Methods and compositions for low toxicity anticholinergic esters

Abstract

Methods and compositions for low toxicity anticholinergic esters are provided. Buccal formulations containing low-toxicity anticholinergic alkyl esters are useful for treating excessive salivation conditions in subjects, such as humans, suffering from hypersalivation. Preferably, at least one low-toxicity anticholinergic ester is provided in an effective amount or concentration in an anhydrous buccal formulation capable of inhibiting excessive salivation resulting from the condition known as hypersalivation. The compositions herein contain at least one low-toxicity anticholinergic agent (which is a low-toxicity ester analog of glycopyrrolate, as described in more detail below) in an effective amount or concentration to inhibit excessive salivation, or hypersalivation.

Description

[Background technology]

[0001] background Various anticholinergic compounds and formulations for these compounds have been reported previously.Muscarinic receptor antagonists are frequently used therapeutic agents that inhibit the effect of acetylcholine by blocking the binding of acetylcholine to muscarinic cholinergic receptors at the neuroeffector sites of smooth muscle, cardiac muscle, and glandular cells, as well as in peripheral ganglia and the central nervous system (CNS).However, their clinical use is often limited by their side effects, which may include dry mouth, photophobia, blurred vision, urinary hesitancy and retention, lethargy, dizziness, restlessness, irritability, disorientation, hallucinations, tachycardia and cardiac arrhythmia, nausea, constipation, and severe allergic reactions.Local administration of anticholinergic agents to targeted areas, such as the oral mucosa, where localized blockade of muscarinic receptors is clinically beneficial, is a desirable therapeutic strategy.However, currently used locally active anticholinergic drugs may exhibit undesirable systemic side effects, which may limit the dosage that can be safely administered.

[0002] Glycopyrrolate is one of several quaternary ammonium anticholinergic drugs with reduced CNS-related side effects due to its inability to cross the blood-brain barrier. However, because glycopyrrolate is primarily excreted as the unchanged drug or as active metabolites, its topical and other localized administration is often accompanied by common, undesirable anticholinergic systemic side effects. To increase the therapeutic index of anticholinergic drugs, the soft (low-addiction) drug approach has been applied with several different designs starting from various lead compounds. However, there is a need for other, more novel soft anticholinergic drugs with clinically relevant biological activity. These novel muscarinic antagonists, like all soft drugs, are designed to induce their intended pharmacological effects at the site of application but, upon entering the systemic circulation, are rapidly metabolized to inactive metabolites designed into their systemic circulation and rapidly eliminated from the body, resulting in reduced systemic side effects and an increased therapeutic index.

[0003] Soft anticholinergic zwitterions are described in U.S. Patent Application Publication No. 2012 / 0141401 (now U.S. Patent No. 8,568,699) and its related patents U.S. Patent Nos. 8,071,639, 7,538,219, and 7,417,147. Soft anticholinergic esters are described in U.S. Patent Application Publication No. 2012 / 0177590 (now U.S. Patent No. 8,628,759) and its related patents U.S. Patent Nos. 8,147,809, 7,576,210, and 7,399,861. While these published applications and patents identified the potential use of zwitterionic or ester forms of anticholinergic drugs to treat various conditions, the fact that the activity and duration of action against salivary hypersecretion are unexpectedly high in the present invention based on comparison with published mydriasis data was not known or previously described. Indeed, the treatment of hypersalivation with these particular compounds has not previously been suggested.

[0004] U.S. Patent Application Publication Nos. 2012 / 0141401 (US Pat. No. 8,568,699) and 2012 / 0177590 (US Pat. No. 8,628,759), and their related patents, US Pat. Nos. 8,147,809, 8,071,693, 7,576,210, 7,538,219, 7,417,147, and 7,399,861, are each incorporated by reference herein in their entirety and relied upon.

[0005] Hypersalivation is persistent or excessive drooling, which may be defined as saliva over the edges of the lips. Such drooling after the age of 3 or 4 years is considered abnormal and is typically It is commonly found in subjects with motor or neurological dysfunction. Hypersalivation is a significant problem in children with cerebral palsy and adults with neurodegenerative disorders (e.g., Parkinson's disease, ALS or Lou Gehrig's disease, muscular dystrophy, or multiple sclerosis). Hypersalivation also affects children with mental retardation and patients of any age with persistent brain injury or stroke, or with esophageal or other cancers of the oral cavity and digestive tract. Hypersalivation can also result from adverse drug reactions to tranquilizers, anticholinesterases, and antiepileptic drugs.

[0006] Hypersalivation can cause a variety of physical and social limitations (e.g., cracked lips, dehydration, odor, speech impediments, severe feeding and swallowing problems, aspiration, skin maceration, and risk of infection, not to mention embarrassment for the patient and caregiver.

[0007] Various approaches to managing the treatment of hypersalivation have been proposed, including biofeedback, positive and negative reinforcement, acupuncture, certain anticholinergic medications, botulinum toxin, gastroesophageal reflux control, radiation therapy, and surgical options.

[0008] Regarding anticholinergic agents, glycopyrrolate has been used in oral tablet form to treat hypersalivation in adults and children; an oral liquid is also available for pediatric use. Unfortunately, the classic side effects of anticholinergic drugs occur: constipation, excessive dry mouth, blurred vision, urinary retention, hyperactivity, and irritability. In clinical trials of the solid oral form in children (the majority of whom had cerebral palsy), over 20% withdrew from the study due to these adverse effects on their medication. While glycopyrrolate was effective in reducing salivation, these adverse events affected 69% of children who took the drug. Based on this data, individual doses of approximately 0.1 mg / kg of glycopyrrolate should show significant improvement in children [see MIER, RICHARD J. et al., Arch Pediatr Adolesc Med, 2000, 154:1214-1218 (published by American Medical Association)]. In clinical trials of the liquid oral form, more than 85% of children had cerebral palsy. The maximum recommended dose of glycopyrrolate was 0.1 mg / kg or 3 mg TID, whichever is lower. The most common adverse events observed were related to glycopyrrolate's mechanism of action as an anticholinergic, as in previous studies of the solid form [see ZELLER, ROBERT S. et al., Ther Clin Risk Manag, 2012, 8, 15-23 (published by Dove Medical Press Ltd)]. Adults (e.g., Parkinson's disease patients) typically start with 0.5 mg orally, 1 to 3 times daily.

[0009] Scopolamine, a topical anticholinergic, has been used in the form of a transdermal patch to treat hypersalivation, but side effects include pruritus at the patch site, urinary retention, blurred vision, dizziness, irritability, and glaucoma. With the exception of pruritus, these are typical systemic side effects of anticholinergics. See HOCKSTEIN, et al., Am Fam Physician, 2004:69:26:28-34 (published by the American Academy of Family Physicians).

[0010] Oral tropicamide films have also been proposed for the treatment of hypersalivation by temporarily reducing saliva production in individuals. Tropicamide is an anticholinergic drug with a relatively rapid onset of action. Rapidly dissolving film compositions of many known anticholinergic drugs, including tropicamide, are described in U.S. Patent Application Publication No. US2008 / 0102102 A1 to Morello et al. Clinical trials of tropicamide oral film compositions in Parkinson's disease patients have also been described. Other oral dosage forms are also described in the above-mentioned Morello et al. document. NH004 - Treatment of Sialorrhea See also rhea, NH004 Program Summary-2015, info@neurohealing.com.

[0011] WO 2001 / 0008681 A1 (published February 8, 2001) describes various methods of administering glycopyrrolate. Systemic administration across the buccal and sublingual membranes is suggested for treating hypersalivation and many other conditions. As noted on page 20 of this WO document, such systemic administration provides rapid onset of action, high blood levels, and avoids the first-pass effect. Permeation enhancers can be included to provide improved transmucosal delivery of systemic glycopyrrolate.

[0012] Orally disintegrating tablets containing glycopyrrolate for treating hypersalivation are also described in U.S. Patent Application Publication No. US2008 / 0260823 to Dillaha (published October 23, 2008). The published application claims that the orally disintegrating tablets described therein are particularly useful for patients with swallowing difficulties and disintegrate within minutes. Contrary to the teachings of WO2001 / 0008681, there is a very general suggestion of reduced systemic side effects; however, in the oral delivery system, permeation enhancers are included by Dillaha, which tend to increase delivery to the bloodstream, not decrease it. Tapolsky et al. also describe a pharmaceutical carrier device suitable for delivering pharmaceutical compounds to mucosal surfaces. The device includes an adhesive layer and a non-adhesive backing layer, and the drug can be in either or both layers. A method for transmucosal delivery of systemic drugs to achieve rapid onset of activity or desired blood levels of the systemic drug is claimed. Among the many drugs commonly mentioned, anticholinergics are commonly mentioned.

[0013] Saliva plays a major role in digestion, lubrication, immunity, and maintaining homeostasis. The major salivary glands that secrete saliva include the parotid (largest), submandibular, and sublingual glands. Under unstimulated conditions, 70% of saliva is secreted by the submandibular and sublingual glands. However, under stimulated conditions, the parotid glands secrete the majority of saliva. Hypersalivation can result from increased production of saliva or can be caused by a failure of the mechanisms that remove or clear saliva from the oral cavity. For example, muscular incoordination inhibits the swallowing reflex. When hypersalivation occurs in patients with neurological disorders, the condition is usually caused by dysphagia. Treatment with anticholinergic drugs is typically, but unfortunately, limited by their systemic side effects. The low-toxicity anticholinergic esters of U.S. Patent Nos. 8,628,729, 8,147,809, 7,576,210, and 7,399,861 have previously been proposed for use in various pharmaceutical forms for a variety of conditions requiring the use of locally active, but not systemically active, anticholinergic agents. That is, these anticholinergic agents (which are soft drugs) are designed to induce their desired pharmacological effects at the site of application but, upon entering the systemic circulation, are rapidly metabolized to inactive metabolites designed to provide reduced side effects. However, these low-toxicity anticholinergic agents have never before been proposed for use in the treatment of hypersalivation. This was due to the fact that the esters were found to be very short-acting in mydriatic studies. In the eye, the unique alkyl ester functional group of these compounds is rapidly hydrolyzed and inactivated, resulting in a very short duration of activity. It was also taught that the unique alkyl ester functionality of the low toxicity esters was rapidly hydrolyzed and inactivated, resulting in these compounds not being useful in treating hypersalivation. [Prior art documents] [Patent documents]

[0014] [Patent Document 1] US Patent Application Publication No. 2012 / 0141401 [Patent Document 2] U.S. Patent No. 8,071,639 [Patent Document 3] U.S. Patent No. 7,538,219 [Patent Document 4] U.S. Patent No. 7,417,147 [Patent Document 5] US Patent Application Publication No. 2012 / 0177590 [Patent Document 6] U.S. Patent No. 8,147,809 [Patent Document 7] U.S. Patent No. 7,576,210 [Patent Document 8] U.S. Patent No. 7,399,861 [Patent Document 9] US Patent Application Publication No. 2008 / 0102102 [Patent Document 10] International Publication No. 2001 / 0008681 [Patent Document 11] US Patent Application Publication No. 2008 / 0260823 [Patent Document 12] U.S. Patent No. 8,628,729 [Non-patent literature]

[0015] [Non-Patent Document 1] MIER, RICHARD J. et al., Arch Pediatr Adolesc Med, 2000, 154:1214-1218 (American Medical Association Press) [Non-patent document 2] ZELLER, ROBERT S. et al., Ther Clin Risk Manag, 2012, 8, 15-23 (published by Dove Medical Press Ltd.) [Non-patent document 3] HOCKSTEIN, et al., Am Fam Physician, 2004:69:26:28-34 (published by the American Academy of Family Physicians) [Non-patent document 4] NH004-Treatment of Sialorrhea, NH004 Program Summary-2015, info@neurohealing.com. Summary of the Invention [Means for solving the problem]

[0016] Abstract The present application relates to methods and oral formulations for treating excessive salivation conditions in subjects, particularly humans suffering from hypersalivation. The compositions herein comprise at least one low-toxicity anticholinergic agent (which is a low-toxicity ester analog of glycopyrrolate, as described in more detail below) in an amount or concentration effective to inhibit excessive salivation, or hypersalivation. One embodiment comprises: (a) a compound of formula (1): [ka] wherein R is methyl or ethyl, and the compound has an R, S, or RS stereoisomeric configuration at the 2-position and at the 1'- and 3'-positions, or a mixture thereof, in an amount effective to inhibit or reduce hypersalivation; and (b) at least one pharmaceutically acceptable carrier or excipient, wherein the oral composition is anhydrous or the oral composition is in solid or film form, and at least a portion of the composition in contact with the compound is anhydrous. In one particular embodiment, R is ethyl, and the pharmaceutically acceptable carrier or excipient (b) comprises absolute ethanol. The use of at least one compound of Formula (1) in the manufacture of an oral composition comprising at least one carrier or excipient for treating or inhibiting hypersalivation is yet another embodiment.

