MXPA06009296A - Compositions for delivering hypnotic agents across the oral mucosa and methods of use thereof. - Google Patents

Abstract

The present invention provides novel compositions for the delivery of a hypnotic agent across the oral mucosa. In particular, the buffer system in the compositions of the present invention raises the pH of saliva to a pH greater than about 7.8, thereby facilitating the substantially complete conversion of the hypnotic agent from its ionized to its un-ionized form. As a result, the dose of hypnotic agent is rapidly and efficiently absorbed by the oral mucosa with surprisingly low inter-subject variability. Furthermore, delivery of the hypnotic agent across the oral mucosa advantageously bypasses hepatic first pass metabolism of the drug and avoids enzymatic degradation of the drug within the gastrointestinal tract. Methods for using the compositions of the present invention for treating sleep disorders such as insomnia are also provided.

Description

COMPOSITIONS FOR THE SUPPLY OF HYPNOTIC AGENTS THROUGH THE ORAL MUCOSA AND ITS METHODS OF USE REFERENCES CROSSED TO RELATED APPLICATIONS

[0001] The present application claims priority of the patent application of the U.S.A. Serial No. 10 / 783,118, filed on February 17, 2004, which has become a provisional US patent application, and the provisional patent application of the U.S.A. Serial No. 60 / 598,629, filed on August 3,2004, each of which is hereby incorporated by reference in its entirety, for all purposes. BACKGROUND OF THE INVENTION

[0002] Insomnia is a condition that affects a person's ability to sleep or maintain sleep. It is the most common sleep disorder, which affects millions of Americans every year. Benzodiazepines, which are available as short-acting, intermediate or prolonged hypnotic agents, have been shown to be useful in treating insomnia. These benzodiazepines are considered to bind non-selectively with benzodiazepine1 (omega1) and benzodiazepine2 (omega2) receptors. This non-selective link may be responsible for some of the potential problems associated with the use of the benzodiazepine compounds as hypnotics. For example, some benzodiazepines are considered to interfere with memory, knowledge and psychomotor function. In addition, problems with altered sleep architecture, rebound insomnia, hangover or hangover effects and potential for abuse have been reported with the use of benzodiazepine.

[0003] Selective benzodiazepine receptor agonists have been developed and studied. For example, zolpidem (Ambien ™, Searle and Co.) and zaleplon (Sonata *, Wyeth-Ayerst Co.) are sedative agents without benzodiazepine, which is considered to bind selectively with benzodiazepine receptors (BZ, Zolpidem, an imidazopyridine, proven to reduce sleep latency, increase sleep duration and reduce nighttime awakenings.In addition, zolpidem has been found to retain sleep in stage III and in stage IV, resulting in less interruption of Ocular Movement sleep Rapid (REM = Rapid Eye Movement), Zaleplon, is a pyrazolopyrimidine derivative, which has also been shown to be useful as a hypnotic agent, however, zolpidem and zaleplon are both poorly soluble in aqueous medium.

[0004] Typically, these hypnotic agents They are supplied as oral doses, which are formulated for example as tablets or capsules for swallowing.Oral administration, however, has several disadvantages, such as losses of the drug. during hepatic first pass metabolism, during enzymatic degradation within the gastrointestinal tract (Gl), and during absorption. These drugs not only lose the increased variability in drug response, but also often require that the drug be delivered in larger initial doses. In addition, because the drug has to pass through the gastrointestinal system to enter the bloodstream, the time to reach a therapeutic effect can be quite long, typically around forty-five minutes or more.

[0005] Accordingly, other routes of administration in drugs, including those involving transport through mucous membranes, have been investigated. Of the various mucosal membranes (for example, oral, rectal, vaginal, ocular, nasal, etc.), the drug supply through mucous membranes in the oral cavity seems to be the most easily tolerated by patients. In addition to avoiding problems with traditional oral administration, the supply of drugs through the mucous membranes of the oral cavity has certain other advantages, due to the properties of the oral mucosa itself. For example, the mucous membranes of the oral cavity are highly vascularized and well supplied with lymphatic drainage sites.

