As used herein, the term 'combination therapy', is intended to define a composition comprising a "two or more compound" agent (as defined above). Oral therapy, therefore, in this application, for " Combination therapy, "composition" and compound / drug secrets " &amp; people" known, and the use of the reference can be referred to as a whole part of the oral therapy + 夕 a The S substance/music agent. Thus, the pharmacology (p_kgy) of each of the two or more compounds/agents may be different: each may be administered at different times or at different times, so it is understood that The composition of the composition may be administered sequentially (eg, before or after) or simultaneously, in the same pharmaceutical combination (ie, together), or in different pharmaceutical blends (I7) Simultaneous administration of the same complex in a same blend, such as a single blending and simultaneous administration in different pharmaceutical blends, is not a single one. Two of the 4 compounds, / each in the combination therapy The pharmacology in the middle may also be different for the route of administration. In the meantime, the term "medicine kit," defines a batch of one or more 14 200918048 pharmaceutical composition unit dose plus metering tools (such as measuring phantom and / or delivery tools (such as inhalers or syringes) ), as needed, all contained within the common ingredient package. In a medical kit comprising a combination of two or more compounds/agents, the individual compounds/agents may be single- or non-monomeric unit dosages may be included The blister pack is included. The medical kit may further include instructions for use as needed. The term "batch" is defined within the same manufacturing process to create ''1熬':: within the limits of 'expected to have Consistent characteristics and quality of the unit. The term encompasses the plural units of measurement produced by both the batch manufacturing method and the continuous manufacturing method. The number of units (or C_V·) is applied to the pharmaceutical composition of the present invention. When measuring the early position, it is a technical term, and the key statistics of the medical composition of the M ^ 疋 number of batches are mixed. The mean value is multiplied by the value of (10). · ν · ^ quasi-deviation divided by Sleeve killing for At the time of the article, the term "medical package" is defined as a batch of a pharmaceutical composition unit, as needed: two: eve packaging. Inclusion - Tanabata from 丨匕a in a common external φ, or eve In the combination of the compound/agent combination, the individual compound/agent can be packaged in the blister package: 'early one compound. The unit agent can be used for instructions. It is used in the baggage used in this article. It contains the 敕徊: the word “patient package” is defined as the medical composition used in the treatment of a disease ^ ^ , , and has a course of treatment. - or a plurality of blister packs 1 々 包 包 整体 整体 整体 整体 整体 整体 整体 整体 : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : Drug Description (package 15 200918048 insert), which is often missing in patients with prescription drugs. The inclusion of a drug description has been shown to improve patient compliance with physician instructions. The muscarinic receptor binding ratio (expressed as M3:M1, M3:M4 and M3:M5 ratio) as described herein is based on LOURY, DN, HEGDE, S_S·, BONHAUS, DW &amp; EGLEN, RM ( The method described in 1999) was calculated based on the average pKi estimated in Tris-EDTA or Tris Krebs' buffer using human recombinant receptors and radioligands. The ionic strength of the assay buffer affects the antagonist binding avidity estimate at the M1-M3 cholinoceptors; Life Sci. 64: 6 or WATS ON, N., DANIELS, DV, FORD, APDW, EGLEN, RM &amp; HEGDE, SS· (1999) Comparative pharmacology of recombinant human M3 and M5 muscarinic receptors expressed in CHO-K1 cells; Br. J. Pharmacol. 127: 590-596. As used herein, the term "equitous treatment" of Salophos defines a treatment that reduces salivation of a patient with Sarowo's disease without causing it The patient's blood pressure changes substantially (eg, decreases) (or does not change (eg, decrease) to a clinically significant extent.) The compositions of the present invention produce therapeutic utility when administered separately from individual compounds/agents. Preferably, the composition of the present invention compresses 25 ± 5% of salivary secretion without causing a significant decrease in blood pressure at the same time. