CN101400347B - Alpha-2 receptor agonist (clonidine) is combined with antimuscarinic drug (oxibutynin) and is used for the treatment of sialorrhea - Google Patents

Abstract

α 2 adrenoceptor agonists as clonidine, brimonidine, moxonidine, lofexidine can be used for by by tongue, Sublingual or buccal routes use and treat sialorrhea.Patient to be treated is also given antimuscarinic drug as oxibutynin, glycopyrronium bromide, Ipratropium Bromured.

Description

Alpha-2 receptor agonist (clonidine) is combined with antimuscarinic drug (oxibutynin) and is used for the treatment of sialorrhea

Technical field

The present invention relates to medication combined and in treatment sialorrhea purposes.

Background technology

Suffer from the patient of severe neurological dysfunction as the dyskinesia (such as cerebral palsy, peripheral nervous muscle disease, facial paralysis, parkinson disease, severe mental retardation and other patient's condition are as apoplexy and the esophageal carcinoma) and can suffer sialorrhea (or sialorrhea), this is the unconscious loss of saliva and other content in oral cavity.Sialorrhea is common in be suffered from the individuality of delayed ischemic neurological deficits.Such as, about 10% suffer from the patient of cerebral palsy and there occurs significant sialorrhea in social activity.More than 3 years old or the persistency sialorrhea of 4 years old think abnormal sialorrhea.Sialorrhea by sialism or swallow impaired and produce; And swallow impaired be a special problem in the patient having dyskinesia.

Sialorrhea causes speech disorder, takes food and swallows problem and suction.Control in the people of sialorrhea sialorrhea (posteriordrooling) after suffering from, to prevent dysphagia and larynx of choking to be very important.The people of impaired movement can use multiple new electronic assistance aids to carry out linking up, advance and providing better integration and take care of oneself in daily life.For the people of those sialorrheas, unfortunately, a lot of auxiliary facilities is controlled by mouth or facial procedures.Sialorrhea may cause Social Loneliness (socialisolation) and can not use new equipment.

Sialorrhea not only for sialorrhea people be troublesome and restrictive, and be also problem concerning care-giver.Care-giver must clean and control saliva, and the saliva in removing drool health, medicated clothing and peripheral facilities.In addition, care-giver also must extreme care in order to avoid be exposed to body fluid as saliva.

Therefore, be recognized that sialorrhea needs medical attention.Current treatment comprises uses anticholinergic (such as glycopyrronium bromide and scopolamine, botuiinum toxin injections) and operation.

When needs anti-current saliva effect (reduction salivation), both not exclusively reduced secretory action and also do not stoped the saliva generation responded food etc. to be suitable.Likely reduce the amount of produced saliva by using anticholinergic, this is confirmed by the good effect of glycopyrronium bromide (tablet) and scopolamine (transdermal patches).Although glycopyrronium bromide a kind ofly arrives the limited quaternary ammonium compound of CNS, it still can not be well tolerable by the patient of about 20 ~ 25%.Equally, scopolamine can be tolerated several days by appropriateness, but has occurred the side effect of multiple general.Therefore the saliva produced after using glycopyrronium bromide or scopolamine very thickness is beastly.

Clonidine is a kind of α 2 adrenoceptor agonists, is mainly used as antihypertensive clinically.It plays and reduces sympathetic nerve to the effect of the tonicity of periphery in central nervous system.Except reduce blood pressure and heart rate except, clonidine also causes obvious sedation and xerostomia.Shown clonidine can effectively reduce caused by clozapine sialorrhea (Grabowski, 1992, J.Clin.Psychopharmacol., 12, 69-70; Praharaj etc., 2005, J.Psychopharmacol., 19, 426-428).17 disturbances in patients with Parkinson disease are oral gives clonidine (0.15mg), finds that sialorrhea significantly reduces.In described 17 patients, there are 4 to there occurs side effect.

Clonidine is the one in numerous imidazole type compounds, and described imidazole type compound is used for the treatment of such as hypertension, the disease such as withdrawal symptom as the subsidiary calmness (premedication) of anesthesia, muscle spasm (tetanic) and Opiate and alcohol abuse clinically.The example of other these compounds is rilmenidine, medetomidine, tizanidine, moxonidine and lofexidine.All these compounds are all produced its clinical effect by α 2 adrenoceptor in excited brain and are caused sedative side effect and xerostomia.