[0006] In general, the mucous membranes of the oral cavity can be divided into five main regions: the floor of the mouth (sublingual), the cheeks (buccal), the gums (gingival), the roof of the mouth (palate) and the covering of the lips . These regions differ with respect to their anatomy, drug permeability and physiological response to drugs. For example, in terms of permeability, sublingual is more permeable than buccal, which is more permeable than the palate. This permeability is generally based on the relative thickness and degree of keratinization of these membranes, with the sublingual mucosa being relatively thin and non-keratinized, the buccal mucosa being thicker and non-keratinized, and the mucosa of the palate intermediate. in thickness but keratinized.

[0007] In addition to the differences in permeability of the various mucous membranes, the extent of drug delivery is also affected by the properties of the drug to be delivered. The ability of a molecule to pass through any mucous membrane depends on its size, its solubility in lipids and the extent to which it is ionized, among other factors.

[0008] The extent to which the drug is ionized has been further investigated regarding the supply of drug through the mucous membranes. The ionization depends on the dissociation constant (pKa), and the pH of the environment surrounding the molecule. In its non-ionized form, a drug is sufficiently lipophilic to pass through a membrane by passive diffusion. In fact, according to the pH partition hypothesis, only non-ionized, non-polar drugs will penetrate a lipid membrane.

[0009] In equilibrium, the concentrations of the non-ionized form of the drug are equal on both sides of the membrane. Since the concentration gradient drives passive diffusion, an increase in the percentage of the non-ionized form of a drug correspondingly increases transmucosal absorption of the drug. Maximum absorption through the membrane is considered to occur when a drug is 100% in its non-ionized form. Similarly, the absorption through the membrane decreases as the extension of the ionization increases. Therefore, the extent of drug absorption through the mucous membranes of the oral cavity can be influenced when the pH of the saliva is altered.

[0010] Some of the known transmucosal dosage forms include the use of a single buffering agent to change the pH of the saliva and tissues surrounding the buccal mucosa. However, these simple buffering agents typically react with an acid or a base to create a final pH that depends on the initial pH of the user's saliva. A buffering agent used to reach a final pH that depends on the initial pH of the user, results in greater variability. The extent of ionization and therefore the extent of absorption through the mucous membranes can not be accurately predicted of any kind. This can present significant problems when calculating precise doses, minimizing variability in patient response, and providing consistency in drug loading for regulatory authorities. In addition, a single buffering agent is typically not able to sustain a given pH over a period of time for optimum absorption. While others in the art have described the use of more than one buffer agent, these aforementioned problems are not easily cured by the impassive addition of an extra buffering agent, which can be unsafe and cause irreversible damage to the mucous membranes of the oral cavity. As such, a buffer system capable of achieving and sustaining a final pH independent of the initial pH to increase transmucosal absorption, has not yet been demonstrated to date.

[0011] Similarly, a buffer system that facilitates a substantially complete conversion of the ionized form of a drug to the non-ionized form in the shortest period of time, is critical to produce a rapid delivery of virtually a full dose of the drug through of the oral mucosa, to date has not been demonstrated. Previous dosage forms result in great variability in drug supply, due to the variability in the proportions in which a drug is released from its carrier. That is, the proportions of drug release in tablets or chewing gums previously described, depend substantially on the user's chewing or sucking speed. The variability in these speeds or proportions from user to user, further exacerbates the ability to predict the final amount of drugs that will enter the systemic circulation. In addition, the drug's release rate of the carrier additionally depends on the drug's ability to dispense with it. Often, the carrier (for example gum base) adheres strongly to the drug, making portions of the drug unavailable for absorption.

