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WO2009022096A1 - Combinaisons de médicaments pour le traitement de la sialorrhée - Google Patents

Combinaisons de médicaments pour le traitement de la sialorrhée Download PDF

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Publication number
WO2009022096A1
WO2009022096A1 PCT/GB2008/002650 GB2008002650W WO2009022096A1 WO 2009022096 A1 WO2009022096 A1 WO 2009022096A1 GB 2008002650 W GB2008002650 W GB 2008002650W WO 2009022096 A1 WO2009022096 A1 WO 2009022096A1
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WO
WIPO (PCT)
Prior art keywords
combination
individuals
muscarinic agent
adrenoceptor agonist
agent
Prior art date
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Ceased
Application number
PCT/GB2008/002650
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English (en)
Inventor
Paul Goldsmith
Alan Geoffrey Roach
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Summit Therapeutics Ltd
Orient Pharma (Samoa) Co Ltd
Original Assignee
Summit Corp PLC
Orient Pharma (Samoa) Co Ltd
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Publication of WO2009022096A1 publication Critical patent/WO2009022096A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to a drug combination and its use in the treatment of sialorrhoea.
  • Drooling causes impairment of speech, feeding and swallowing problems and increases the risk of aspiration into the lungs, with attendant morbidity and mortality. Control of drooling is important in preventing choking and gagging in persons with posterior drooling.
  • sialorrhoea requires medical attention.
  • Current treatment includes administration of anticholinergic agents such as glycopyrrolate and scopolamine, botulinum toxin injections and surgery.
  • anticholinergic agents such as glycopyrrolate and scopolamine
  • glycopyrrolate is a quaternary ammonium compound with restricted access to the CNS, it is not well tolerated by around 20-25% of patients.
  • scopolamine is reasonably tolerated for a few days, but many systemic side-effects are encountered.
  • the saliva produced following administration of glycopyrrolate or scopolamine may be extremely thick and as such is unpleasant. This is due to blockade of the parasympathetic tone to the salivary glands, which maintains predominantly aqueous component of saliva, leaving unopposed the sympathetic innervation to the glands responsible for the more viscous mucus/proteinaceous component.
  • Clonidine is an ⁇ 2-adrenoceptor agonist and is primarily used clinically as an antihypertensive agent. Besides lowering blood pressure and heart rate, clonidine also causes pronounced sedation and dry mouth. Clonidine has been shown to be effective in reducing sialorrhoea induced by clozapine (Grabowski, 1992, J. Clin. Psychopharmacol., 12, 69-70; Praharaj et al., 2005, J. Psychopharmacol., 19, 426-428). Clonidine (0.15 mg) has been given peros to 17 Parkinson's patients and found to significantly reduce sialorrhoea. Four of the 17 patients experienced side-effects.
  • Clonidine is one of many imidazole-type compounds that are used clinically to treat conditions such as hypertension, sedation as an adjunct to anaesthesia (premedication), muscle spasm (spasticity), and withdrawal symptoms of opiate and alcohol abuse. Examples of other such compounds are rilmenidine, dexmedetomidine, tizanidine, moxonidine and lofexidine.
  • Sialorrhoea can be a side-effect of the administration of certain drugs.
  • clozapine-induced sialorrhoea has been treated with some success with solutions of the non-selective muscarinic receptor antagonist ipratropium, a quaternary derivative of atropine, given either sublingually or intranasally (O. Freudenheim et al., 2004, J. Clin. Psychopharmacol., 24, 98-100; J. Calderon et al., 2000, Int. Clin. Psychopharmacol., 15, 49-52).
  • ipratropium a non-selective muscarinic receptor antagonist
  • ipratropium nasal spray (0.03-0.06%) sublingually to 8 patients receiving clozapine and who suffered from excessive drooling. After several weeks of use, a full response was reported in 2 patients and a partial response (symptoms controlled for 2-8 hours) in 5 patients, while 1 patient was a non-responder.
  • One drawback with the ipratropium solution is its bitter taste.
  • an ophthalmic solution of atropine given sublingually was found to reduce clozapine-induced sialorrhoea (A. Sharma et al., 2004, Ann. Pharmacother., 38, 1538).
  • Atropine is a non-selective muscarinic antagonist that exhibits significant central nervous system side-effects.