[0017] A preferred embodiment of the oral composition is (a) a compound represented by the following stereospecific formula (2): [ka] wherein R is methyl or ethyl, and the compound has an R stereoisomeric configuration at the 2-position and an R, S, or RS stereoisomeric configuration at the 1'- and 3'-positions (indicated by an asterisk), or a mixture thereof, in an amount effective to inhibit or reduce hypersalivation; and (b) at least one pharmaceutically acceptable carrier or excipient, wherein the oral composition is anhydrous or the oral composition is in solid or film form, and at least a portion of the composition in contact with the compound is anhydrous. In one specific embodiment, R is ethyl, and the pharmaceutically acceptable carrier or excipient (b) comprises absolute ethanol. The amount of compound (2) is sufficient to inhibit hypersalivation. Another embodiment is the use of at least one compound of formula (2) in the manufacture of an oral pharmaceutical composition comprising at least one compound and at least one carrier or excipient for treating / inhibiting hypersalivation.

[0018] Yet another embodiment provides an oral pharmaceutical composition comprising (a) one or more compounds of formula (2) above, where R=ethyl, (b) absolute ethanol, and (c) one or more additional pharmaceutically acceptable carriers or excipients, wherein the oral composition is anhydrous or the oral composition is in solid or film form, and at least a portion of the composition in contact with the compound is anhydrous. Yet another embodiment provides an oral composition comprising (a) and (b) as described above in this paragraph; (c) optionally at least one film-forming, gelling, viscosity-controlling, or mucoadhesive component; and (d) optionally at least one additional carrier or excipient; wherein the oral composition is anhydrous or in a solid or film form, and at least a portion of the composition in contact with the compound is anhydrous. The composition is anhydrous, or the oral composition is in solid or film form, wherein at least the portion of the composition in contact with the compound is anhydrous and contains a sufficient amount of the compound of formula (2) to significantly reduce excessive salivation, i.e., inhibit hypersalivation. Yet another embodiment is the use of a compound of formula (2) in the preparation of an oral pharmaceutical composition for inhibiting hypersalivation.

[0019] Despite the above, while anhydrous forms are suitable for storage stability, the oral formulation does not necessarily need to be anhydrous at the time of administration. For example, a freshly prepared aqueous solution can be used. Thus, anhydrous powder or tablets in a sealed aluminum packing can be dissolved in water or juice and held in the oral cavity and swirled inside. If anhydrous ethanolic solutions are too concentrated to be sprayed into the oral cavity, they can be diluted with excess water immediately before administration.

[0020] Also included is a method for treating, inhibiting, or improving excessive salivation, including hypersalivation, using at least one compound of formula (1) or (2) above, or the oral composition as described herein.The method includes, for example, administering an oral preparation comprising at least one compound of formula (2) or at least one alkyl ester of formula (2) above and at least one anhydrous pharmaceutically acceptable non-toxic carrier or excipient to the oral mucosa of a subject suffering from hypersalivation (particularly, orally to the oral mucosa, sublingually to the sublingual mucosa, or to the tongue or gingival mucosa to the gums), wherein the oral preparation is anhydrous, or the oral preparation is in solid or film form, wherein at least the portion of the composition that is in contact with the compound is anhydrous, and the amount of the compound of formula (2) is sufficient to significantly reduce excessive salivation, i.e., inhibit hypersalivation. The anhydrous carrier may be or include ethanol when R is ethyl; if it is not ethanol, it should be selected so as not to cause undesired transesterification of the ethyl ester group.

[0021] The compositions of the present application may be formulated as solids or semi-solids, powders, film compositions, gels, creams, lotions, foams, liquids, suspensions, aerosols, patches, wipes, emulsions, etc., and are formulated for intraoral application to treat, inhibit, or ameliorate hypersalivation. More preferably, the compositions as defined above are formulated as anhydrous intraoral solid or film compositions, or the solid or film compositions, at least a portion of which is in contact with the active compound, are anhydrous, and these compositions may contain absolute ethanol, which may provide certain advantages, including superior stability or increased shelf life for the composition, as well as the benefit of minimizing or eliminating the need for a separate preservative in the composition.

[0022] Other advantages of oral anhydrous solid or film composition, or at least part of the solid or film composition that is in contact with active compound is anhydrous, include herein the following characteristics: controlled dissolution and the time of absorption in the mouth, sublingually, tongue and gums, and the possibility of dispensing a preset amount of product per application.Certain formulations can also mask the sticky properties that some low-addiction anticholinergics (for example, certain compounds described herein) may have.

[0023] One exemplary formulation contains about 0.01% to about 10% of the ethyl ester compound in 90% to 99.99% ethanol, a non-aqueous solvent, which may further include one or more additional carriers or excipients (e.g., film-forming, gelling, viscosity-controlling, or mucoadhesive excipients) that are themselves anhydrous, i.e., non-aqueous.

[0024] Thus, in one aspect, provided herein is a method for treating, inhibiting, or ameliorating hypersalivation in a subject suffering from hypersalivation, the method comprising administering to the subject at least one compound having formula (1), or (a) a compound of formula (1): [ka] wherein R is methyl or ethyl, and the compound has an R, S, or RS stereoisomeric configuration at the 2-position and at the 1'- and 3'-positions, or a mixture thereof; (b) optionally, absolute ethanol; (c) optionally, at least one gelling, viscosity-controlling, film-forming, or mucoadhesive component; and (d) at least one anhydrous pharmaceutically acceptable, non-toxic carrier or excipient; wherein the oral composition, or at least a portion thereof in contact with the compound, is anhydrous; and the compound of formula (1) is administered in an amount effective to treat / inhibit hypersalivation, from about 0.01 mg to about 10 mg per dose, up to three times a day. Of particular interest are oral compositions in the form of solids or films adapted for application to the oral, sublingual, or gingival mucosa.

[0025] In another aspect, further provided herein is a method for treating, inhibiting, or ameliorating hypersalivation in a subject suffering from hypersalivation, said method comprising administering to said subject at least one compound having formula (2): [ka] wherein R is methyl or ethyl, and the compound has the R stereoisomeric configuration at the 2-position and the R, S, or RS stereoisomeric configuration at the 1'- and 3'-positions, or a mixture thereof; the composition comprises (a) the compound; (b) optionally, absolute ethanol; (c) optionally, at least one gelling, viscosity-controlling, film-forming, or mucoadhesive component; and (d) at least one anhydrous, pharmaceutically acceptable, non-toxic carrier or excipient; provided that the oral composition is anhydrous, or, when the composition is in a solid or film form, at least the portion of the composition in contact with the compound is anhydrous. Of particular interest are such oral compositions in the form of solids or films adapted for application to the oral, sublingual, or gingival mucosa.

[0026] Advantageously, the method can surprisingly provide a reduction in excessive salivation compared to baseline conditions for at least about 6 hours, to an extent that is substantially equivalent to the reduction in salivation resulting from administration of a composition containing the same amount of glycopyrrolate, also compared to baseline conditions, this low-toxicity ester previously thought to be too rapidly hydrolyzed to provide substantially equivalent activity.

[0027] The method of the present invention is preferably carried out by intra-oral administration of the compound or composition to a human subject to the oral mucosa of the subject. Preferably, the anatomical area for application or administration of the composition is selected from the oral mucosa, sublingual mucosa, tongue and gums, particularly the oral mucosa.

[0028] The methods of the present invention may reduce saliva production by at least 25%. In several clinical trials of children using glycopyrrolate to treat hypersalivation, saliva reduction was measured using the modified Teacher's Drooling Scale (mTDS), a 9-point scale based on the frequency and severity of the drooling effect on fabrics and surrounding areas. The scale ranges from 1 (dry, never drooling) to 4-5 (moderate; occasional or frequent wetting of lips and chin), 7 (severe, drooling to the point where clothing is frequently wet), and 9 (profuse, frequent wetting of clothing, hands, and objects). A 3-point reduction in this score from baseline was considered a response to treatment in clinical trials of glycopyrrolate oral solution. Administration of an ester of formula (1) or (2) in an amount equivalent to glycopyrrolate may provide an equivalent response but may have an improved safety profile, as evidenced by the extremely low or even non-existent incidence of systemic side effects plaguing the use of glycopyrrolate. The three-point improvement is therefore a clinically important endpoint for indications for treating hypersalivation.

[0029] As described above, the method may use compositions formulated as solids or semisolids, film compositions, powders, gels, creams, lotions, foams, liquids, suspensions, aerosols, patches, wipes, emulsions, etc., and may contain about 0.01 mg to about 10 mg of the compound per dose or unit dosage form. Also, as indicated above, the method may use aqueous solutions (e.g., in water or fruit juice) made just before administration from anhydrous powders or tablets (e.g., in sealed aluminum packages), or even from anhydrous solutions or suspensions.

[0030] Methods according to the present description may include the step of orally administering to a subject, as needed (prn), a composition (whether anhydrous or not) as defined herein. Administration is preferably one to three times daily, more preferably twice daily, in the morning and afternoon, about 6 to 8 hours apart. A typical single dose for an adult is about 1 mg to about 10 mg, preferably about For children, a typical dose is about 0.02 mg / kg to about 1.0 mg / kg, administered once, twice, or three times per day, preferably twice per day.

[0031] Surprisingly, the methods of the present invention can reduce hypersalivation to a clinically effective extent and with fewer systemic side effects than glycopyrrolate after single or multiple administrations.

[0032] Preferred compositions herein include: one or more low-toxicity esters of formula (1) or (2) as active ingredients; and at least one anhydrous carrier; with the proviso that the composition, or in the case of a solid or film, at least the portion thereof in contact with the active ingredient, is anhydrous; or as previously described, a simultaneously prepared aqueous solution or suspension.