[0012] Accordingly, there is a need in the art for compositions to deliver hypnotic agents through the oral mucosa., which have buffer systems that facilitate the absorption of agents in a safe and stable manner. Similarly, there is a need in the art for compositions to deliver hypnotic agents through the oral mucosa which have a buffer system that produces a final pH, regardless of the initial pH, and sustain this final pH for a determined period of time. In addition, there is a need in the art for compositions capable of rapidly facilitating substantially complete conversion of the hypnotic agent, from its ionized to non-ionized form. The present invention satisfies these and other needs. BRIEF SUMMARY OF THE INVENTION

[0013] The present invention provides novel compositions for the delivery of a hypnotic agent through the oral mucosa. In particular, the buffer system in the compositions of the present invention increases the pH of the saliva to a pH greater than about 7.8, thereby facilitating the substantially complete conversion of the hypnotic agent from its ionized form to its non-ionized form. As a result, the dose of the hypnotic agent is rapidly and efficiently absorbed by the oral mucosa, with surprisingly low inter-subject variability (eg, less variability than absorption through the intestine in the same patient). In addition, the supply of the hypnotic agent through the oral mucosa advantageously derives the metabolism of the hepatic first step of the drug and prevents enzymatic degradation of the drug within the gastrointestinal tract. Methods for use of the compositions of the present invention for treating sleep disorders such as insomnia are also provided.

[0014] As such, in one aspect, the present invention provides a solid composition for delivery of a hypnotic agent through the oral mucosa, the composition comprising: (a) a hypnotic agent selected from the group consisting of an imidazopyridine, a dihydropyrrolopyrazine, a pyrazolopyridine and its pharmaceutically acceptable salts; (b) a carrier that provides complete buccal or sublingual disintegration in approximately 5 minutes or less after oral administration; and (c) a binary buffer system comprising a carbonate salt and a bicarbonate salt, wherein the binary buffer system elevates the pH of the saliva to a pH greater than about 7.8, regardless of the initial pH of the saliva.

[0015] In another aspect, the present invention provides a composition for delivery of a hypnotic agent through the oral mucosa, the composition comprising: (a) a hypnotic agent selected from the group consisting of an imidazopyridine, a dihydropyrrolopyrazine, a pyrazolopyrimidine , and its pharmaceutically acceptable salts; (b) a carrier; and (c) a binary buffer system comprising a carbonate salt and a bicarbonate salt, wherein the binary buffer system elevates the pH of the saliva to a pH greater than about 7.8, regardless of the starting or initial pH of the saliva.

[0016] In yet another aspect, the present invention provides a composition for delivery of a hypnotic agent through the oral mucosa, the composition comprising: (a) a hypnotic agent selected from the group consisting of an imidazopyridine, a dihydropyrrolopyrazine, a pyrazolopyrimidine, and its pharmaceutically acceptable salts; (b) a carrier; and (c) a binary buffer system comprising a carbonate salt or a bicarbonate salt and a second buffering agent, wherein the binary buffer system elevates the pH of the saliva to a pH greater than about 7.8, regardless of the initial pH of the saliva .

[0017] In still another aspect, the present invention provides a composition for delivery of a hypnotic agent through the oral mucosa, the composition is characterized by comprising: (a) a hypnotic agent selected from the group consisting of an imidazopyridine, a dihydropyrrolopyrazine, a pyrazolopyrimidine, and pharmaceutically acceptable salts thereof; (b) a carrier; and (c) a primary buffer system comprising a metal oxide and a citrate, phosphate or borate salt, wherein the binary buffer system elevates the pH of the saliva to a pH greater than about 7.8, regardless of the initial pH of the saliva .

[0018] In a further aspect, the present invention provides a composition for delivery of a hypnotic agent through the oral mucosa, the composition comprising: (a) a hypnotic agent selected from the group consisting of an imidazopyridine, a dihydropyrrolopyrazine, a pyrazolopyrimidine, and its pharmaceutically acceptable salts; (b) a carrier; and (c) a ternary buffer system comprising a carbonate salt, a bicarbonate salt and a third buffering agent, wherein the ternary buffer system elevates the pH of the saliva to a pH greater than about 7.8, regardless of the initial pH of the saliva .