  • the use of non-selective muscarinic antagonists that extensively enter the brain and produce undesirable side-effects should be avoided, particularly in patients with Parkinson's disease (PD).
  • a new generation of anticholinergic muscarinic antagonists is being developed for indications such as urinary incontinence, overactive bladder, irritable bowel syndrome or COPD.
  • These compounds include tolterodine, darifenacin, solifenacin, zamifenacin, Ro- 3202904 (PSD-506), trospium, revatropate and tiotropium.
  • cholinergic muscarinic receptors have been pharmacologically and genetically characterised into 5 subtypes.
  • General findings from knock out studies in mice indicate that the predominant muscarinic receptor subtype influencing salivation is the M3 receptor subtype but that M1 , M4 and M5 receptor stimulation may have a small contribution to the overall parasympathetic effect on salivation.
  • Glycopyrrolate and scopolamine are older generation anti-muscarinic drugs and block all 5 muscarinic receptor subtypes. In order to achieve significant reduction in salivary flow but not complete inhibition an antagonist which selectively or preferentially blocks M3 receptors would be desirable.
  • the combinations of the invention may produce a therapeutically efficacious effect relative to the therapeutic effect of the individual compounds when administered separately.
  • efficacious includes advantageous effects such as additivity, synergism, reduced side effects, reduced toxicity, increased time to disease progression, sensitization or resensitization of one agent to another, or improved response rate.
  • an efficacious effect may allow for lower doses of each or either component to be administered to a patient, thereby decreasing the toxicity/side effects, whilst producing and/or maintaining the same therapeutic effect.
  • a “synergistic” effect in the present context refers to a therapeutic effect produced by the combination which is larger than the sum of the therapeutic effects of the components of the combination when presented individually.
  • additive effect in the present context refers to a therapeutic effect produced by the combination which is larger than the therapeutic effect of any of the components of the combination when presented individually.
  • a "pharmaceutical composition” is a solid or liquid composition in a form, concentration and level of purity suitable for administration to a patient (e.g. a human or animal patient) upon which administration it can elicit the desired physiological changes.
  • Pharmaceutical compositions are typically sterile and/or non-pyrogenic.
  • non-pyrogenic as applied to the pharmaceutical compositions of the invention defines compositions which do not elicit undesirable inflammatory responses when administered to a patient.
  • the terms “combined” and “combining” in this context are to be interpreted accordingly.
  • the association of the two or more compounds/agents in a combination may be physical or non-physical. Examples of physically associated combined compounds/agents include:
  • compositions e.g. unitary formulations
  • two or more compounds/agents in admixture (for example within the same unit dose);
  • compositions comprising material in which the two or more compounds/agents are chemically/physicochemically linked (for example by crosslinking, molecular agglomeration or binding to a common vehicle moiety);
  • compositions comprising material in which the two or more compounds/agents are chemically/physicochemically co-packaged (for example, disposed on or within lipid vesicles, particles (e.g. micro- or nanoparticles) or emulsion droplets);
  • non-physically associated combined compounds/agents examples include:
  • material e.g. a non-unitary formulation
  • material comprising at least one of the two or more compounds/agents together with instructions for the extemporaneous association of the at least one compound/agent to form a physical association of the two or more compounds/agents
  • material e.g. a non-unitary formulation
  • material comprising at least one of the two or more compounds/agents together with instructions for combination therapy with the two or more compounds/agents
  • material comprising at least one of the two or more compounds/agents together with instructions for administration to a patient population in which the other(s) of the two or more compounds/agents have been (or are being) administered;
  • references to “combination therapy”, “combinations” and the use of compounds/agents "in combination” in this application may refer to compounds/agents that are administered as part of the same overall treatment regimen.
  • the posology of each of the two or more compounds/agents may differ: each may be administered at the same time or at different times. It will therefore be appreciated that the compounds/agents of the combination may be administered sequentially (e.g. before or after) or simultaneously, either in the same pharmaceutical formulation (i.e. together), or in different pharmaceutical formulations (i.e. separately).
  • the term "pharmaceutical kit” defines an array of one or more unit doses of a pharmaceutical composition together with dosing means (e.g. measuring device) and/or delivery means (e.g. inhaler or syringe), optionally all contained within common outer packaging.