[0033] As described herein, the formulations of the present invention are preferably solid or film compositions. Thus, more preferred compositions are: one or more low-toxicity esters of formula (1) or (2) as active ingredients; and at least one anhydrous carrier; and one or more gelling agents, viscosity control agents, film forming agents, or mucoadhesive agents with the proviso that the formulation is anhydrous, or if the formulation is a solid or film, at least a portion of it in contact with the active ingredient is anhydrous.

[0034] The low-toxicity esters of formula (1) or (2) are low-toxicity anticholinergic esters. The absence of water results in much greater storage stability. Suitable anhydrous formulations, and formulations in which the part of the active ingredient is in contact with the anhydrous formulation, are described hereinafter.

[0035] Advantageously, when R in formula (1) or (2) is ethyl, absolute ethanol can provide a self-preserving composition, which can provide microbial stability to the composition without the addition of preservatives.

[0036] Absolute ethanol can also inhibit bacterial growth and provide deodorizing properties to the composition.

[0037] A further advantage of such compositions according to the present description is provided by the fact that the non-aqueous solvent, absolute ethanol, is volatile, and therefore it is possible to use absolute ethanol as the solvent for the drug in the preparation of the drug-containing layer, which is then incorporated into the final intraoral film or solid composition.

[0038] A preferred gelling or viscosity controlling agent may be a modified cellulose, such as hydroxypropyl cellulose (HPC), such as commercially available KLUCEL™, which can preferably provide a viscosity of the composition of from about 100 to about 10,000 cps. In certain embodiments, for example, the following are provided: (Item 1) 1. A method for treating hypersalivation in a subject suffering from hypersalivation, comprising: The method comprises reacting a compound of the formula: [ka] wherein R is methyl or ethyl, and the compound has the R stereoisomeric configuration at the 2-position and the R, S, or RS stereoisomeric configuration at the 1' and 3' positions, or a mixture thereof, to a subject suffering from hypersalivation in an amount of the compound of formula (2) from about 1 mg to about 10 mg per adult dose or from about 0.02 mg / kg to about 1.0 mg / kg per pediatric dose. (Item 2) The compound of formula (2) is (iii) (2R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (iv) (2R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (v) (2R,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (vi) (2R,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (vii) (2R,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (viii) (2R,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (ix) (2R,1'R,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (x) (2R,1'S,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (xi) (2R,1'R,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (xii) (2R,1'S,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (xiii) (2R,1'R,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (xiv) (2R,1'S,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (xv) (2R,1'R,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; and (xvi) (2R,1'S,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide The method according to item 1, selected from the group consisting of: (Item 3) 3. The method according to item 1 or 2, wherein the compound of formula (2) is (2R,3′R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide or (2R,3′R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide. (Item 4) 4. The method according to any one of items 1 to 3, wherein the compound of formula (2) is administered in an amount of about 1 mg to about 2 mg per adult dose. (Item 5) 4. The method according to any one of items 1 to 3, wherein the compound of formula (2) is administered in an amount of about 0.02 mg / kg to about 1.0 mg / kg per pediatric dose. (Item 6) 6. The method according to any one of items 1 to 5, which is carried out 1 to 3 times a day. (Item 7) The method according to item 5, which is carried out twice a day, in the morning and in the afternoon, with an interval of about 6 to 8 hours. (Item 8) In the preparation of an oral pharmaceutical composition, [ka] wherein R is methyl or ethyl, and the compound has the R stereoisomeric configuration at the 2-position and the R, S, or RS stereoisomeric configuration at the 1' and 3' positions, or a mixture thereof, the composition comprising the at least one compound and at least one pharmaceutically acceptable, non-toxic carrier or excipient in an amount of about 1 mg to about 10 mg per adult dose or about 0.02 mg / kg to about 1.0 mg / kg per pediatric dose of the compound of formula (2) for the oral treatment of hypersalivation. Including in the quantity of something, use. (Item 9) The compound of formula (2) is (iii) (2R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (iv) (2R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (v) (2R,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (vi) (2R,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (vii) (2R,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (viii) (2R,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (ix) (2R,1'R,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (x) (2R,1'S,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (xi) (2R,1'R,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (xii) (2R,1'S,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (xiii) (2R,1'R,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (xiv) (2R,1'S,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (xv) (2R,1'R,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; and (xvi) (2R,1'S,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide 9. The use according to item 8, selected from the group consisting of: (Item 10) 10. The use according to item 8 or 9, wherein the compound of formula (2) is (2R,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide or (2R,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide. (Item 11) 11. The use according to any one of items 8 to 10, wherein the compound of formula (2) is present in an amount of about 1 mg to about 2 mg per adult dose. (Item 12) 11. The use according to any one of items 8 to 10, wherein the compound of formula (2) is present in an amount of about 0.02 mg / kg to about 1.0 mg / kg per pediatric dose. (Item 13) 13. The use according to any one of items 8 to 12, carried out 1 to 3 times a day. (Item 14) The use according to Item 12 is carried out twice a day, in the morning and in the afternoon, with an interval of approximately 6 to 8 hours. (Item 15) formula: [ka] and a pharmaceutically acceptable, non-toxic carrier or excipient, wherein R is methyl or ethyl, and the compound has the R stereoisomeric configuration at the 2-position and the R, S, or RS stereoisomeric configuration at the 1' and 3' positions, or a mixture thereof, and is present in an amount of the compound of formula (2) from about 1 mg to about 10 mg per adult dose or from about 0.02 mg / kg to about 1.0 mg / kg per pediatric dose. (Item 16) The compound of formula (2) is (iii) (2R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (iv) (2R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (v) (2R,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (vi) (2R,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (vii) (2R,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (viii) (2R,3'S)3-(2-cyclopentyl-2-phenyl-2-hydrogen (Ethoxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (ix) (2R,1'R,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (x) (2R,1'S,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (xi) (2R,1'R,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (xii) (2R,1'S,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (xiii) (2R,1'R,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (xiv) (2R,1'S,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (xv) (2R,1'R,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; and (xvi) (2R,1'S,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide Item 16. The composition according to item 15, selected from the group consisting of: (Item 17) 17. The composition according to item 15 or 16, wherein the compound of formula (2) is (2R,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide or (2R,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide. (Item 18) 18. The composition according to any one of items 15 to 17, wherein the compound of formula (2) is present in an amount of about 1 mg to about 2 mg per adult dose. (Item 19) 18. The composition according to any one of items 15 to 17, wherein the compound of formula (2) is present in an amount of about 0.02 mg / kg to about 1.0 mg / kg per pediatric dose. (Item 20) 20. The composition according to any one of items 15 to 19, which is carried out 1 to 3 times a day. (Item 21) Item 19. The composition of item 19, administered twice a day, in the morning and afternoon, approximately 6 to 8 hours apart. (Item 22) An oral composition, the composition comprising: (a) Formula: [ka] wherein R is methyl or ethyl, and the compound has the R stereoisomeric configuration at the 2-position and the R, S, or RS stereoisomeric configurations at the 1' and 3' positions, or a mixture thereof; and (b) absolute ethanol or the dried residue of about a 15% to about 50% solution or suspension of the compound of formula (2) in absolute ethanol; or (c) at least one anhydrous, non-toxic pharmaceutically acceptable carrier or excipient; wherein the oral composition or at least a portion thereof in contact with the compound is anhydrous, and the composition comprises about 1 mg to about 10 mg of a compound of formula (2) per dose, and the composition is in the form of a solid or film that can dissolve in the oral cavity. (Item 23) 23. The composition according to item 22, further comprising at least one gelling or viscosity controlling or film forming or mucoadhesive component, and / or the carrier or excipient comprises a cyclodextrin. (Item 24) The compound of formula (2) is (iii) (2R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (iv) (2R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (v) (2R,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (vi) (2R,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (vii) (2R,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (viii) (2R,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (ix) (2R,1'R,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (x) (2R,1'S,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (xi) (2R,1'R,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (xii) (2R,1'S,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (xiii) (2R,1'R,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (xiv) (2R,1'S,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (xv) (2R,1'R,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; and (xvi) (2R,1'S,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide 24. The composition according to item 22 or 23, selected from the group consisting of: (Item 25) 25. The composition according to any one of items 22 to 24, wherein the compound of formula (2) is (2R,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide or (2R,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide. (Item 26) 26. The composition according to any one of items 22 to 25, wherein the compound of formula (2) is present in an amount of about 1 mg to about 10 mg per dose, or the compound of formula (2) is present in an amount of about 1 mg to about 2 mg per dose, or the compound of formula (2) is present in an amount of about 0.02 mg / kg to about 1.0 mg / kg per dose. (Item 27) 26. The composition according to item 24 or 25, wherein the compound of formula (2) is about 1% to about 20% of the composition. (Item 28) 24. The composition of claim 23, wherein the gelling or viscosity-controlling or film-forming or mucoadhesive component is hydroxypropyl cellulose and / or the cyclodextrin comprises one or more members selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, randomly methylated β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin and sulfobutylated-β-cyclodextrin. (Item 29) 29. The composition according to any one of items 22 to 28, wherein the composition is in the form of a buccal film or in the form of an intraoral solid that is a candy or gum. (Item 30) 1. A method for treating hypersalivation in a subject suffering from hypersalivation, comprising: The method includes a step of orally administering the oral composition according to any one of Items 22 to 29 to a subject suffering from hypersalivation in an amount of the compound of formula (2) of about 1 mg to about 10 mg per adult dose or about 0.02 mg / kg to about 1.0 mg / kg per pediatric dose. (Item 31) In preparing the oral composition according to any one of items 22 to 29 for treating hypersalivation in the oral cavity, a compound of the formula: [ka] wherein R is methyl or ethyl, and the compound has the R stereoisomeric configuration at the 2-position and the R, S or RS stereoisomeric configuration at the 1' and 3' positions, or a mixture thereof, in an amount of the compound of formula (2) from about 1 mg to about 10 mg per adult dose or from about 0.02 mg / kg to about 1.0 mg / kg per pediatric dose. (Item 32) 30. The composition according to any one of items 22 to 29 for use in treating hypersalivation in the oral cavity. DETAILED DESCRIPTION OF THE INVENTION

[0039] Detailed Description Throughout the specification and claims, the following definitions, general statements, and illustrations are applicable.

[0040] The patents, published applications, and scientific literature referred to herein establish the knowledge of those skilled in the art and are incorporated herein by reference in their entirety to the same extent as if each were specifically and individually indicated to be incorporated by reference. Any discrepancy between any reference cited herein and the specific teachings of this specification shall be resolved in favor of the latter. Similarly, any discrepancy between the definition of a word or phrase as understood in the art and the definition of a word or phrase specifically taught herein shall be resolved in favor of the latter.

[0041] As used herein, whether in transitional phrases or in the body of a claim, the terms "comprise(s)" and "comprising" are to be construed as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases "having at least" or "including at least." When used in the context of a process or method, the term "comprising" means that the process or method includes at least the recited steps, but may include additional steps. When used in the context of a composition, the term "comprising" means that the composition includes: It means to include at least the recited features or components, but may also include additional features or components.

[0042] The terms "consists essentially of" or "consisting essentially of" have a partially closed meaning. That is, these terms do not permit the inclusion of steps or features or components that would substantially alter the essential characteristics of the process or composition, e.g., steps or features or components that would significantly interfere with the desired properties of the compounds or compositions described herein. That is, the process or composition is limited to the specified steps or materials and those that do not substantially affect the basic and novel characteristics of the process or composition.

[0043] The terms "consists of" and "consists" are closed terminology and allow only for the inclusion of the listed steps or features or components.