Sialorrhea can be the side effect of using some drugs.Such as, the solution that the sialorrhea that clozapine causes has utilized Sublingual or intranasal to give non-selective muscarinic receptor antagonist Ipratropium Bromured (atropinic season derivant) has carried out successful treatment (O.Freudenreich etc. to a certain extent, 2004, J.Clin.Psychopharmacol. 24, 98-100; J.Calderon etc., 2000, Int.Clin.Psychopharmacol., 15, 49-52).Freudenreich etc. (2004) accept clozapine to 8 and give ipratropium nasa spray (0.03-0.06%) by the patient Sublingual that excessive sialorrhea perplexs.After using a few week, it is reported that 2 patients reply completely, 5 patient part's response (symptom is by control 2-8 hour), and 1 patient's nonreply.A shortcoming of use ipratropium solution is its bitterness.In addition, Sublingual give atropinic ophthalmic solution find to reduce sialorrhea that clozapine causes (A.Sharma etc., 2004, Ann.Pharmacother., 38, 1538).In a small-scale case research, giving eye atropine solution to suffering from Parkinsonian patient Sublingual, being recorded to saliva production and significantly reducing.But, have in 7 patients 2 occurred hallucination (H.C.Hyson etc., 2002, Mov.Disorders, 17, 1318-1320).Atropine is a kind of non-selective muscarinic antagonist, and it shows obvious central nervous system's side effect.Should avoid using and extensively enter in brain and produce the non-selective muscarinic antagonist of less desirable side effect, particularly in the patient suffering from parkinson disease (PD).

Another kind of known medicine is antimuscarinic drug.The indication of such as urinary incontinence, overactive bladder (overactivebladder), irritable bowel syndrome or COPD is just being used at the anticholinergic muscarine antagonist of Development of New Generation.These compounds comprise tolterodine, darifenacin, solifenacin (solifenacin), zamifenacin (zamifenacin), Ro-3202904 (PSD-506), oxibutynin, Spasmo 3, Revatropate (revatropate) and tiotropium bromide (tiotropium).

The patient suffering from PD is easier to occur mental disorder and hallucination, particularly when their progression of disease.May to become permeability higher for its blood brain barrier in addition.Therefore, when being given anticholinergic, their mental disorder and hallucination are easier to worsen many.Sleeping problems are also very common in PD.Therefore α 2 agonist hypnotic is undesirable in PD.In addition, in more old crowd, cardiovascular problems is more more common, particularly in the male of bladder outlet obstruction (BOO).α 2 agonist is undesirable for the former; Antimuscarinic drug is all undesirable for the two.

Summary of the invention

The present invention can combine based on antimuscarinic drug and α 2 adrenoceptor agonists and be used for the treatment of on this discovery of sialorrhea.Described associating can have the effect of improvement and/or the side effect of minimizing.This two classes medicament can be used together, use with single composition forms, side by side or sequentially uses.

In addition, if described agonist not through blood brain barrier or use in the mode being not easy to enter CNS or not occur that the concentration of undesirable central action gives time, then can estimate by stimulating α 2 adrenoceptor to reduce salivary flow to the cholinergic nerve of domination salivary gland and orthosympathetic negative feedback, and do not produce the side effect of maincenter mediation, such as hypotension and calmness.Therefore, described α 2 adrenoceptor agonists is at least use preferably by tongue other (paralingual), Sublingual or buccal routes.

Accompanying drawing explanation

Fig. 1 and 2 be drug administration respectively after the block diagram of salivation, show following reported experimental result.

Detailed description of the invention

Clonidine, Aplonidine, brimonidine, rilmenidine (rilmedinide), medetomidine, tizanidine, moxonidine and lofexidine for preferred α 2 adrenoceptor agonists of the present invention.Tolterodine, darifenacin, solifenacin, zamifenacin, oxibutynin, Spasmo 3, Revatropate, tiotropium bromide and Ro-3202904 (PSD-506) for preferred antimuscarinic drug of the present invention.

According to the present invention, often kind of activating agent all can use in any suitable form, such as, as salt, hydrate or prodrug.If chiral molecule, it can also racemic modification, non-racemic mixture or substantially single enantiomeric forms use.

Generally speaking, often kind of activating agent all can any suitable preparation by by tongue, Sublingual or buccal routes use.Preferably be mixed with colloid (gum), spray, lozenge, lozenge or dispersible tablet.

Each activating agent can be formulated in single dosage form together.Or it can be prepared respectively and be packaged together, or it can by individual application.In some cases, patient can accept the other medicines being used for the treatment of another kind of indication, then the present invention includes and use described other medicines.