  • dosing means e.g. measuring device
  • delivery means e.g. inhaler or syringe
  • the individual compounds/agents may unitary or non-unitary formulations.
  • the unit dose(s) may be contained within a blister pack.
  • the pharmaceutical kit may optionally further comprise instructions for use.
  • batch defines a plurality of dose units intended to have uniform character and quality, within specified limits, produced in the same manufacturing run.
  • the term covers plural dose units produced by both batch manufacturing processes and continuous manufacturing processes.
  • the co-efficient of variation (or CV.) as applied to the dose units of the pharmaceutical compositions of the invention is term of art defining a key statistic of the quality of batches of a formulated pharmaceutical composition. Specifically, the CV. is the standard deviation divided by the mean multiplied by 100.
  • the term "pharmaceutical pack” defines an array of one or more unit doses of a pharmaceutical composition, optionally contained within common outer packaging.
  • pharmaceutical packs comprising a combination of two or more compounds/agents
  • the individual compounds/agents may unitary or non-unitary formulations.
  • the unit dose(s) may be contained within a blister pack.
  • the pharmaceutical pack may optionally further comprise instructions for use.
  • patient pack defines a package, prescribed to a patient, which contains pharmaceutical compositions for the whole course of treatment. Patient packs usually contain one or more blister pack(s).
  • muscarinic receptor binding ratios described herein are those calculated on the basis of mean pKi estimated in Tris-EDTA or
  • Tris Krebs' buffers using human recombinant receptors and radioligands according to the methods described in LOURY, D.N., HEGDE, S.S., BONHAUS, D.W. & EGLEN, R.M.
  • the term "equitensive treatment of sialorrhoea” defines a treatment which reduces saliva secretion in a patient suffering from sialorrhoea without also causing a substantial alteration (e.g. lowering) of that patient's blood pressure (or without altering (e.g. lowering) it to a clinically significant extent).
  • the combinations of the invention may produce a therapeutically efficacious effect relative to the therapeutic effect of the individual compounds/agents when administered separately.
  • the combinations of the invention suppress saliva secretion by 25 ⁇ 5% without also causing significant falls in blood pressure.
  • the present invention is based on the finding that a combination of an anti-muscarinic agent and an ⁇ 2-adrenoceptor agonist is useful in the treatment of sialorrhoea.
  • the combination can have an improved effect and/or reduced side-effects.
  • the two agents may be administered together, in a single composition, or simultaneously, or sequentially.
  • the agonist does not cross the blood-brain barrier or is administered in such a way that it does not readily enter the CNS or is given at such concentration that undesired central effects are not seen, it might be expected to reduce salivary flow by stimulating the negative feedback of ⁇ 2-adrenoceptors on cholinergic and sympathetic nerves supplying the salivary glands, without producing centrally mediated side-effects such as hypotension and sedation. Therefore, the ⁇ 2-adrenoceptor agonist at least is preferably administered by the paraungual, sublingual or buccal route.
  • ⁇ 2 adrenoceptor agonist or antimuscarinic agent or combination thereof are given in such a way that the concentrations are higher in the salivary glands and/or accessory salivary glands than in the systemic circulation, this will also help minimise systemic (non CNS) effects such as those on the heart and bladder.
  • the invention contemplates a combination comprising an ⁇ 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 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.
  • sialorrhoea for example clozapine- induced sialorrhoea
  • a patient subgroup selected from those suffering from, or at risk of suffering from: (a) a pathological confused mental state; (b) hallucin
  • the invention contemplates a combination comprising an ⁇ 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: (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 1.1 and 1.2 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
  • the invention contemplates a combination comprising an ⁇ 2- adrenoreceptor agonist and an anti-muscarinic agent for the treatment or prevention of sialorrhoea, for example clozapine-induced sialorrhoea, wherein the ⁇ 2-adrenoceptor agonist and anti-muscarinic agent are in the form of dose units wherein the inter-dose co- efficient of variation in the concentration of ⁇ 2-adrenoceptor agonist and anti-muscarinic agent in said dose units is less than 50%.
  • FIGS 1 and 2 are each bar charts of saliva secretion following drug administration, showing the results of experiments reported below.
  • Preferred ⁇ 2-adrenoceptor agonists for use in the invention are clonidine, apraclonidine, brimonidine, rilmenidine, dexmedetomidine, tizanidine, monoxidine and lofexidine.