[0044] As used herein, the singular forms "a," "an," and "the" specifically include the plural forms of the terms they refer to, unless the content clearly dictates otherwise.

[0045] The term "about" is used herein to mean approximately, in the region of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the terms "about" or "approximately" are used herein to modify a numerical value to accommodate a 20% variation above and below the stated value.

[0046] As used herein, the description of a numerical range for a variable is intended to convey that the variable can be equal to any value within that range. Thus, for a variable that is inherently discrete, the variable can be equal to any integer value in the numerical range, including the end points of the range. Similarly, for a variable that is inherently continuous, the variable can be equal to any real value in the numerical range, including the end points of the range. By way of example, a variable described as having a value between 0 and 2 can be 0, 1, or 2 for a variable that is inherently discrete, and 0.0, 0.1, 0.01, 0.001, or any other real value for a variable that is inherently continuous.

[0047] As used in this specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. As used herein, unless specifically indicated otherwise, the word "or" is used in the inclusive sense of "and / or" and not the exclusive sense of "either / or."

[0048] Unless otherwise defined, the technical and scientific terms used herein have the meanings that are commonly understood by those skilled in the art to which this description belongs.In this specification, reference is made to various methodologies and materials known to those skilled in the art.Standard references that show the general principles of pharmacology include Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th edition, McGraw Hill Companies Inc., New York (2001).

[0049] As used herein, "treating" means reducing, preventing or inhibiting the onset of, controlling, inhibiting, alleviating, and / or ameliorating symptoms in an individual to whom a compound of Formula (1) or (2) or a composition comprising a compound of Formula (1) or (2) has been administered, compared to symptoms in an individual not receiving the compound or composition. The practitioner will understand that the combinations, compositions, dosage forms, and methods described herein should be used in conjunction with continuous clinical evaluation by a skilled professional (physician or veterinarian) to determine subsequent therapy. Such evaluations are helpful and informative in assessing whether to increase, decrease, or continue a particular treatment dose and / or alter the mode of administration.

[0050] The compounds or compositions may also prevent symptoms or prevent the onset of symptoms in individuals administered a composition containing a compound of formula (1) or (2) above, compared to symptoms in individuals not administered the compound or composition. This is by inhibiting the manifestation of the condition for the period of time that the administered dose is effective (several hours), and therefore does not prevent salivation or excessive drooling in an absolute sense, nor does it prevent the medical condition.

[0051] The methods described herein are intended for use with any subject / patient who may experience these benefits. Thus, the terms "subject," as well as "patient," "individual," and "warm-blooded animal" and "mammal," include human and non-human subjects, such as animals that may experience excessive salivation.

[0052] The terms "intra-oral" and "intra-orally" refer to the oral mucosa and routes of administration in the oral cavity, but do not extend to the digestive tract. Intra-oral administration includes buccal, lingual, sublingual, and gingival administration, i.e., buccal administration (to the oral (cheek) mucosa), lingual administration (to the tongue), sublingual administration to the sublingual mucosa (under the tongue), and gingival administration (to the gingival mucosa (to the gums)).

[0053] Compounds useful in the methods or compositions of the invention include those of formula (1): [ka] where R is methyl or ethyl, and the compound has the R, S, or RS stereoisomeric configuration at the 2-position and the 1' and 3' positions, or a mixture thereof.

[0054] Compounds having the R configuration about chiral center 2 are of particular interest for use in the present methods and compositions. For example, preferred compounds useful in the methods or compositions of the present invention have the stereospecific formula (2): [ka] wherein R is methyl or ethyl, said compound having the R stereoisomeric configuration at the 2-position and the R, S, or RS stereoisomeric configurations at the 1' and 3' positions (indicated by an asterisk), or a mixture thereof.

[0055] The following compounds are of particular interest for use in the methods or compositions of the present description: (i) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (ii) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (iii) (2R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (iv) (2R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (v) (2R,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (vi) (2R,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (vii) (2R,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (viii) (2R,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (ix) (2R,1'R,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (x) (2R,1'S,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (xi) (2R,1'R,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (xii) (2R,1'S,3'R)3-(2-cyclopentyl-2-phenyl-2 -hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (xiii) (2R,1'R,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (xiv) (2R,1'S,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (xv) (2R,1'R,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; and (xvi) (2R,1'S,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide.

[0056] The compounds (i) to (xvi) above can be used alone, or two or more of the compounds can be used in combination in a single composition. Various methods for making the compounds of the present invention are described in the art. Preferred compounds for use herein are compounds (v) or (vii) above (also known as BOD-06 and BOD-07, respectively).

[0057] An anticholinergic-effective amount of such an agent inhibits the effects of acetylcholine by blocking its binding to muscarinic cholinergic receptors at neuroeffector sites. Subjects in need of methods for inducing an anticholinergic response are those suffering from conditions that respond to treatment with anticholinergic agents, including subjects suffering from excessive salivation or hypersalivation.

[0058] The compound of formula (1) or (2) is typically administered in the form of a pharmaceutical composition containing an anticholinergically effective amount of the compound, absolute ethanol, and / or other non-toxic, pharmaceutically acceptable, anhydrous carriers or excipients, provided that the composition itself, or at least a portion of the composition in contact with the compound, is also anhydrous. Pharmaceutically acceptable carriers or diluents are well known in the art. The carrier can be any inert substance, organic or inorganic powder, liquid, or gas suitable for administration, such as alcohol (e.g., hexylene glycol), gelatin, gum arabic, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talc, colloidal silicon dioxide, etc., provided that the components, or at least those in contact with the compound, are anhydrous.

[0059] It has been discovered that the formulation of the present invention has advantageous properties when neither water nor aqueous carrier is added to the formulation.Therefore, the composition herein is an anhydrous formulation.The term "anhydrous" means the usual scientific meaning of this term, that is, neither water nor aqueous excipients are added to the formulation.However, as previously mentioned, anhydrous powders, tablets, etc. can be dissolved or suspended in water or other aqueous carriers at the time of administration.

[0060] The anhydrous composition also does not contain conventional additives (e.g., solvents, stabilizers, wetting agents, emulsifiers, buffers, binders, disintegrants, flavors, lubricants, glidants, antiadherents), so long as the additives and composition (or the portion thereof in contact with the compound) are anhydrous, i.e., free of water to the extent required to avoid a significant negative impact on the storage stability of the composition (due to hydrolysis of the methyl or ethyl ester drug). ), propellants, etc.

[0061] When R in formula (1) or (2) is ethyl, the active ingredient is readily soluble in absolute ethanol as a solvent in which the compound is soluble or at least slightly soluble (if desired). At higher concentrations, suspensions or slurries can be prepared. For example, about 15% to about 50% solutions or suspensions of the ethyl ester in absolute ethanol can be made as part of the preparation of suitable film compositions.

[0062] The anhydrous compositions herein can be formulated as solids, semi-solids, or liquids (e.g., in the form of tablets, film compositions, powders, liquids, lotions, creams, gels, sprays, aerosols, solutions, suspensions, emulsions, etc.) and are formulated for buccal administration. By way of example only, for treating hypersalivation, buccal solid or film compositions are often preferred.

[0063] In preparing a formulation, it may be appropriate to mill the active compound to provide a precise particle size before combining it with other ingredients. The active compound may be milled to a particle size of less than 200 mesh.

[0064] Some examples of suitable oral carriers or excipients for addition to the compositions herein include alcohols (e.g., propylene glycol), dimethicone, PGE, allantoin, glycerin, vitamin A and E oils, mineral oil, PPG2, myristyl propionate, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, methylcellulose, and cyclodextrins, including α-, β-, and γ-cyclodextrin and their alkylated and hydroxyalkylated derivatives (e.g., randomly methylated β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxyethyl-γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, sulfobutylated-β-cyclodextrin, and mixtures thereof). β-cyclodextrin, γ-cyclodextrin and randomly methylated β-cyclodextrin are particularly preferred carriers.Formulations may also contain lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers and suspending agents; and preservatives such as methyl hydroxybenzoate and propyl hydroxybenzoate.By using procedures known in the art, compositions can be formulated to provide immediate, controlled, sustained or delayed release or activity of active ingredients after administration and / or application to subject.The use of separate preservatives can be avoided by judiciously selecting other ingredients, as will be discussed in more detail below.

[0065] Composition may further contain one or more optional additives, such as coloring agent, flavoring agent, sweetener, etc.In practice, each of these optional additives should be compatible with active compound.Compatible additives are those additives that do not interfere with the use of compound or do not cause compound to be decomposed in the manner described herein.

[0066] For illustrative purposes, dosage amounts for liquid formulations are expressed based on percent solution (g / 100 ml) or percent concentration (w / v) unless otherwise specified. For dosage amounts for solid formulations, percent concentration may be expressed as mg / mg or w / w concentration unless otherwise specified. Those skilled in the art will readily understand percent concentration in the context of the type of formulation being described.

[0067] Generally, a therapeutically effective or anticholinergic effective amount of a compound of Formula (1) or (2) herein is an amount sufficient to significantly reduce excessive salivation / inhibit hypersalivation. For adult patients, this amount is generally about 1 mg to about 10 mg, preferably about 1 mg to about 2 mg, administered one to three times daily. For children, this amount is generally about 0.02 mg / kg to about 1.0 mg / kg of body weight, administered one to three times daily. The exact dosage of the compound in the compositions of the present invention may vary depending on its efficacy, mode of administration, area of application, age and weight of the subject, and the nature and severity of the condition to be treated.

[0068] Administration of a composition as described herein can result in substantially the same or similar clinical response in a subject (reduced frequency and abundance of salivation) when compared to administration of a composition containing the same concentration of glycopyrrolate. Thus, this finding is surprising in light of previously published mydriatic studies that showed that the compound needed to be present in the composition at a concentration 5 to 10 times higher than the concentration of glycopyrrolate compositions to produce a similar or substantially identical clinical response.

[0069] Furthermore, this finding is particularly surprising because it was previously thought that the low-toxicity alkyl esters would be too rapidly hydrolyzed to be useful in treating hypersalivation. Indeed, these esters are known to have plasma half-lives of approximately 10 minutes, and it was thought that they would be rapidly hydrolyzed in saliva by the enzyme butyrylcholinesterase (BChE). It has now been unexpectedly discovered that these esters are hydrolyzed by paraoxonase 1. Although paraoxonase 2 is present in saliva, paraoxonase 1 is not. Thus, the esters of formulas (1) and (2) are surprisingly not hydrolyzed by saliva and can be successfully delivered to the oral mucosa (intraorally, lingually, sublingually, or gingivally) and act in the salivary glands to treat hypersalivation. The absence of paraoxonase 1 in the salivary glands facilitates particularly long-acting activity in treating hypersalivation. At the same time, the drug's design-in breakdown by hydrolysis to non-toxic entities when it reaches the bloodstream avoids or greatly reduces the systemic side effects that characterize anticholinergic drugs (e.g., glycopyrrolate). Moreover, paraoxonase 1 is also not present in the gastrointestinal tract or stomach, which surprisingly enables the treatment of conditions such as ulcers, Crohn's disease, and ulcerative colitis with compounds of formulas (1) and (2).