[0019] In another aspect, the present invention provides a composition for delivery of a hypnotic agent through the oral mucosa, the composition comprising: (a) a hypnotic agent selects the group consisting of an imidazopyridine, a dihydropyrrolopyrazine, a pyrazolopyrimidine , and its pharmaceutically acceptable salts; (b) a carrier; and (c) a buffer system comprising a carbonate salt or a bicarbonate salt and two or more buffering agents selected from the group consisting of a metal oxide, a citrate salt, a phosphate salt and a borate salt, wherein the buffer system Raises the pH of the saliva to a pH greater than about 7.8, regardless of the initial pH of the saliva.

[0020] In still another aspect, the present invention provides a method for treating a sleep disorder in a subject that requires it, the method comprising: administering to the subject a composition comprising a therapeutically effective amount of a hypnotic agent selected from the group consists of an imidazopyridine, a dihydropyrrolopyrazine, a pyrazolopyrimidine, and their pharmaceutically acceptable salts; a carrier; and a binary buffer system comprising a carbonate salt and a bicarbonate, wherein the binary buffer system increases the pH of the saliva to a pH greater than about 7.8, regardless of the initial pH of the saliva.

[0021] Other objects, features and advantages of the present invention will be apparent to a person skilled in the art from the following detailed description and figures. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 is a bar diagram illustrating the relationship between pH and membrane permeation for zolpidem tartrate.

[0023] Figure 2 shows the average dissolution profiles for a rapidly dissolving tablet of zolpidem and a zolpidem pellet of the present invention.

[0024] Figure 3 shows the plasma concentration over time in each subject for Formulation A (sublingual zolpidem powder tablet) and a swallow time of 2 minutes.

[0025] Figure 4 shows the plasma concentration over time in each subject for Formulation A at a swallow time of 5 minutes.

[0026] Figure 5 shows the plasma concentration over time in each subject for Formulation A at a swallow time of 10 minutes.

[0027] Figure 6 shows the average plasma concentration over time for Formulation A, at three different times of swallowing and formulation B (POAmbien ™), which is obtained from the literature.

[0028] Figure 7 shows the average plasma concentration over time for Formulation A, at 2 and 5 minute swallow times using data from all subjects or excluding data from subjects 3, 6 and 7. [ 0029] Figure 8 is an expanded view of the first 90 minutes shown in Figure 4.

[0030] Figure 9 shows a plasma concentration over time representative for Formulation C (Tablet SL) at swallow times of 2 and 5 minutes and for Formulation B.

[0031] Figure 10 shows a plasma concentration with the representative time for Formulation D (Tablet FS) at times of swallowing of 2 and 5 minutes and for Formulation B. DETAILED DESCRIPTION OF THE INVENTION I. Definitions

[0032] As used herein, the following terms have the meanings assigned to them, unless specified otherwise.

[0033] The term "sleep disorder" refers to a disorganized sleep pattern that arises from many causes, including without limitation dysfunctional sleep mechanisms, abnormalities in physiological functions during sleep, abnormalities in the biological clock and disturbances of sleep which they are induced by extrinsic factors to the dream process. In particular, the term encompasses disorders associated with difficulties in remaining asleep and / or beginning to sleep such as insomnia (eg, transient, short-term and chronic), delayed-sleep phase syndrome, hypnosis-dependent sleep disorder, and sleep disorder dependent on stimulants; disorders associated with difficulty staying awake such as sleep apnea, narcolepsy, inguite leg syndrome, obstructive sleep apnea, central sleep apnea, idiopathic hyperinsomnia, sleep disorder associated with weak muscles; disorders associated with difficulties in complying with a regular sleep program such as poor perception of sleep status, sleep disorder due to work change, chronic time zone change syndrome, and irregular sleepwalking syndrome; disorders associated with abnormal behaviors such as sleep terror disorder (ie, parainsomnia) and sleepwalking; and other disorders such as sleep bruxism, fibromyalgia, and nightmares.