  • Preferred anti-muscarinic agents for use in the invention are tolterodine, darifenacin, solifenacin, zamifenacin, oxybutynin, trospium, revatropate, tiotropium and Ro-3202904 (PSD-506).
  • a reference to a particular ⁇ 2-adrenoceptor agonist or anti-muscarinic agent herein is intended to include ionic, salt, solvate, isomers, tautomers, ester, prodrugs, metabolites, isotopes, derivatives, analogues and protected forms thereof.
  • Each active agent may be used, according to the invention, in any appropriate form, e.g. as a salt, hydrate or prodrug. If a chiral molecule, it may be used as a racemate, as a non- racemic mixture or as a substantially single enantiomer.
  • the present invention contemplates all optical isomers, racemic forms and diastereomers of the components of the combinations of the invention.
  • references to the various components for use in the combinations of the present invention encompass a mixture of diastereomers, individual diastereomers, a mixture of enantiomers as well as in the form of individual enantiomers. In cases where the stereochemical form of the component is important for pharmaceutical utility, the invention contemplates use of an isolated eutomer.
  • the combination may be provided in the form of a plurality of dose units wherein the inter- dose co-efficient of variation in the concentration of component(s) in said dose units is less than 50%. Particularly preferred are dose units wherein the inter-dose co-efficient of variation in the concentration of component(s) in said dose units is less than 40%, 30%, 20%, 10% or 5%.
  • the plurality of dose units may constitute a batch of dose units.
  • each active agent may be administered in any suitable formulation, by paraungual, sublingual or buccal route. It is preferably formulated as a gum, spray, pastille, lozenge or dispersible tablet.
  • the respective active agents may be formulated together in a single dosage form. Alternatively, they may be formulated separately and packaged together, or they may be administered independently. In certain cases, a patient may be receiving one drug for the treatment of another indication; this invention then comprises administering the other drug.
  • compositions for use in the invention may be formulated in a manner known to those skilled in the art so as to give a controlled release, for example rapid release or sustained release, of the agonist and/or antimuscarinic agents of the present invention.
  • Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art.
  • the compositions of the invention may contain 0.1-99% by weight of active compound.
  • the compositions of the invention are generally prepared in unit dosage form. Preferably, a unit dose comprises the active ingredient in an amount of 0.001 to 100 mg.
  • the excipients used in the preparation of these compositions are the excipients known in the art.
  • Appropriate dosage levels may be determined by any suitable method known to one skilled in the art. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the condition to be treated.
  • the active agent is administered at a frequency of 1 to 4 times per day.
  • a typical daily dosage is 1 to 1000 ⁇ g, e.g. 10 to 500 ⁇ g.
  • compositions for oral administration include known pharmaceutical forms for such administration, for example lozenges, pastilles, dispersible tablets, powders or granules or as a liquid for spraying into the mouth.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example com starch or alginic acid; binding agents, for example starch gelatin, acacia, microcrystalline cellulose or polyvinyl pyrrolidone; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time-delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • the composition may be in any form that will release the active agent, when held in the mouth, whether for a short time or for a matter of hours. It may be malleable and non-disintegrating, and/or chewable or dispersible. Preferred examples of such compositions are gums, as well as wafers and dispersible tablets (described above).
  • a flavorant will typically be included. It is particularly desirable if the flavorant has mucolytic properties. An example of such a flavorant is menthol.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids, for example polyoxyethylene sorbitan monooleate.
  • suspending agents for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, polyoxyethylene hydrogenated castor oil, fatty acids such as oleic acid, or in a mineral oil such as liquid paraffin or in other surfactants or detergents.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable sweetening, flavouring and colouring agents may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin, or mixtures of these.
  • Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid, find use in the preparation of injectables.
  • the or each active agent may be administered together with a mucolytic agent such as menthol.
  • a mucolytic agent such as menthol.
  • Menthol or another oil, e.g. eucalyptus oil, may be used to make the formulation more palatable.
  • the subjects were assessed on each dosing occasion for saliva production pre-dose and 1 h, 2.5h, 4h and 6h post-dose. Vital signs were recorded at specified times during each study period and adverse events were reported throughout.
  • the maximum % reduction in saliva production compared to placebo was calculated for each dose level.