[0070] Exemplary compositions for use herein in treating hypersalivation may include one or more excipients selected from the group consisting of plasticizers, mucoadhesives, stabilizers, taste-masking agents (e.g., sweeteners), flavors, breath fresheners, colorants, inert fillers, preservatives, nonionic polymers, anionic polymers, softeners, bulking agents, chelating agents, effervescent agents, and foaming agents. Convenient dosage forms include oral sprays or drops, films, candies, gums, buccal patches, lingual tablets, sublingual tablets, and fast-dissolving tablets, particularly films, candies (e.g., lozenges or lollipops, pastilles, or troches), and gums.

[0071] Whatever the final dosage form, the readily hydrolyzable nature of the esters of formula (1) or (2) must be taken into consideration in the preparation of such dosage forms. The preparation method must be such that the drug is not combined with moisture-containing components that would hydrolyze the drug during preparation or storage of the dosage form. Furthermore, to avoid the introduction of a different, less desirable ester via transesterification, absolute ethyl alcohol is preferred to dissolve or, at high concentrations, suspend ethyl ester drugs where R is ethyl. This does not mean that ethanol must remain in the final composition, nor that water cannot be used in preparing the non-drug-containing portion of the composition. By way of example, films or tablets or other dosage forms can be prepared in layers. One or more of the layers themselves may contain water or moisture-containing components. After drying, one or more layers can be coated with an absolute (anhydrous) ethanolic solution or suspension of the drug (the drug being at a concentration of 15% to 50% by weight). The ethanol is then evaporated, leaving a layer of drug on one or more of the previously constructed layers, which can then be combined. It is also possible to combine the methyl or ethyl ester of formula (1) or (2) with one or more anhydrous cyclodextrins (anhydrous or crystalline, depending on the particular one selected) as identified hereinabove by kneading methods well known in the cyclodextrin art. This blending method does not introduce water. Other anhydrous carrier ingredients may be introduced during or after the kneading process. The product may be dried and compressed, injection molded, or extruded into a dosage form such as an oral (e.g., buccal) tablet, which may be packaged in aluminum foil to protect its anhydrous nature. Alternatively, the product may be micronized and used to form a layer, for example, in a layered tablet or film, or micronized and placed in an aluminum foil package to protect its anhydrous nature until administration, when it may be mixed with water or other aqueous carrier just before administration.

[0072] Plasticizers for use in the film compositions described herein can include glycerin, sorbitol, propylene glycol, polyethylene glycol, triacetin, triethyl citrate, acetyltriethyl citrate, and other citrate esters.

[0073] Stabilizing agents for use in the film compositions described herein include antioxidants, chelating agents, and enzyme inhibitors (e.g., ascorbic acid, vitamin E, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, dilauryl thiodipropionate, thiodipropionic acid, acacia gum, citric acid and its salts, and glutathione).

[0074] Film dosage forms can vary in size depending on placement in the oral cavity.

[0075] Some preferred film dosage forms have an adhesive layer or properties (e.g., a mucoadhesive layer or properties) that, when wet, serve to adhere the composition to the epithelial surface of the oral cavity. The adhesive layer can also be designed to preferentially release the compound of Formula (1) or (2) into the oral cavity and minimize systemic release of the drug into the bloodstream (where it is inactivated). Preferably, such adhesive dosage forms do not stick to fingers when dry, to facilitate insertion.

[0076] Natural and artificial flavors or flavoring agents that can be used in the film composition include those known to those skilled in the art. The flavors are selected based on their ability to increase salivary response and / or their ability to mask the taste of the active agent. Representative flavoring agents can be selected from synthetic flavor oils, flavoring aromatics, oleoresins, and extracts derived from plants, leaves, flowers, and fruits. Representative flavor oils include spearmint oil, cinnamon oil, peppermint oil, clove oil, bay oil, thyme oil, cedar leaf oil, nutmeg oil, sage oil, and bitters. Oil of mond. Artificial, natural, or synthetic fruit flavors (e.g., vanilla, chocolate, coffee, cocoa, grape, and various citrus oils (e.g., lemon, orange, lime, and grapefruit)) are also useful. Fruit essences, including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, and the like, are also useful. Flavoring agents can also be used individually or in combination. Other flavoring agents that can be used in the compositions herein include aldehydes and esters, including cinnamyl acetate, cinnamaldehyde, citral, diethyl acetal, eugenyl formate, p-methylanisole, and the like. Further examples of aldehyde flavoring agents include, for example, acetaldehyde (apple); benzaldehyde (cherry, almond); cinnamaldehyde (cinnamon); citral, e.g., alpha citral (lemon, lime); neral, i.e., beta citral (lemon, lime); decanal (orange, lemon); ethyl vanillin (vanilla, cream); heliotropin, e.g., piperonal (vanilla, cream); vanillin (vanilla, cream); alpha-amyl cinnamaldehyde (spicy fruit-like flavors); decanal (citrus). Citrus fruits); aldehyde C-8 (citrus fruits); aldehyde C-9 (citrus fruits); aldehyde C-12 (citrus fruits); 2-ethylbutyraldehyde (berry fruits); hexenal, such as trans-2 (berry fruits); tolyl aldehyde (cherries, almonds); veratraldehyde (vanilla); 2,6-dimethyl-5-heptenal, such as melon (melon); 2,6-dimethyloctanal (immature fruits); and 2-dodecenal (citrus fruits, mandarin); cherry; grape, and combinations thereof. Generally, any flavor or food additive (e.g., those described in "Chemicals Used in Food Processing," Publication 1274, pp. 63-258, by the National Academy of Sciences) can be used. The flavor effect can be enhanced using flavor enhancers such as tartaric acid, citric acid, vanillin, and higher alcohols.

[0077] Breath freshening agents for use in the film compositions include menthol and other flavors or fragrances commonly used for oral hygiene or oral cleansing, including various quaternary ammonium bases.

[0078] The film composition may also include one or more colorants (dyes, colorants), known in the art as "FD&C" dyes and lakes.

[0079] Nonionic polymers suitable for use in the film composition include, for example, cellulose polymers (e.g., carboxymethylcellulose, hydroxyethylcellulose, methylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose); polyvinylpyrrolidone (PVP); polyvinyl alcohol (PVA); polyethylene oxide; modified starch; gelatin; agar; guar gum; locust bean gum; bentonite; and combinations thereof. Preferred nonionic polymers useful in the film composition are polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, gelatin, polyethylene oxide, or combinations thereof. Particularly useful nonionic polymers herein are polyvinyl alcohol, gelatin, hydroxypropylmethylcellulose, or combinations thereof. The cyclodextrins mentioned above are also highly preferred for use herein.

[0080] Anionic polymers useful in the film composition include polyacrylic acids (e.g., carbopol, polycarbophil, poly(methyl vinyl ether-co-methacrylic acid) ), poly(2-hydroxyethyl methacrylate), poly(methyl methacrylate), poly(isobutyl cyanoacrylate), poly(isohexyl cyanoacrylate), and polydimethylaminoethyl methacrylate); acacia; alginate; carrageenan; guar gum derivatives; karaya gum; pectin; tragacanth gum; xanthan gum; dextran; sodium carboxymethylcellulose ("sodium CMC"); hyaluronic acid; and combinations thereof. Preferably, the anionic polymer useful herein is carbopol, polycarbophil, alginate, carrageenan, pectin, sodium CMC, or a combination thereof. Most preferably, the anionic polymer useful herein is carbopol, polycarbophil, alginate, carrageenan, sodium CMC, or a combination thereof.

[0081] Suitable emollients for use in preparing film compositions may include propylene glycol, water, polyethylene glycol, glycerin, triacetin, diacetylated monoglyceride, diethyl phthalate, triethyl citrate, and combinations thereof.More preferably, the emollients useful in the composition are propylene glycol, water, glycerin, polyethylene glycol, or combinations thereof.Most preferably, the emollients suitable for use in the composition are water, propylene glycol, glycerin, or combinations thereof.However, with respect to all of its components, care must be taken to remove water or alcohols other than absolute ethanol so that the final composition (or at least the portion thereof that is in contact with the active ingredient) is anhydrous and avoid the risk of hydrolyzing the ester group of the drug or exchanging the ester group of the drug into a less desirable ester.

[0082] Chelating agents suitable for use in the films include, for example, ethylenediaminetetraacetic acid ("EDTA") and its salts (e.g., disodium EDTA, tetrasodium EDTA, and calcium disodium EDTA); diethylenetriaminepentaacetic acid ("DTPA") and its salts; hydroxyethylethylenediaminetriacetic acid ("HEDTA") and its salts; nitrilotriacetic acid ("NTA"); and combinations thereof. Preferably, the chelating agent useful herein is EDTA, HEDTA, a salt thereof, or a combination thereof. Most preferably, the chelating agent useful in the present invention is EDTA or a salt thereof.

[0083] Another type of film composition provided herein is a water-erodable film device for adhesion to a mucosal surface, e.g., a layered film disc having a backing layer and an adhesive layer and having a compound of formula (1) or (2) in or between one or more of the layers.

[0084] In another embodiment, the water-degradable film device further comprises a third layer between the first adhesive layer and the second backing layer. The third layer is a water-degradable adhesive layer that covers the first adhesive layer and has a surface area sufficient to contact the mucosal surface. In this way, local delivery of the low-toxicity ester can be achieved in a unidirectional manner toward the mucosal layer.

[0085] The adhesive layer(s) may comprise film-forming polymers (e.g., hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl methyl cellulose, polyvinyl alcohol, polyethylene glycol, polyethylene oxide, ethylene oxide-propylene oxide copolymers, collagen and derivatives, gelatin, albumin, polyamino acids and derivatives, polyphosphazenes, polysaccharides and derivatives, chitin or chitosan), either alone or in combination, and bioadhesive polymers (e.g., polyacrylic acid, polyvinylpyrrolidone or charcoal). sodium carboxymethylcellulose), alone or in combination.

[0086] The non-adhesive backing layer(s) comprise hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, polyethylene glycol, polyethylene oxide, or ethylene oxide-propylene oxide copolymers, alone or in combination.

[0087] In another embodiment, the number of layers of the water-degradable film device can be further varied to adjust the degradation kinetics and provide a convenient means of varying the release of the drug and the lifespan of the device.

[0088] In a preferred embodiment, the backing layer comprises two or more layers with different degradability kinetics.

[0089] Also, unlike bioadhesive tablets known in the art, the biodegradable film device herein minimizes the discomfort associated with the application of foreign substances for a period sufficient to provide effective drug delivery to the treatment site. Users of prior art bioadhesive tablets often experience discomfort due to their solidity, bulkiness, and, if degradable, slow dissolution time (especially when used orally). Furthermore, due to the typical thickness of bioadhesive tablets (which may or may not be water-soluble), the preferred application site is the upper gingival region. This site is usually insufficient for local delivery of the type of compound to be delivered, limiting their bioavailability and pharmacokinetics. In contrast to tablets, the film device herein offers the advantages of effective residence time, minimal discomfort, and ease of use, and, given its thinner, more flexible form, is a suitable vehicle for the local delivery of low-toxicity esters.

[0090] Unlike known film systems used to deliver drugs through the skin or mucosa, the film device provided herein is made from water-degradable components and is therefore biodegradable. The use of water-degradable components allows the carrier to slowly dissolve or degrade in natural body fluids (saliva), allowing the device to degrade over a period of time, while the active ingredient remains at the application site. Unlike bandages and other non-water-degradable film systems, the subject or caregiver does not need to remove the film device after treatment. In addition, the subject does not experience the sensation of a foreign body on the mucosal surface or in the oral cavity, given that the device softens upon application due to moisture absorption and slowly dissolves and degrades over time.