[0034] The term "insomnia" refers to a sleep disorder with characteristics that include, without limitation, difficulty in sleeping, difficulty in remaining asleep, intermittent awakening and / or awakening very soon. The term also encompasses diurnal symptoms such as drowsiness, anxiety, impaired concentration, impaired memory and irritability. Insomnia types suitable for treatment with the compositions of the present invention include, without limitation, transient, short-term and chronic insomnia. The term "transient insomnia" refers to insomnia that lasts a few nights. The term "short-term insomnia" refers to insomnia that lasts for about 2 to about 4 weeks. The term "chronic insomnia" refers to insomnia that lasts for at least a month.

[0035] The terms "therapeutic agent" and "drug" are used interchangeably to refer to a substance that has a pharmaceutical, pharmacological, psychosomatic or therapeutic effect. Preferably, the therapeutic agent or drug in a hypnotic agent. Suitable hypnotic agents for use in the present invention include, without limitation, an imidazopyridine compound, such as zolpidem or alpidem; a dihydropyrrolopyrazine compound such as zopeclon; a pyrazolopyrimidine compound such as zaleplon or indiplon; its pharmaceutically acceptable salts; and its combinations. In a particularly preferred embodiment, the hypnotic agent is zolpidem, in all convenient ways.

[0036] The term "therapeutically effective amount" refers to the amount of a hypnotic agent which is capable of achieving a therapeutic effect in a subject that regu- lates it. For example, a therapeutically effective amount of a hypnotic agent may be the amount that is capable of preventing or alleviating one or more of the symptoms associated with a sleep disorder.

[0037] The term "bioavailability" refers to the proportion and / or extent in which a drug is absorbed or available to the treatment site in the body.

[0038] The terms "disintegration" and "dissolution" are used interchangeably with "agui" to refer to the reduction of the solid dosage form of the present invention to a "liguid" form. More particularly, a complete disintegration or dissolution of a solid dose form refers to less than about 25% by weight of the solid dosage form that is gum in the mouth, after an appropriate period of time, for example 5 minutes or less , after administration. Suitable methods known in the art for determining the disintegration profile of a solid dosage form include, for example, the disintegration test of the US Pharmacopoeia. (USP = United States Pharmacopeia). Convenient methods known in the art for determining the dissolution profile of a solid dosage form include for example USP dissolution tests such as USP < 711 > Apparatus 1 or USP < 711 > Apparatus 2.

[0039] As used herein, the phrase "substantially complete conversion of the hypnotic agent from its ionized form to its non-ionized form" refers to more than about 50% conversion of the hypnotic agent from its ionized form to its non-ionized form. For example, the damping system can favor at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% conversion of the hypnotic agent from its form ionized to its non-ionized form. In some embodiments, the conversion occurs within approximately 10 minutes after administration.

[0040] The term "variability" refers to variability between subjects in terms of the relative standard deviation percent (RSD = Relative Standard Deviation) for the maximum concentration in plasma (Craax) and the time to reach the maximum concentration in plasma (Tmax). Notably, the compositions of the present invention have an RSD for Cmax, of about 27% versus about 45% for commercial oral tablets such as Ambien tablets. In addition, the compositions of the present invention have an RSD for Tmax of about 50% versus about 100% for commercial oral tablets such as Ambien tablets.

[0041] The term "administer" refers to the administration of the compositions of the present invention in the mucous membranes of the oral cavity (ie, oral mucosa). Examples of convenient sites of administration within the oral mucosa include, without limitation, the mucous membranes of the floor of the mouth (sublingual mucosa), the cheeks (buccal mucosa), the gums (gingival mucosa), the roof of the mouth (palatal mucosa), the lining of the lips and their combinations. Preferably, the compositions of the present invention are administered to the sublingual mucosa, buccal mucosa or a combination thereof. II. General

[0042] The present invention provides novel compositions for the delivery of a hypnotic agent through the oral mucosa. In particular, the buffer system in the compositions of the present invention increases the pH of the saliva to a pH greater than about 7.8, thereby facilitating the substantially complete conversion of the hypnotic agent from its ionized form to its non-ionized form. As a result, the dose of a hypnotic agent is rapidly and efficiently absorbed by the oral mucosa with surprisingly low inter-subject variability in terms of maximum plasma concentration (C max) and time to reach the maximum plasma concentration (T max). In addition, the supply of the hypnotic agent through the oral mucosa advantageously derives the hepatic first pass metabolism of the drug and prevents enzymatic degradation of the drug in the gastrointestinal tract, resulting in increased bioavailability of the hypnotic agent and reduced time to onset of the therapeutic activity compared to traditional dosage forms for oral administration (e.g. tablets). Methods for using the compositions of the present invention to treat sleep disorders such as various types of insomnia are also provided.