  • a mixed effects regression analysis of the % reduction in saliva versus dose with subject as a random effect was performed for both clonidine and oxybutynin. From this model, an approximate ED 3 O and an ED 50 were calculated. The doses that gave the best approximate reduction of 30% (ED 30 ) in salivary flow was then used as a combination treatment. The mean maximum % reduction in saliva production compared to placebo was also plotted by dose.
  • the key observation in this study is based on the Saxon test. See Kohler & Winter, Arthritis Rheum. (1985) 28:1128-32, and Stevens et al, Am. J. Diseases Children (1990) 144:570-571.
  • the Saxon method for assessing salivary flow involves vigorously chewing on a sterile gauze sponge.
  • results show a trend towards a reduction in saliva production over time, following administration of oxybutynin and clonidine alone. This effect was most pronounced following administration of clonidine and was significant with increasing dose levels.
  • AUCs AUC(0-6 hours)
  • the AUC was reduced following administration of 10mg oxybutynin when compared to placebo.
  • the ability of oxybutynin to reduce saliva production was more pronounced following administration in combination with clonidine.
  • a reduction in saliva production was observed when the AUC following administration of placebo was compared to the AUC following administration of a combination of (i) 2 mg oxybutynin and 50 meg clonidine or (ii) 2 mg oxybutynin and 100 meg clonidine.
  • a combination of oxybutynin and clonidine resulted in a significant reduction in the AUC when 2 mg oxybutynin was compared to a combination of (i) 2 mg oxybutynin and 50 meg clonidine and (ii) a combination of 2 mg oxybutynin and 100 meg clonidine.

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Abstract

L'invention porte sur une combinaison comprenant un agoniste des adrénorécepteurs α2 et un agent anti-muscarinique pour le traitement ou la prévention de la sialorrhée, par exemple la sialorrhée induite par la clozapine, dans un sous-groupe de patients choisi parmi : (I) ceux souffrant de, ou risquant de souffrir de : (a) un état mental confus pathologique ; (b) hallucinations ; (c) une démence, par exemple une démence à corps de Lewy ; (d) perturbations cognitives ; (e) une obstruction d'écoulement de vessie ; (f) un prostatisme, par exemple une hypertrophie prostatique bénigne ou un cancer de la prostate ; (g) un glaucome ; (h) une hypotension ; (i) une somnolence; (j) une hypertension oculaire et (k) la phobie des aiguilles ; ou (II) (a) des individus avec des corps de Lewy corticaux ; (b) des hommes avec une prostate agrandie ; (c) des individus avec une tendance à la présyncope ou à la syncope ; (d) des individus avec un score ≥ 1 aux questions 1.1 et I.2 sur le UPDRS ou <88/100 sur l'évaluation cognitive de Addenbrooke (ACE) de Cambridge ; (e) des individus avec un score ≥ 1 sur l'indice de symptôme de l'Association américaine d'urologie ; (f) des individus avec une pression intraocculaire de >20 mmHg ou prenant un médicament pour diminuer la pression intraocculaire précédemment augmentée ; (g) des individus avec une phobie des aiguilles ; (h) des individus avec un score 1 sur Q42 à la section C du UPDRS (échelle de classement de maladie de Parkinson unifiée) ; (i) des individus avec un score de 1 sur Q41 à la section C du UPDRS ; Q) des individus avec un ESS (Score de somnolence de Epworth) > 10 ; (k) des individus avec une barrière hémato-encéphalique qui fuit.