Can prepare in the manner known to persons skilled in the art for compositions of the present invention to obtain the controlled release (such as discharging fast or sustained release) of the compounds of this invention.The pharmaceutically suitable carrier being applicable to such compositions is well known in the art.Compositions of the present invention can comprise the reactive compound of 0.1 ~ 99% (by weight).Compositions of the present invention is prepared with the form of unit dosage forms usually.Preferably, unit dosage forms packet content is the active component of 0.001 ~ 100mg.Excipient for the preparation of these compositionss is excipient as known in the art.

Suitable dosage level is determined by any appropriate method well known by persons skilled in the art.But, be to be understood that, for any concrete patient, concrete dosage level will depend on many factors, comprise the order of severity of the activity of the particular compound used, age, body weight, general health situation, sex, diet, time of application, route of administration, discharge rate, disease medication combined and to be treated.Preferably, with the frequency administering active agents of 1 to 4 time every day.Typical daily dose is 1 ~ 1000 μ g, such as 10 ~ 500 μ g.

Comprise such as, for this known pharmaceutical forms used, lozenge, lozenge, dispersible tablet, powder or granule for Orally administered compositions, or as the liquid be used in entrance.Can prepare according to any method for the preparation of pharmaceutical composition as known in the art the compositions be intended to for orally using, such compositions can comprise one or more and be selected from agent in sweeting agent, flavoring agent, coloring agent and antiseptic with the preparation providing pharmaceutical elegant good to eat.Tablet comprises active component and the mixture of nontoxic pharmaceutically acceptable excipient being suitable for preparing tablet.These excipient can be such as inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent, such as corn starch or alginic acid; Binding agent, such as starch, gelatin, arabic gum, microcrystalline Cellulose or polyvinylpyrrolidone; And lubricant, such as magnesium stearate, stearic acid or Talcum.Tablet can be non-coating, or by known technology by its coating to delay disintegrate in the gastrointestinal tract and absorption, thus provide the continuous action of long period.Such as, the material that the up time postpones, such as glyceryl monostearate or distearin.

For Orally administered, described compositions can be when being placed in mouth at short notice or within a few hours, discharge any form of activating agent.It can be flexible not disintegrate and/or can to chew or dispersible.The preferred embodiment of such compositions is colloid and cake (wafer) and dispersible tablet (as mentioned above).Usually flavorant can be comprised.If described flavorant has mucolytic character, then desirable especially.An example of such flavorant is menthol.

Water suspension comprises active substance and the mixture of pharmaceutically acceptable excipient being suitable for preparing water suspension.Such excipient is suspending agent, such as sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl emthylcellulose, sodium alginate, polyvinylpyrrolidone, Tragacanth and arabic gum; Dispersant or wetting agent can be natural phospholipid such as lecithin, or the condensation product of alkylene oxide and fatty acid such as Myrj 45, or the condensation product of oxirane and long-chain fatty alcohol such as heptadecaethylene oxycetanol (heptadecaethyleneoxycetanol), or oxirane and be derived from the condensation product such as Polysorbate 80 of partial ester of fatty acid.Water suspension also can comprise one or more antiseptic such as ethylparaben or P-hydroxybenzoic acid n-propyl, one or more coloring agent, one or more flavoring agents and one or more sweeting agents (such as sucrose or glucide).

Oil suspension is prepared: vegetable oil, such as Oleum Arachidis hypogaeae semen, olive oil, Oleum sesami or Oleum Cocois, polyoxyethylene hydrogenated Oleum Ricini by being suspended in following substances by active component; Fatty acid is oleic acid such as; Mineral oil is liquid paraffin such as; Other surfactant or detergent.Oil suspension can comprise thickening agent, such as Cera Flava, hard paraffin or spermol.Can add sweeting agent (than as the above-mentioned those) and flavoring agent to provide good to eat oral formulations.These compositionss are stored by adding antioxidant such as ascorbic acid.

What be suitable for preparing by adding water water suspension dispersibles the mixture that powder and granule provide active component and dispersant or wetting agent, suspending agent and one or more antiseptic.Also can there is suitable sweeting agent, flavoring agent and coloring agent.

Pharmaceutical composition of the present invention can also be the form of oil-in-water emulsion.Described oil phase can be vegetable oil as the mixture of olive oil or Oleum Arachidis hypogaeae semen or mineral oil such as liquid paraffin or these oil.Suitable emulsifying agent can be naturally occurring glue such as arabic gum or Tragacanth, naturally occurring phospholipid such as soybean lecithin and be derived from the ester of fatty acid and hexitan or the condensation product such as Polysorbate 80 of partial ester such as dehydrated sorbitol mono-fatty acid ester and described partial ester and oxirane.Described Emulsion also can comprise sweeting agent and flavoring agent.