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT DESCRIPTION Preferred α2-adrenal glands for use in the present invention The receptor agonists are clonidine, apraclonidine, rilmenidine, dextran 16 200918048 dexmedetomidine, tizanidine, moxonidine and Lofidine (l〇fexidine) brimonidine. The preferred anti-muscarinic agents used in the present invention are toherodine, daifenacin, sophos Nasin (solifenacin ^ ^ zamifenacin, oxybutynin, tr〇spium, revatr〇pate: tiotropium and R〇_32〇 29〇4 (pSD_5〇6). The reference to specific α2-adrenoreceptor agonists or anti-muscarinic drugs is intended herein to include ionic, salt, solvate, isomer, and mutual mutation. Tautomers, vinegars, prodrugs, metabolites, isotopes, neoplasms, analogs and protected forms. According to the invention, each active agent can be used in any suitable form, such as salt, hydration Or a prodrug. If it is a chiral m〇lecule, it can be used in the form of a racemate, a non-singular mixture or a substantially mono-mirroromer. Thus, the present invention encompasses the composition of the present invention. All optical isomers, racemic forms, and non-image isomers of the ingredients contained. Thus, references to components in the compositions of the present invention encompass mixtures of non-image isomers, individual non-image isomers Object, mirror image isomer mixture, and in the form of a fine isomer In the case where the stereochemical form of the component is for pharmaceutical utility, the present invention encompasses the isolated eutomer. /, '. &amp; T T &amp; In the form of a dosage unit, the inter-agent coefficient of variation of the concentration of the components in the early position of the 6th juxtaposition is less than 5%. Particularly preferred are those in which the concentration of the agent(s) in the units of measurement is less than 4%, 3%, 2%, 1%, or 5% of the dose of 17 200918048 units. The plurality of dosage units can constitute a batch dosage unit. Typically, each active agent can be administered by any suitable early-adjusting person's tongue, sublingual or frequency route via a sputum spray. It is preferably formulated as a pastille, lozenge or dispersible tablet. The individual active agents can be formulated together in a single package and packaged together, or in a single or &lt;... X tester 4 can be administered separately. In some cases, a drug can be administered to treat another, and the present invention then comprises administering another drug.里周应症

Preferably, the agonist and/or anti-drug test is in a sustained release formulation. In this particular example, as systemic drugs are metabolized, ladders are maximized: as the compositions used in the present invention can be formulated in such a manner as to be known to give the agonists of the present invention and / or anti-drug test; controlled release, such as rapid release or sustained release of the drug-acceptable carrier is technically familiar:::::: adult: contains (M'% by weight Active compound. The present invention is prepared in a unit dosage form. Preferably, the unit dosage form comprises the active ingredient in an amount of from (2) to two to 100 grams, and the excipients used in the preparation of such compositions are all in the art. Known excipients, and the dosage levels of the two can be determined by a suitable method known to those skilled in the art, and the specific agent level for any particular patient is determined by a variety of factors. Including the activity, age, weight, general health, sex, diet, time of administration, route, rate of excretion, composition of the drug, and severity of condition to be treated: Xingyijia's 6 Hai activity Dosing The daily dose of the frequency administration type is 1 to 1 microgram, such as 10 to 500 micrograms. /, 18 200918048 The composition for oral administration includes a form such as a tablet, a soft lozenge, or a sputum. It is known in the art that it is a liquid for spraying into intraoral tablets, powders or granules, which are known in the art for the manufacture of pharmaceutical compositions: the composition may comprise - or a plurality of selected from two to be prepared according to such compositions And a medicament in the group consisting of preservatives