PCT/GB2008/002650 2007-08-13 2008-08-04 Combinaisons de médicaments pour le traitement de la sialorrhée Ceased WO2009022096A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0715790.2A GB0715790D0 (en) 2007-08-13 2007-08-13 Drug combination for the treatment of sialorrhoea
GB0715790.2 2007-08-13

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8445526B2 (en) 2011-02-03 2013-05-21 Glaucoma & Nasal Therapies Llc Compositions and methods for treatment of glaucoma
US8765758B2 (en) 2009-12-17 2014-07-01 Eye Therapies Llc Compositions and methods for eye whitening
US8952011B2 (en) 2008-08-01 2015-02-10 Eye Therapies Llc Compositions and methods for the treatment of nasal conditions
US8987270B2 (en) 2009-07-27 2015-03-24 Eye Therapies Llc Formulations of selective alpha-2 agonists and methods of use thereof
US8999938B2 (en) 2013-06-21 2015-04-07 Gnt Llc Ophthalmic lipophilic drug delivery vehicle formulations
KR101891846B1 (ko) 2010-11-16 2018-08-24 알러간, 인코포레이티드 (3-(1-(1h-이미다졸-4-일)에틸)-2-메틸페닐)메탄올을 포함하는 약제학적 조성물
US11596600B2 (en) 2008-08-01 2023-03-07 Eye Therapies, Llc Vasoconstriction compositions and methods of use
US12246013B2 (en) 2008-08-01 2025-03-11 Eye Therapies Llc Vasoconstriction compositions and methods of use

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19612504A1 (de) * 1996-03-29 1997-08-21 Boehringer Ingelheim Kg Neue Wirkstoffkompositionen
WO2001008681A1 (fr) * 1999-08-02 2001-02-08 First Horizon Pharmaceutical Corporation Methodes d'administration de compositions de glycopyrrolates
WO2007093824A1 (fr) * 2006-02-13 2007-08-23 Summit Corporation Plc Combinaison d'un agoniste du récepteur alpha 2 (clonidine) et d'un agent anti-muscarinique (oxybutynine) pour le traitement de la sialorrhée

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19612504A1 (de) * 1996-03-29 1997-08-21 Boehringer Ingelheim Kg Neue Wirkstoffkompositionen
WO2001008681A1 (fr) * 1999-08-02 2001-02-08 First Horizon Pharmaceutical Corporation Methodes d'administration de compositions de glycopyrrolates
WO2007093824A1 (fr) * 2006-02-13 2007-08-23 Summit Corporation Plc Combinaison d'un agoniste du récepteur alpha 2 (clonidine) et d'un agent anti-muscarinique (oxybutynine) pour le traitement de la sialorrhée

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PRAHARAJ SAMIR KUMAR ET AL: "IS CLONIDINE USEFUL FOR TREATMENT OF CLOZAPINE-INDUCED SIALORRHEA?", JOURNAL OF PSYCHOPHARMACOLOGY, OXFORD UNIVERSITY PRESS, GB, vol. 19, no. 4, 1 July 2005 (2005-07-01), pages 426 - 428, XP009082948, ISSN: 0269-8811 *
ROGERS D P ET AL: "THERAPEUTIC OPTIONS IN THE TREATMENT OF CLOZAPINE-INDUCED SIALORRHEA", PHARMACOTHERAPY, BOSTON, US, vol. 20, no. 9, 1 January 2000 (2000-01-01), pages 1092 - 1095, XP009082797, ISSN: 0277-0008 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8952011B2 (en) 2008-08-01 2015-02-10 Eye Therapies Llc Compositions and methods for the treatment of nasal conditions
US11596600B2 (en) 2008-08-01 2023-03-07 Eye Therapies, Llc Vasoconstriction compositions and methods of use
US11833245B2 (en) 2008-08-01 2023-12-05 Eye Therapies Llc Vasoconstriction compositions and methods of use
US12246013B2 (en) 2008-08-01 2025-03-11 Eye Therapies Llc Vasoconstriction compositions and methods of use
US12311050B2 (en) 2008-08-01 2025-05-27 Eye Therapies Llc Vasoconstriction compositions and methods of use
US8987270B2 (en) 2009-07-27 2015-03-24 Eye Therapies Llc Formulations of selective alpha-2 agonists and methods of use thereof
US8765758B2 (en) 2009-12-17 2014-07-01 Eye Therapies Llc Compositions and methods for eye whitening
US9259425B2 (en) 2009-12-17 2016-02-16 Eye Therapies Llc Compositions and methods for eye whitening
KR101891846B1 (ko) 2010-11-16 2018-08-24 알러간, 인코포레이티드 (3-(1-(1h-이미다졸-4-일)에틸)-2-메틸페닐)메탄올을 포함하는 약제학적 조성물
US8445526B2 (en) 2011-02-03 2013-05-21 Glaucoma & Nasal Therapies Llc Compositions and methods for treatment of glaucoma
US8999938B2 (en) 2013-06-21 2015-04-07 Gnt Llc Ophthalmic lipophilic drug delivery vehicle formulations

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GB0715790D0 (en) 2007-09-26
TWI419689B (zh) 2013-12-21

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