[0091] The residence time of the biodegradable film device of the present invention depends on the erosion rate of the water-degradable polymer used in the formulation and its concentration. The erosion rate can be adjusted, for example, by mixing components with different solubility properties or chemically different polymers (e.g., hydroxyethyl cellulose and hydroxypropyl cellulose); by using different molecular weight grades of the same polymer, for example, by mixing low-molecular-weight and medium-molecular-weight hydroxyethyl cellulose; by using excipients or plasticizers with various lipophilic or water-soluble properties (including essentially insoluble components); by using water-soluble inorganic and organic salts; by using crosslinking agents (e.g., glyoxal and polymers such as hydroxyethyl cellulose for partial crosslinking); or by post-treatment irradiation or curing (which can change the physical state of the film, including its crystallinity or phase transition, once obtained). These methods can be used alone or in combination to modify the degradation kinetics of the device.

[0092] Upon application, the film delivery device adheres to the mucosal surface and is held in place. The device softens upon absorbing moisture, thereby reducing the sensation of a foreign body. The drug delivery occurs while the device is on the mucosal surface. The residence time can be adjusted over a wide range, depending on the desired timing of compound delivery and the desired lifespan of the carrier. Preferably, the residence time is adjusted from about 1 hour to about 8 hours.

[0093] In one embodiment, a film disc is provided having an adhesive layer and a non-adhesive backing layer, which may be composed of components with similar or different hydrophilicities. The active ingredient may be contained in either layer, but preferably the active ingredient is contained in the adhesive layer closest to the treatment site and which has a slower degradation time, given that the backing layer protects the inner adhesive layer and typically degrades first.

[0094] The adhesive layer may comprise at least one film-forming, hydrolyzable polymer ("film-forming polymer") and at least one pharmacologically acceptable polymer known for its bioadhesive capabilities ("bioadhesive polymer"). The film-forming polymer may comprise, alone or in combination, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, polyvinyl alcohol, polyethylene glycol, polyethylene oxide, ethylene oxide-propylene oxide copolymers, collagen and derivatives, gelatin, albumin, polyamino acids and derivatives, polyphosphazenes, polysaccharides and derivatives, chitin, and chitosan. Preferably, the film-forming polymer comprises hydroxyethyl cellulose and hydroxypropyl cellulose. Preferably, in the case of hydroxyethyl cellulose, the average molecular weight (Mw estimated from intrinsic viscosity measurements) is in the range of 10 2 ~10 6 and more preferably in the range 10 3 ~10 5 whereas in the case of hydroxypropyl cellulose, the average molecular weight (Mw obtained from size exclusion chromatography measurements) is in the range 50×10 3 ~1.5×10 6 , and more preferably 80 × 10 3 ~5×10 5 It is between.

[0095] The bioadhesive polymer of the adhesive layer may include polyacrylic acid (PAA), which may or may not be partially crosslinked, sodium carboxymethylcellulose (NaCMC), and polyvinylpyrrolidone (PVP), or a combination thereof. These bioadhesive polymers are preferred because they have good and immediate mucoadhesive properties in the dry film state. In the case of sodium carboxymethylcellulose, typical average molecular weights include 50,000 to 700,000, and preferably 60,000 to 500,000, with a degree of substitution of 0.7. The substitution range varies between 0.5 and 1.5, preferably between 0.6 and 0.9. Polyvinylpyrrolidone can be characterized according to its average molecular weight, which is generally between 5,000 and 150,000, and preferably between 10,000 and 100,000. The simultaneous use of some grades of PAA and PVP may result in precipitation of one or both components. This precipitation may not be ideal for obtaining a homogeneous layer and may slightly alter the overall adhesive properties of the device.

[0096] The ratio of bioadhesive polymer to film-forming polymer in the adhesive layer can vary depending on the amount of compound of formula (1) or (2) to be used. However, the content of the combined components in the adhesive layer is usually between 5% and 95% by weight, preferably between 10% and 80% by weight. With regard to the weight percentages of the various bioadhesive polymers, PAA, NaCMC, and PVP, those skilled in the art can easily adjust the percentages to obtain a film device with the desired properties for use herein. Preferred combinations include PAA and NaCMC, NaCMC and PVP, or PAA and PVP, and also Also, different grades of the same polymer may be used.

[0097] The non-adhesive backing layer may comprise, alone or in combination, a water-degradable, film-forming, pharmaceutically acceptable polymer (e.g., hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl methyl cellulose, polyvinyl alcohol, polyethylene glycol, polyethylene oxide, ethylene oxide-propylene oxide copolymers, collagen and derivatives, gelatin, albumin, polyamino acids and derivatives, polyphosphazenes, polysaccharides and derivatives, chitin, and chitosan). The backing layer component may be crosslinked or non-crosslinked, depending on the desired degradation kinetics. In one embodiment, the preferred backing layer component comprises hydroxyethyl cellulose or hydroxypropyl cellulose, more preferably hydroxyethyl cellulose. Preferably, in the case of hydroxyethyl cellulose, the average molecular weight (Mw, estimated from intrinsic viscosity measurements) is in the range of 10 2 ~10 6 , and more preferably in the range 10 3 ~10 5 whereas in the case of hydroxypropyl cellulose, the average molecular weight (Mw obtained from size exclusion chromatography) is 50×10 3 ~1.5×10 6 , and more preferably 80 × 10 3 ~5×10 5 is in the range.

[0098] Furthermore, it has been discovered that a particularly preferred combination for the backing layer comprises hydroxypropyl cellulose and an alkyl cellulose (e.g., methyl cellulose or ethyl cellulose). Such a combination comprises a film-forming amount of alkyl cellulose, hydroxypropyl cellulose, and a suitable solvent. Advantageously, the properties of the film formed from the gel can be modified depending on the ratio of hydroxypropyl cellulose to alkyl cellulose. Such modifiable properties advantageously include the degradation kinetics.

[0099] Typically, the ratio of hydroxypropyl cellulose to alkyl cellulose is that required to form a suitable film. This ratio can vary based on the other components and the type of alkyl cellulose. However, when ethyl cellulose is used, the ratio of hydroxypropyl cellulose to ethyl cellulose is usually about 1000:1 to about 3:1, preferably about 200:1 to about 4:1, and more preferably about 200:1 to about 8:1. Typically, as the ratio of hydroxypropyl cellulose to alkyl cellulose increases, the hydrodegradability increases, i.e., the film is more easily washed away. Thus, ethyl cellulose is a component that acts to regulate the degradability kinetics of the device.

[0100] Crosslinkers known in the art are suitable for use in film devices and may include glyoxal, propylene glycol, glycerol, various sizes of dihydroxy-polyethylene glycols, butylene glycol, and combinations thereof. The amount of crosslinker used may vary depending on the particular polymer and crosslinker, but typically should not exceed 5% molar equivalent of the polymeric material, and preferably constitutes 0% to 3% molar equivalent of the polymeric material.

[0101] Furthermore, for water-insoluble polymeric materials (e.g., polyesteraliphatic family (copolymers of lactide-glycolide, caprolactone, etc.)), the average molecular weight (Mw) is in the range 10 2 ~10 5 , and more preferably 10 3 ~10 4 While in the case of the cellulose family (ethyl cellulose, cellulose acetate, etc.), the average molecular weight (Mw estimated from intrinsic viscosity measurements) is in the range 10 2 ~10 6 , and more preferably in the range 10 3 ~10 5 is located.

[0102] Yet another way to modify the degradation kinetics of any layer is by using excipients that simultaneously plasticize the film. The excipients or plasticizers often improve the mechanical properties of the device and / or modify the release profile or disintegration time of the active. Suitable excipients or plasticizers that modify the degradation behavior of the layer(s) can include alkyl glycols (e.g., propylene glycol, polyethylene glycol, glycerol oleate, sebacate, or stearate, or esters, phthalates, etc.). Other suitable plasticizers include esters such as acetyl citrate, amyl oleate, myristyl acetate, butyl oleate and butyl stearate, dibutyl sebacate, phthalates (e.g., diethyl phthalate, dibutyl phthalate, and diethoxyethyl phthalate), fatty acids (e.g., oleic acid and stearic acid), fatty alcohols (e.g., cetyl alcohol, myristyl alcohol, and stearyl alcohol). Additionally, in some cases, polymers or solvent residues can act as plasticizers.

[0103] It is also possible to modify the degradation kinetics of the film device herein by adjusting the thickness and number of the layers. Typically, the thicker the layer, the slower the release of the compound of formula (1) or (2) and the longer the release profile. Correspondingly, the more layers present, the slower the release of the soft drug and the longer the release profile. In a preferred embodiment, the backing layer comprises two or more layers with different degradation kinetics.

[0104] Furthermore, combinations of different or similar polymers with distinct molecular weight characteristics can be used to achieve the desired film-forming ability, mechanical properties and dissolution kinetics in any layer.Some combinations for use herein can include: 3 / 4 hydroxyethyl cellulose and 1 / 4 hydroxypropyl cellulose; 4 / 5 low molecular weight hydroxyethyl cellulose and 1 / 5 medium molecular weight hydroxyethyl cellulose; and 8 / 9 low molecular weight hydroxyethyl cellulose and 1 / 9 high molecular weight hydroxyethyl cellulose.A combination of water-degradable polymers can be used to modify the degradation kinetics of the device.A particularly preferred combination includes 1 / 2 hydroxyethyl cellulose, 1 / 6 hydroxypropyl cellulose, and 2 / 6 pseudolatex (i.e., a polymeric emulsion of lactide-glycolide copolymer).

[0105] Plasticizers, flavorings and colorants, and preservatives may also be included in the film delivery devices of the present invention in the adhesive layer, the backing layer, or both. Although the amount of each may vary, typically these components comprise no more than 50%, preferably no more than 30%, and most preferably no more than 15% by total weight of the device.

[0106] The thickness of the device can vary depending on the thickness of each layer and the number of layers. As described above, both the thickness and amount of layers can be adjusted to vary the degradation kinetics. Preferably, when the device has only two layers, the thickness ranges from 0.05 mm to 3 mm, preferably 0.1 to 1 mm, and more preferably 0.1 to 0.5 mm. The thickness of each layer can vary from 10% to 90% of the total thickness of the layered device, preferably 30% to 60%. Thus, the preferred thickness of each layer can vary from 0.01 mm to 0.9 mm, and more preferably 0.03 to 0.6 mm.

[0107] While the film device described above only requires two layers, namely, an adhesive layer and a backing layer, it is often preferable to have additional layers. One example where this may be advantageous is when a specific unidirectional flow of the compound of formula (1) or (2) toward the mucosal layer is required. The layered device described above provides some directional release. That is, release is primarily toward the mucosa and not, for example, toward the oral cavity. However, due to the expansion properties of the thin film, small amounts of soft drug may also be released through the sides of the device and the backing layer, provided that all layers are of approximately the same surface area and are essentially on top of each other.

[0108] In such cases where unidirectional release is desired, an additional layer may be disposed between the first adhesive layer and the second backing layer. The third layer is a water-degradable adhesive layer having sufficient surface area to cover the first adhesive layer and contact the mucosal surface. The third layer may be composed of any of the components described above with respect to the first adhesive layer, and may be the same as or different from the first adhesive layer.

[0109] If the bioadhesive layer is to have a smaller surface area than the other layers, it is usually between about 5% and about 50% smaller, preferably between about 10% and about 30% smaller than the other layers.