to provide::::a colorant and a preparation. The tablet comprises an active ingredient, which is a pharmaceutically acceptable excipient of the genus Mixing. These are inert diluents such as carbon-, sodium sulphate, lactose, for example, sodium; granulating and disintegrating agents, such as corn I, strontium: acid such as gelatin, Ejiao, microcrystalline cellulose ^ 'binder, and lubricants, such as magnesium stearate, stearic acid or talc = sapphire; coated or they can be coated by known techniques = two hai: The agent may be non-disintegrating and absorbing and thereby providing continuous action over a longer period of time: in the intestinal tract a time-delaying material such as glycerin; for example, a distearate. When the composition is known to be administered orally, the composition may be in the mouth, the active agent may be released, and the drug is not administered. Keep it in a malleable and ugly manner. Within a few hours or a few hours. Equal to the composition of the two or ... chew or dispersible. This agent u said) bloody powder tablets (_ called and dispersible Sex film ^} /, open space may include flavoring. If the marriage + decomposed nature (mucol ti ... taste agent has an example of mucopolysaccharide (four) load z: rr is particularly suitable. These seasoning liquid, mixed Suitable for the manufacture of aqueous suspension excipients as suspending agents such as 竣methylcellulose 19 200918048 sodium, methyl cellulose, propyl propyl methyl cellulose 1 sodium alginate, polyvinyl pyrrolidone, tragacanth And Ejiao; Λ 刀 又 又 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 磷脂 磷脂 磷脂 磷脂 磷脂 磷脂 磷脂 磷脂 磷脂 磷脂 磷脂 磷脂 磷脂 磷脂 磷脂 磷脂 磷脂 磷脂 磷脂 磷脂 磷脂 磷脂 磷脂 磷脂 磷脂 磷脂 磷脂 磷脂 磷脂 磷脂 磷脂 磷脂...m...for example, polyoxyethylene hard..., ... condensation products of oxyethylene and long-chain fatty alcohols, such as ten It is a condensation product of ethoxylated ethoxylated alcohol or a partial vinegar derived from epoxy broth and fatty acid, such as polyoxyethylene sorbitan-oleic acid vinegar. Waterborne

The W liquid may also contain one or more preservatives such as vinegar or n-propyl ... or a plurality of coloring agents, one or more flavoring agents, and one or more sweeteners such as sucrose or saccharin. An oily suspension may be suspended in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil 'polyoxyethylene gasified cannabis oil, fatty acid such as oil 35' or mineral oil such as liquid stone or other surfactant or Detergents are formulated inside. The oily suspension may contain an agent such as candied fruit, solid stone soil or wort. The sweetness is such as the above description and a flavoring agent may be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid. Suitable for preparing hydrazine, hydrazine, and water by adding water. The dispersible powder and granules for the suspension are provided with active ingredients and dispersing or wetting agents, suspending agents and one or more preservatives. mixture. Suitable sweeteners, flavorings, and coloring agents can also be included. The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil such as eucalyptus oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture of such. Suitable emulsifiers may be naturally occurring gums such as Ejiao or Astragalus #, natural, occurring dish fats 20 200918048, such as soy-printed phospholipids, and vinegars derived from fatty acids and hexitol needles (1 to 1 anhydride S). Or a half ester, such as sorbitan-oleate, and a sigma product of the manholes of the partial esters and ethylene oxide, such as polyoxyethylene sorbitol needle-oleic acid. The emulsion may also contain sweeteners and flavoring agents. The sugar polysaccharides and elixirs may be formulated with sweetening agents such as glycerin, propylene glycol, sorbitol or sucrose. These blends may also contain demuleent, preservatives, flavoring agents, and coloring agents. The chlorhexidine composition can be in the form of a sterile injectable aqueous or oily suspension. The suspension may be formulated according to the known art using suitable dispersing agents or wetting agents and suspending agents as mentioned above, or may be non-toxic, non-toxic, non-toxic, non-invasive, A sterile injectable solution or a sputum in a solvent or a solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution (8) nger, s soluti〇n) and isotonic sodium chloride solution. In addition, auxin fixed oils are also conventionally used as solvents or suspending media. For this purpose, any mildly fixed oil can be used, and the white cup is a mono- or di-ester of s. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Alpha or the like or each active agent can be administered together with a mucopolysaccharide decomposing agent such as menthol. Menthol or another oil, such as eucalyptus oil ((4) Mail (10) 〇u), can be used to make the blend more palatable. The following study provides evidence for the usefulness of the present invention. The effects of clonidine and oxybutynin on the drip of nine well-being male volunteers were studied. This is an open-label, non-randomized, two-phase, increasing dose (rising d〇se) study. The research and development of the nine subjects before the pre-dose and after the administration of 21 200918048 (post-dose)! hours, the acceptance of saliva production assessment 2 Λ 4 small: robbing and 6 hours of each dosing field of life signs and from the vine $丨尸# P豕 was recorded at specific times during the study and adverse events were reported from beginning to end. For each fish, the scorpion image was compared with the drug-free control group (placebo). The maximum reduction rate of the solution was +4 ^ liquid. Using this information, both Cloning and Ouwu 眚, 曰布τ, under the random effect of the object, she reduced the saliva by θ 々 Η丨 '; From this model ^ Ε〇 30 and ΕΕ &gt; 5 〇. A combination of the best near (four) rate of 30 〇/〇 on the salivary flow is then used as a combination therapy. Also will be ;.,,, medicine! • The % reduction in the average maximum saliva production of the control control group was plotted against the dose. Results There were reports of serious or critical adverse events. The most common events that occur are headaches and fatigue. At the study period of $, there were no clinically significant changes in the observed biochemical hematology or urinalysis results. The bond observations in this study were based on the Saxon test (Sax〇n). See Kohler &amp; Winter, Arthritis Rheum. (1985) 28.1 128-32, and Stevens et al, Am. J· Diseases Children. (1990) 144: 570-571 ° The Saxon method used to assess saliva flow involves vigorously chewing a sterile gauze sponge. A piece of sterile gauze (1 〇 x 1 cm) was folded twice to the final size of 5 x 5 cm and placed in a sterile, screw-cap plastic container, which was then weighed. Ask the subject to swallow. Place the gauze block in the mouth of the subject and ask the subject to chew hard for exactly 2 minutes. At the end of the two-minute chewing period, the subject is immediately required to place the gauze block within the screw cap plastic container and weigh the 22 200918048 valley again. Printed by Shi Bu, I, I 〇 j 士 ^ D has recorded this measurement. The amount of saliva produced can be obtained by subtracting the dry weight of the gauze and the tube from the %* and the gauze weight towel, and the soil and the 丨+y. The results obtained using this method are presented in Figures 1 and 2.

These results show that after oxybutynin and clonidine are administered separately, a decreasing tendency toward saliva occurs over time. This effect is most important after being given to Coke Hall and is evident as the dose increases. Similarly, after administration of micronized sputum and 100 micrograms of clonidine, there was also a decrease in AUCs (AUC (0-6 hours)) compared to the drug-free component control group. After administration of ι 〇 mg oxybutynin, it was reduced &gt; compared to the drug-free control group. The ability of oxybutynin to reduce saliva production is more pronounced after combination with clonidine. After the combination of Auc after administration of the drug-free control group with the combination of 2 mg oxybutynin and 50 μg clonidine or (ii) 2 mg oxybutynin and 100 μg clonidine A reduction in saliva production was observed when AUC was compared. Similarly, when 2 mg oxybutynin was compared to (丨) 2 mg oxybutynin and 50 μg clonidine; and (ϋ) 2 mg oxybutynin and 1 〇〇 microgram of colonine At the time, the combination of oxybutynin and clonidine resulted in a significant reduction in AUC. The description of the equivalent %^ rigid face details the presently preferred embodiments of the present invention. In their implementations, those skilled in the art are expected to have many modifications and variations after considering these descriptions. Such modifications and variations are intended to be included within the scope of the appended claims. 23 200918048 ' [Simple description of the diagram] Figures 1 and 2 are bar graphs of saliva secretion after drug administration, showing the experimental results reported below. [Main component symbol description] None