Sweeting agent (such as glycerol, propylene glycol, sorbitol or sucrose) syrup blend and elixir can be utilized.Such preparation also can comprise demulcent (demulcent), antiseptic, flavoring agent and coloring agent.Pharmaceutical composition can also be the form of aseptic injection water suspension or aseptic injection oil suspension.Those suitable dispersants above-mentioned or wetting agent and suspending agent can be utilized to prepare this suspensoid according to prior art.Described aseptic injection preparation can also be the form of aseptic injectable solution in the acceptable diluent of nontoxic parenteral or solvent or sterile suspensions, such as, be the solution in 1,3 butylene glycol.Available acceptable carrier and solvent are water, ringer's solution (Ringer ' ssolution) and isotonic sodium chlorrde solution etc.In addition, aseptic fixed oil is often used as solvent or suspension medium.For this purpose, the fixed oil of any gentleness can be used, comprise monoglyceride or the diglyceride of synthesis.In addition, fatty acid (such as oleic acid) also can be used for preparing injection.

Described activating agent or often kind of activating agent can be used together with mucolytic agent (mucolyticagent) such as menthol.Menthol or another kind of oil (such as Eucalyptus oil) can be used for making described preparation better to eat.

Below research provides the evidence of practicality of the present invention.

research

This research has investigated clonidine and oxibutynin to the impact of saliva production in 9 men's health volunteers.This is an opening, nonrandom, two cycles, cumulative dose of quantifier elimination.

Before administration with administration after 1 hour, 2.5 hours, 4 hours and 6 hours, evaluate the saliva production of object under each dosage.Particular point in time record vital sign in each research cycle, records adverse events in research whole process.

For each object, calculate the maximum reduction % relative to the saliva production of placebo under each dosage level.Utilize this information, using object as stochastic effect, saliva is carried out for clonidine and oxibutynin and reduces the melange effect regression analysis of % relative to dosage.Model calculates approximate ED thus ₃₀and ED ₅₀.Then, the dosage (ED will salivary flow being made preferably to reduce about 30% ₃₀) as therapeutic alliance.Also the average maximum reduction % relative dosage of the saliva production relative to placebo is mapped.

result

That do not report severe or serious adverse events.Modal adverse events is headache and fatigue.Biochemistry, the changing significantly clinically of hematology or urinalysis result is not observed during research.Do not observe vital sign (comprising blood pressure) during research, changing significantly clinically of ECG is led in health check-up or 12.

Critical report in this research is based on Saxon inspection.See Am.J.DiseasesChildren (1990) 144:570-571 such as Kohler & WinterArthritisRheum. (1985) 28:1128-32 and Stevens.These results as shown in figs. 1 and 2.

The trend that after result is presented at and uses separately oxibutynin and clonidine, saliva production reduces in time.This effect is more considerable after using clonidine, and more remarkable with dosage level increase.Equally, compared to placebo, after using 50mcg and 100mcg clonidine, AUCT reduces.Compared to placebo, after using oxibutynin, dose on saiiva production does not affect significantly, but after using oxibutynin 10mg, AUCT reduces.After co-administered clonidine, the ability that oxibutynin reduces saliva production is more remarkable.When the AUCT used after the AUCT after placebo and co-administered (i) 2mg oxibutynin and 50mcg clonidine or (ii) 2mg oxibutynin and 100mcg clonidine is compared, observe saliva production and reduce.Equally, when by 2mg oxibutynin and (i) 2mg oxibutynin and 50mcg clonidine combine and (ii) 2mg oxibutynin and 100mcg clonidine combine compare time, oxibutynin and clonidine combine the remarkable reduction causing AUCT.

Claims (7)

1. one kind comprises α 2 adrenoceptor agonists clonidine and antitoxin the product of alkali medicine oxibutynin, its as have more relative to single administration oxibutynin reduce saliva production effect combination formulations with the form used simultaneously or sequentially for reducing saliva production.

2. the product of claim 1, wherein said product by by tongue, Sublingual or buccal routes use.

3. the product of claim 1 or claim 2, wherein said product is formulated into colloid, spray, lozenge, lozenge or dispersible tablet.

4. the product of aforementioned claim 1 or 2, wherein also comprises mucolytic agent.

5. the product of aforementioned claim 3, wherein also comprises mucolytic agent.

6. the product of claim 4, wherein said mucolytic agent is menthol or Eucalyptus oil.

7. the product of claim 5, wherein said mucolytic agent is menthol or Eucalyptus oil.