[0110] Another suitable dosage form herein is an intraoral tablet that disintegrates after contact with saliva to deliver the less toxic methyl or ethyl ester to the oral mucosa and salivary glands.

[0111] Orally disintegrating tablets disintegrate or dissolve in the oral cavity, so that the taste of the soft drug and other auxiliary ingredients is preferably masked. Taste masking can be achieved in any suitable manner, including the addition of flavorings and / or sweeteners, roller compaction with other excipients to minimize the surface area of the soft drug, spray drying, coating with suitable coating materials (e.g., hydroxypropyl methylcellulose, ethyl cellulose, methacrylate, Kollicoat TM This can be achieved by sealing with polyvinylpyrrolidone and polyvinylpyrrolidone, as well as encapsulation. TM includes copolymers of methyl acrylate and ethyl acrylate.

[0112] For example, granules of the drug and disintegrant (eg, low-substituted hydroxypropyl cellulose) can be coated with a water-insoluble polymer (eg, ethyl cellulose) to mask the taste of the soft drug.

[0113] Suitable flavoring agents include those described hereinabove. The flavoring agent or mixture thereof is typically present in an amount of from about 0.0001% to about 5% by weight.

[0114] Suitable sweeteners include, for example, sugars (e.g., sucrose, lactose, and glucose), cyclamate and its salts, saccharin and its salts, ammonium glycyrrhizinate, and aspartame. Other possible sweeteners are sucralose and stevia. The sweetener or mixture thereof is typically present in an amount of about 0.001% to about 70% by weight.

[0115] The orally disintegrating tablets can be prepared by methods well known in the pharmaceutical field, for example, by methods described in Remington: The Science and Practice of Pharmacy, 21st Edition, Philadelphia, Pa.: Lippincott Williams & Co. Wilkins, 2005. Such methods include the step of bringing the active ingredient into association with a carrier (i.e., a pharmaceutically acceptable carrier) which constitutes one or more accessory ingredients. Such accessory ingredients include those conventional in the art, such as fillers (e.g., polyhydric alcohols, such as mannitol, sorbitol, and xylitol, or mixtures thereof); binders (e.g., acacia, tragacanth, gelatin, sucrose, alpha-isopropyl alcohol, etc.); disintegrating agents; lubricants (e.g., talc, magnesium stearate, mineral oil, and mixtures thereof); coloring agents; flavoring agents; preservatives (e.g., alkyl hydroxybenzoates or salts thereof (e.g., methyl hydroxybenzoate, ethyl hydroxybenzoate, propyl hydroxybenzoate, and / or butyl hydroxybenzoate); sorbic acid or salts thereof; benzoic acid or salts thereof, and mixtures thereof); wetting agents; and cyclodextrins, particularly β-cyclodextrin, γ-cyclodextrin, and randomly methylated β-cyclodextrin.

[0116] In particular, orally disintegrating tablets may be prepared by processes including, but not limited to, tableting, direct compression, mass extrusion, and microencapsulation.

[0117] Direct compression can be applied to orally disintegrating tablets when disintegrants and / or sugar-based excipients are included in the tableting process. Methods for preparing orally disintegrating tablets by direct compression are known in the art. Microcrystalline cellulose, cross-linked sodium carboxymethylcellulose, cross-linked polyvinylpyrrolidone, and low- or partially substituted hydroxypropyl cellulose absorb moisture and expand due to capillary action, making them effective disintegrants in the preparation of orally disintegrating tablets. Agar powder can also be used as a disintegrant because it absorbs moisture and expands significantly at physiological temperatures without forming a gel. Sugar-based excipients (e.g., dextrose, fructose, isomalt, maltitol, maltose, mannitol, sorbitol, starch hydrolysates, polydextrose, and xylitol) can also be used in direct compression processes to impart water solubility and sweetness. Furthermore, rapid tablet disintegration can be achieved, if desired, by incorporating a foaming disintegrant (which generates gas).

[0118] Suitable effervescent disintegrants include agents that release gas through a chemical reaction that occurs when the effervescent disintegrant is exposed to the moisture in saliva in the oral cavity. The reaction is most often the result of a soluble acid source and an alkali monocarbonate or carbonate source, which produces carbon dioxide gas upon contact with the moisture in saliva. The acid source can be any that is safe for human consumption, including citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, and succinic acid. Carbonate sources include dry, solid carbonates and bicarbonates (e.g., sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, and magnesium carbonate). Reactants that generate oxygen or other gases that are safe for human consumption are also suitable.

[0119] In another embodiment, an orally disintegrating tablet for administration herein, preferably for a buccal delivery system, comprises an adhesive layer comprising a hydrophilic polymer having one surface adapted to contact and adhere to a first tissue of the oral cavity when wetted, and an opposite surface in contact with and adhere to an adjacent drug layer comprising a low-toxicity ester composition. The drug layer contacts and is in drug-transfer relationship with the oral mucosa when the adhesive layer contacts and adheres to the first tissue, preferably the gums. Typically, the hydrophilic polymer is selected from the group consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, ethyl cellulose, carboxymethyl cellulose, dextran, guar gum, polyvinylpyrrolidone, pectin, starch, gelatin, casein, acrylic acid polymers, polymers of acrylic acid esters, acrylic acid copolymers, vinyl polymers, vinyl copolymers, polymers of vinyl alcohol, alkoxy polymers, polyethylene glycol, PEG-10 copolymers ... The polymers include compounds selected from the group consisting of oxide polymers, polyethers, and mixtures thereof.

[0120] The adhesive layer may further comprise one or more components including, for example, fillers, tableting excipients, lubricants, flavors, and dyes. The drug layer may further comprise one or more components such as tableting excipients, fillers, flavors, taste masking agents, dyes, stabilizers, enzyme inhibitors, and lubricants. [Example]

[0121] The following examples further illustrate the compositions described herein. They are illustrative and should not be construed as limiting in any way, as numerous variations in materials and methods will be apparent to those skilled in the art.

[0122] Example 1 77.8 grams of polyethylene oxide are mixed using a mechanical mixer, and the following additional ingredients are added during mixing: Compound (v), i.e., BOD-06, or Compound (vii), i.e., BOD-07 (5.5 g), peppermint (3.7 g), propylene glycol (3.7 g), aspartame (3.0 g), citric acid (2.6 g), polyoxyethylene hydrogenated castor oil (CREMOPHOR). TM EL40 (3.7 g) and benzoic acid (0.05 g). The blend is allowed to mix while maintained at about 70°C until uniform. It is then extruded through an extrusion die to form a 0.125 mm thick film. The film is then cut into dosage forms ready for packaging.

[0123] Example 2 42.49% by weight of water, 43.49% by weight of ethyl alcohol, 0.02% of FD&C Red 40, 10% by weight of hydroxyethyl cellulose (molecular weight 9 × 10 4 ), 4% by weight of hydropropylcellulose (molecular weight 5 × 10 5 ) is coated using a knife over roll technique. A backing layer formulation using 42.49% by weight water, 42.49% by weight ethyl alcohol, 0.02% FD&C Red Dye 40, 12% by weight hydroxyethyl cellulose (molecular weight 9×10 4 A backing preparation made from 100% oleic acid and 3% by weight oleic acid is cast and dried. The resulting two-layer backing film is 0.15 mm thick.

[0124] Example 3 The adhesive layer formulation was prepared by mixing 45.6% by weight water (USP), 45% by weight ethyl alcohol, 2% by weight hydroxyethyl cellulose NATROSOL® 99-250 L NF (Aqualon), 2.9% by weight of polyacrylic acid NOVEON® AA1 USP (BF Goodrich), and 4.5% by weight of sodium carboxymethylcellulose, cellulose gum 7 LF PH (Aqualon). This preparation is a bioadhesive preparation but does not contain any active ingredients.

[0125] Example 4 A 100 ml solution for the adhesive layer was prepared using 45.1 wt. % water (USP), 46 wt. % ethyl alcohol, 1.8 wt. % hydroxyethyl cellulose NATROSOL® 99-250 L NF (Aqualon), 2.6 wt. % polyacrylic acid NOVEON® AA1 USP (BF Goodrich), and 4.5 wt. % sodium carboxymethyl cellulose, cellulose gum 7 LF PH (Aqualon). It is made using

[0126] Example 5 The film obtained according to Example 2 is used as the substrate for the final multilayer film of this example. The bioadhesive preparation of Example 3 is cast directly onto the film of Example 2 and allowed to dry. A three-layer film is thus obtained. The final layer is bioadhesive but does not contain any active agent. The preparation of Example 4 is then covered using a mask (the mask is a 0.500 mm polyester film in which an oval is placed and punched onto the three-layer laminate) and allowed to dry. A solution of compound (vii), i.e., BOD-07 (20% by weight in absolute ethanol), is then applied and allowed to dry. One or both of the previous steps can be repeated if necessary. The mask is then peeled off. The resulting film is a multilayer film composed of a thin backing layer and a thin bioadhesive layer, of which the final component contains the active agent and is the smaller surface. This system limits diffusion from either the side or back, allowing for unidirectional release of the active ingredient into the mucosal tissue.

[0127] Example 6 Prepare a backing layer gel that contains, by weight, 79.44% water, 0.01% FD&C Red 40, 0.05% sodium benzoate, 2.5% peppermint flavor, 13.5% hydroxyethyl cellulose, and 4.5% hydroxypropyl cellulose.Then, this gel is first coated with a 0.8 mm thick layer of substrate on the substrate, and then dried at 80 ° C for 8 minutes, thereby making it into a two-layer flexible backing film with a thickness of 0.17 mm.Then, a second 0.8 mm thick layer is directly coated on the top of this first layer, and dried at 80 ° C for 8 minutes.

[0128] A bioadhesive layer gel containing, by weight, 45.2% water (USP), 47.2% ethyl alcohol, 1.6% hydroxyethyl cellulose, 0.6% hydroxypropyl cellulose, 2.8% polyacrylic acid NOVEON® AA1 USP, 2.5% sodium carboxymethyl cellulose, and 0.1% titanium dioxide is prepared. Using this gel, a 0.5 mm first bioadhesive layer is coated directly on top of a two-layer flexible backing film and then dried at 60°C for 8 minutes or until sufficient water has been removed. A solution of compound (vii), i.e., BOD-07 (dissolved at 20% by weight in absolute ethanol), is then applied and dried to evaporate the ethanol. A 0.7 mm second bioadhesive layer is then coated directly on top of the BOD-07 layer and dried at 60°C for 20 minutes or until sufficient water has evaporated.

[0129] Example 7 By weight, the solution was 42.49% water, 42.49% ethyl alcohol, 0.02% FD&C Red 40, and 14% hydroxyethyl cellulose (mw 9 × 10 4A backing layer gel containing 1% PEG-40 ...

[0130] By weight, the solution was 45.95% water (USP), 46.85% ethyl alcohol, 1.6% hydroxyethyl cellulose NATROSOL® 99-250 L NF (Aqualon), 2.2% polyacrylic acid NOVEON® AA1 USP (BF Goodrich), and 3.4% sodium carboxymethyl cellulose. A bioadhesive gel containing cellulose gum 7 LF PH (Aqualon) is prepared. Using this gel, a 0.5 mm first bioadhesive layer is coated onto two backing layers and dried at 60°C for 10 minutes or until the water is removed. A mixture of compound (vii) or BOD-07 (dissolved at 20% by weight in absolute ethanol) is then applied and dried to evaporate the ethanol. A 0.8 mm second bioadhesive layer is coated onto the compound (vii) layer and dried at 60°C for 20 minutes or until sufficient water is removed.