twenty four

Claims (1)

200918048 X. Patent Application Range: 1. A composition comprising an a2-adrenoceptor agonist and an anti-muscarinic agent, the composition being used for treatment Or prevention of Sialorrhoea from a subgroup of patients such as clozapine-induced Salouho disease: (I) those who have the following or who are at risk: (a a mental state of pathological disorder; (b) hallucinations; (c) dementia, such as Lewy body dementia; (d) cognitive impairment; (e) bladder outlet obstruction; (f) prostate syndrome 'such as benign Prostatic hyperplasia or prostate cancer; (g) glaucoma; (h) hypertension; (i) narcolepsy; (j) high intraocular pressure and ocular phobia; or (II) (a) individuals with cortical Louise; b) men with prostatic hypertrophy; (c) individuals with a tendency to faint or fainting; ((1) in UPDRS (uniform (1 Parkins(), s disease rating scale)) On the questionnaires Ι·1 and 1.2 with & [scoring or in Cambridge Individuals with a score of &lt; 88/100 on ACE (Addenbrooke's Cognitive Assessment); (e) individuals with a score of > 1 on the American Urology Association Signature Index; (f) with &gt 20 mmHg intraocular pressure or an individual taking medication to reduce previously elevated intraocular pressure; (g) an individual with an injection phobia; (h) an individual with a score of 1 on Q42 of the UPDRS C section; ) individuals with score 1 on Q41 of the UPDRS C section, (j) individuals with &gt;丨〇 (Epworth sleepiness score); (k) with leaky blood brain barriers Individual. 2_--a composition comprising an α2-adrenoreceptor agonist and an anti-sputum test 25 200918048 for treating or preventing Sarowo disease such as milk disorder-induced Salouho disease, wherein Α2-adrenal gland, sputum, sputum, serotonin, and anti-muscarinic drugs are all in the form of a unit of measurement, in which the 2- 丄隹 丄隹 丄隹 丄隹 什 什 _ _ Receptor agonist and anti-sputum drug test, The inter-dose coefficient of variation is less than 50%. 'As claimed in the scope of the patent application, wherein the adrenergic receptor agonist is: (4) central-(tetra); or (8) non-central-acting And/or (4) may penetrate the blood-brain barrier; or (4) may not penetrate the blood-brain barrier; or the anti-muscarinic drug (4) may penetrate the blood-brain barrier; or (f) * may penetrate the blood-brain barrier. 4_=The composition of the scope of the patent application [ or 2, wherein the anti-muscarinic drug is: (a) an antagonist capable of accepting the M3 receptor relative to mi and/or M4 and/or M5 Blocking selectively or preferentially; and/or (b) having a ratio of M3.M1 receptor binding affinity of >1; and/or (c) having a ratio of M3:M4 receptor binding affinity; and/or ( d) m3:m5 receptor binding affinity ratio with &gt; !. 5. The composition of claim 2 or 2, wherein the α2_adrenergic receptor agonist is selected from the group consisting of cl〇nidine, apraclonidine, and brimonidine. ), rilmenidine, dexnie (ietomidine), tizanidine, moxonidine, and lofexidine ° 6. The composition of claim 1 or 2, wherein the anti-muscarinic drug is selected from the group consisting of daifenacin, sofinin (s〇Hfenacin), 26 200918048 zamifenacin, ochi Oxybutynin, glycopenrrolate, trospium, tolterodine, fesoterodine, revatropate, Ro-3202904 (PSD) -506), ipratropium and tiotropium. 7. The composition of claim 1 or 2, wherein the α2-adrenergic receptor agonist and the anti-scorpion The test is physically combined. 8. The composition of claim 7, wherein the α2-kidney The adrenergic receptor agonist is mixed with the anti-muscarinic drug line: (a) (eg, within the same unit dosage); (b) chemically/physically chemically linked (eg, via cross-linking, molecule) Molecular agglomeration or binding to a common media moiety; (c) co-packaged by chemical/physical chemistry (eg, configured in liquid media, particles (eg micron) (particles or nanoparticles) or on or above the emulsion droplets; (d) unmixed but co-packaged or co-presented (eg as part of a unit batch) 9. As claimed in the patent scope Or a composition of 2, wherein the α2_adrenergic receptor agonist is non-physically bound to the anti-muscarinic drug line. 10. The composition of claim 9 wherein the composition comprises : (a) at least one of the a2-adrenergic receptor agonist and the anti-muscarinic agent is added to indicate an ad hoc binding of the a2-adrenergic receptor agonist to the anti-muscarinic drug. To form a physical bond; or (b) at least one of an a2 adrenergic receptor agonist and an anti-muscarinic drug The above specification is directed to the use of one of the combination therapies, (a) at least one of an alpha 2 adrenergic receptor agonist and an anti-sputum drug to add instructions to indicate the administration of a patient group 27 200918048, Wherein the patient population has taken (or is taking) the other of the two or more compounds/agents; (d) an a2_adrenergic receptor agonist, the amount or form thereof being specifically Adapted for use in combination with an anti-muscarinic agent; or (e) an anti-muscarinic agent in an amount or form thereof specifically adapted for combination with an a2_adrenoreceptor agonist. A pharmaceutical pack, kit or patient pack' which comprises a composition as defined in claim 1 or 2. Plant 12. An a2. adrenergic receptor agonist for use in combination therapy with an anti-drug test as defined in claims 1 to 1 of the patent application. U. An anti-muscarinic agent for use in combination therapy with an a2-adrenoreceptor agonist as defined in claims 1 to 10 of the patent application. 14_ Use of an a2-adrenergic receptor agonist for the manufacture or prevention of a medicament for use in a medicament for treatment with an anti-muscarinic drug as defined in paragraphs i to 10 of the patent application. 15_The use of two anti-muscarinic drugs for the manufacture or prevention of a medicament for use in a patient treated with a2. adrenergic receptor agonist as defined in the scope of claims 1 to 10. 16. The use of any of items 11 to 15 of the patent application, wherein the composition is used separately or simultaneously. 17. A composition comprising an a2_adrenergic receptor agonist and an anti-muscarinic agent for use in the treatment or prevention of saroshoeia, such as clozapine-induced sauroxosis, There is a need for a 'mouth' as defined in any of the preceding paragraphs, wherein the agonist and/or antimuscarinic agent is administered in a salivary gland at a higher concentration than in the systemic circulation. 28 200918048 Volume-response ratio and/or reduced side effects. 18. If the patent application is also in the 17th paragraph, the person &amp;&gt; mainly recognizes that the sputum 'the agonist and the /3⁄4 ^ 1 A or buccal route are administered, thereby delivering the ratio in the salivary gland The concentration of the strip 2 in the circulatory system. 19. If the applicant and the anti-drug test are in the slow release:: the agonist 20. If the patent application is in the scope of patents 1, 2, 丨丨 H 13, 14. The invention of clauses 15 or 17, wherein the agonist and/or the main anti-anthraquinone drug are administered in the form of a gelatin, a soft bond, a lozenge or a dispersible tablet. 21. If you apply for a patent scope! 2, u 10 and ", 13, 14, 15 or 17 seedlings invention, wherein the composition of the other member of the initial addition of a mucolytic agent ° 22 · as claimed in the scope of the 21st product , τ ° 黏 mucopolysaccharide decomposer is 4 lunar month 6) (menthol) or eucalyptus oil (eucaiyptus. 23.- species as defined in the scope of the patent scope of the item _ in the manufacture of any of the scope of patent application Use of a medicament for any of the medical uses defined in the preceding paragraph. 24. A method of treating or preventing a disease or disorder as defined in any of the preceding claims, which includes administering to a patient in need thereof An effective amount of a composition as defined in any preceding paragraph of the patent application. 25--A composition comprising an α2_adrenergic receptor agonist and an anti-protozoal 2 music A group of mouthparts as defined in any of the preceding paragraphs, which is used for equitensive treatment or prevention of sauroxosis, such as nitrozapine-induced sauroxosis. 29 200918048 ψ 26. 1, 2, 11, 12, 13, 14, 15, 17 23, 24 or 25 of the invention, wherein the α2- adrenergic agonist than clonidine and / or the anti - Dian muscarinic drug oxybutynin than 30