[0131] Example 8 500 mg of BOD-06 is mixed with 5 g of β-cyclodextrin and dispensed into aluminum pouches (each containing 5 mg of BOD-06 and 50 mg of β-cyclodextrin) and sealed. Immediately before use, the contents of the pouch are dissolved in 50 ml of water and rinsed / swirled in the mouth.

[0132] Example 9 500 mg of BOD-07 is mixed with 5 g of γ-cyclodextrin and dispensed into aluminum pouches (each containing 5 mg of BOD-07 and 50 mg of γ-cyclodextrin) and sealed. Immediately before administration, the contents of the pouch are dissolved in 50 ml of water and rinsed or swirled in the mouth.

[0133] Example 10 Blend the following ingredients using a V-blender equipped with an intensifier bar and mix for approximately 5-10 minutes: [Table 1] Tablets weighing about 0.05 g / tablet are formed using a compression force of about 1000 psi and are suitable for oral use.

[0134] Example 11 All of the ingredients listed below are blended together and then tableted at 1.2 tonnes / cm in a rotary type tablet press equipped with 10 mm diameter beveled edge forming punches. 2 to provide buccal tablets each weighing 400 mg and containing 5 mg of active ingredient. [Table 2]

[0135] While certain preferred and alternative embodiments have been set forth for purposes of disclosure, modifications to the disclosed embodiments will occur to those skilled in the art, and it is therefore intended herein to cover all embodiments, combinations and modifications thereof that do not depart from the spirit and scope of the following claims.

Claims

1. A patch for use in treating hypersalivation by intraoral application, the patch comprising a compound of formula (2) in an amount of about 1 mg to about 10 mg per adult dose or about 0.02 mg / kg to about 1.0 mg / kg per pediatric dose. 【Chemistry 12】 and a pharmaceutically acceptable, non-toxic carrier or excipient therefor, wherein R is methyl or ethyl, and the compound has the R stereoisomeric configuration at the 2-position and the R, S, or RS stereoisomeric configurations at the 1' and 3' positions, or a mixture thereof.

2. The patch of claim 1 , wherein the patch is a buccal patch.

3. 3. The patch of claim 1 or 2, further comprising at least one gelling or viscosity controlling or film forming or mucoadhesive component.

4. The patch of claim 3 , wherein the gelling or viscosity controlling or film forming or mucoadhesive component is hydroxypropyl cellulose.

5. The patch of any one of claims 1 to 4, wherein the carrier or excipient comprises a cyclodextrin.

6. 6. The patch of claim 5, wherein the cyclodextrin comprises one or more members selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, randomly methylated β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, and sulfobutylated-β-cyclodextrin.

7. The compound of formula (2) is (iii) (2R) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (iv) (2R) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (v) (2R,3′R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (vi) (2R,3′S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (vii) (2R,3′R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (viii) (2R,3′S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (ix) (2R,1'R,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (x) (2R,1'S,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (xi) (2R,1'R,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (xii) (2R,1'S,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (xiii) (2R,1′R,3′S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (xiv) (2R,1'S,3'S)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; (xv) (2R,1′R,3′R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide; and (xvi) (2R,1'S,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide The patch according to any one of claims 1 to 6, wherein the patch is selected from the group consisting of:

8. The patch according to any one of claims 1 to 7, wherein the compound of formula (2) is (2R,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(ethoxycarbonylmethyl)-1-methylpyrrolidinium bromide or (2R,3'R)3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(methoxycarbonylmethyl)-1-methylpyrrolidinium bromide.

9. The patch according to any one of claims 1 to 8, wherein the compound of formula (2) is used in an amount of about 1 mg to about 2 mg per adult dose.

10. The patch according to any one of claims 1 to 8, wherein the compound of formula (2) is used in an amount of about 0.02 mg / kg to about 1.0 mg / kg per pediatric dose.

11. The patch according to any one of claims 1 to 10, wherein the compound of formula (2) is about 1% to about 20% by weight of the patch.

12. The patch of any one of claims 1 to 11, wherein the patch is formulated for use 1 to 3 times daily.

13. The patch of any one of claims 1 to 12, wherein the patch is formulated for use twice daily, in the morning and in the afternoon, approximately 6 to 8 hours apart.

14. The patch according to any one of claims 1 to 13, further comprising absolute ethanol.

15. The patch according to any one of claims 1 to 13, wherein about 15% to about 50% by weight of the compound of formula (2) is in a solution or suspension containing absolute ethanol.

16. The patch according to any one of claims 1 to 13, wherein the patch is in the form of a gel.

17. The patch of any one of claims 1 to 13, wherein the patch is formulated for mixing with an aqueous solution.

18. The patch of any one of claims 1 to 13, wherein the pharmaceutically acceptable, non-toxic carrier or excipient is anhydrous.

19. 14. The patch of any one of claims 1 to 13, further comprising one or more selected from the group consisting of plasticizers, mucoadhesives, stabilizers, taste masking agents, flavors, breath fresheners, colorants, inert fillers, preservatives, nonionic polymers, anionic polymers, emollients, swelling agents, chelating agents, foaming agents, effervescent agents, and any combination thereof.

20. The patch of any one of claims 1 to 13, further comprising an enzyme inhibitor.

21. The patch of any one of claims 1 to 13, further comprising a lubricant.

22. An oral composition, comprising: formula: 【Chemistry 13】 wherein R is methyl or ethyl, and the compound has the R stereoisomeric configuration at the 2-position and the R, S, or RS stereoisomeric configurations at the 1' and 3' positions, or a mixture thereof; and at least one anhydrous, non-toxic, pharmaceutically acceptable excipient; Including, An intraoral composition, wherein the intraoral composition is anhydrous, and the intraoral composition is in the form of a solid or film that can dissolve in the oral cavity.

23. 23. The oral composition of claim 22, further comprising at least one anhydrous, non-toxic, pharmaceutically acceptable carrier.

24. 24. The oral composition of claim 22 or 23, wherein the oral composition is in the form of an anhydrous powder or tablet.

25. 25. The oral composition according to any one of claims 22 to 24, wherein the oral composition is in the form of oral drops, a buccal film, or an oral solid that is a candy or gum, a tongue tablet, a sublingual tablet, or a fast dissolving tablet.

26. The oral composition of any one of claims 22 to 25, wherein the oral composition is formulated for mixing with an aqueous solution.

27. 27. The oral composition of any one of claims 22-26, further comprising a plasticizer, a mucoadhesive agent, a stabilizer, a taste masking agent, a flavor, a breath freshener, a colorant, an inert filler, a preservative, a nonionic polymer, an anionic polymer, a softener, a bulking agent, a chelating agent, a foaming agent, a foaming agent, or any combination thereof.

28. The oral composition of any one of claims 22 to 26, further comprising a taste-masking agent.

29. 29. The oral composition of claim 28, wherein the taste-masking agent is sugar, cyclamate and its salts, saccharin and its salts, ammonium glycyrrhizinate, aspartame, sucralose, stevia, or any combination thereof.

30. 30. The oral composition of claim 29, wherein the taste-masking agent is present in an amount of from about 0.001% to about 70% by weight.

31. An oral composition, the composition comprising: (a) Formula: 【Chemistry 14】 wherein R is methyl or ethyl, and the compound has the R stereoisomeric configuration at the 2-position and the R, S, or RS stereoisomeric configurations at the 1' and 3' positions, or a mixture thereof; and (b) taste masking agent Including, The oral composition comprises an anti-hyper-salivation effective amount of a compound of formula (2) from about 1 mg to about 10 mg per adult dose or an anti-hyper-salivation effective amount of a compound of formula (2) from about 0.02 mg / kg to about 1.0 mg / kg per pediatric dose, and the oral composition is capable of dissolving in the oral cavity.

32. 32. The oral composition of claim 31, wherein the taste-masking agent is a flavoring agent, a sweetener, a flavorless masking agent, and / or combinations thereof.

33. 33. The oral composition of claim 32, wherein the flavoring agent is a flavor oil, a flavoring aromatic, an oleoresin, a natural or synthetic extract, an essence, and / or a combination thereof.

34. 33. The oral composition of claim 32, wherein the flavor oil is spearmint oil, cinnamon oil, peppermint oil, clove oil, bay oil, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, oil of bitter almond, and / or combinations thereof.

35. 33. The oral composition of claim 32, wherein the extract is a plant extract, a leaf extract, a flower extract, a fruit extract, and / or a combination thereof.

36. 33. The oral composition of claim 32, wherein the extract is vanilla extract, chocolate extract, coffee extract, cocoa extract, grape extract, or citrus oil extract.

37. 34. The oral composition of claim 33, wherein the essence is apple essence, pear essence, peach essence, strawberry essence, raspberry essence, cherry essence, plum essence, pineapple essence, apricot essence, and / or combinations thereof.

38. 33. The oral composition of claim 32, wherein the flavoring agent is an aldehyde, an ester, and / or a combination thereof.

39. 33. The oral composition of claim 32, wherein the flavoring agent is cinnamyl acetate, cinnamaldehyde, citral, diethyl acetal, eugenyl formate, p-methylanisole, and / or combinations thereof.

40. 33. The oral composition of claim 32, wherein the flavoring agent is alpha citral, neral, beta citral, decanal, ethyl vanillin, heliotropin, piperonal, vanillin, alpha-amylcinnamaldehyde, aldehyde C-8, aldehyde C-9, aldehyde C-12, 2-ethylbutyraldehyde, hexenal, trans-2 hexenal, tolyl aldehyde, veratraldehyde, 2,6-dimethyl-5-heptenal, melonal, 2,6-dimethyloctanal, 2-dodecenal, a quaternary ammonium base, and / or a combination thereof.

41. 41. The oral composition of any one of claims 31 to 40, further comprising a flavor enhancer.

42. 42. The oral composition of claim 41, wherein the flavor enhancer is tartaric acid, citric acid, vanillin, alcohol, and / or combinations thereof.

43. 43. The oral composition of claim 42, wherein the alcohol is menthol, a higher alcohol, and / or a combination thereof.

44. 33. The oral composition of claim 32, wherein the flavoring agent is present in an amount of about 0.0001% to about 5% by weight.

45. 33. The oral composition of claim 32, wherein the sweetener is sugar and / or sugar substitutes, cyclamate and / or salts thereof, saccharin and / or salts thereof, ammonium glycyrrhizinate, aspartame, and / or combinations thereof.

46. 46. The oral composition of claim 45, wherein the sugar is sucrose, lactose, glucose, sucralose, stevia, and / or combinations thereof.

47. 33. The oral composition of claim 32, wherein the sweetener is present in an amount of from about 0.001% to about 70% by weight.

48. 33. The oral composition of claim 32, wherein the unflavored masking agent is a suitable coating material.

49. 36. The oral composition of any one of claims 31 to 35, wherein the suitable coating is (i) hydroxypropyl methylcellulose, (ii) ethylcellulose, (iii) methacrylate, (iv) polyvinylpyrrolidone, (v) copolymers of methylacrylic acid and ethyl acrylate, and (vi) combinations thereof.

50. 33. The oral composition of claim 32, wherein the masking agent is a coating of a water-insoluble polymer.

51. 32. The oral composition of claim 31, wherein the masking agent is ethyl cellulose.

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