[0043] The present invention is based on the surprising discovery that the supply of zolpidem compositions containing the buffer systems described herein, provide both increased bioavailability of the therapeutic agent and reduced time for onset of therapeutic activity far exceeding those observed for commercial oral tablets such as tablets as well as oral tablets such as zolpidemFlashDose ™ tablets (Biovail Technologies Ltd., Chantilly, VA). In fact, it was counter-intuitive to expect that the solid dose forms of zolpidem of rapid disintegration described above would provide rapid uptake and marked increase in bioavailability of zolpidem which was observed. As a result, the zolpidem in the compositions of the present invention reaches the systemic circulation in a substantially shorter period of time and at a substantially higher concentration than the zolpidem in any of the commercial tablet compositions. In this way, the zolpidem compositions of the present invention are superior to commercial tablet compositions in reducing the time for onset of therapeutic activity, maintaining sleep (for example, total sleep time, number of awakenings), improved quality of sleep, eliminating the effect of food, and reducing any residual effects of the next morning. III. Description of Modalities

[0044] In one aspect, the present invention provides a solid composition for the delivery of a hypnotic agent through the oral mucosa, the composition comprising: (a) a hypnotic agent selected from the group consisting of an imidazopyridine , a dihydropyrrolopyrazine, a pyrazolopyrimidine, and their pharmaceutically acceptable salts; (b) a carrier that provides complete buccal or sublingual disintegration in approximately 5 minutes or less after oral administration; and (c) a binary buffer system comprising a carbonate salt and a bicarbonate salt, wherein the binary buffer system elevates the pH of the saliva to a pH greater than about 7.8, regardless of the initial pH of the saliva.

[0045] In certain instances, the primary buffer system increases the pH of the saliva to a pH greater than about 8.5, regardless of the initial pH of the saliva. In certain other instances, the binary buffer system increases the pH of the saliva to a pH greater than about 9 (eg, about -11), regardless of the initial pH of the saliva. In one embodiment, the hypnotic imidazopyridine agent is selected from the group consisting of zolpidem and alpidem. Preferably, the hypnotic imidazopyridine agent is zolpidem. Any form of zolpidem is suitable for use in the compositions described herein, for example a salt form of zolpidem (for example zolpidem tartrate), a zolpidem-free base form, or a mixture thereof. In another embodiment, the hypnotic agent of dihydropyrrolopyrazine is zopeclon. In yet another embodiment, the hypnotic pyrazolopyrimidine agent is selected from the group consisting of zaleplon and indiplon salts.

[0046] In certain instances, the carrier provides complete buccal or sublingual disintegration in approximately 2 minutes or less after administration. In certain other instances, the carrier comprises at least one binder and at least one disintegrating agent in a relative proportion to provide a buccal or sublingual disintegration time of about 5 minutes or less, preferably about 2 minutes or less, after administration . Preferably, the ratio of binder to disintegrant is from about 0.1 to about 10.0, more preferably from about 0.1 to about 1.0, and in particular from about 0.26 to about 0.79. However, a person skilled in the art will appreciate that the compositions of the present invention can be made without binders, for example, to produce a highly friable dosage form.

[0047] In another embodiment, the carbonate salt is selected from the group consisting of sodium carbonate, potassium carbonate, calcium carbonate, ammonium carbonate and magnesium carbonate. In yet another embodiment, the bicarbonate salt is selected from the group consisting of sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, ammonium bicarbonate, and magnesium bicarbonate. In a preferred embodiment, the binary buffer system comprises sodium carbonate and sodium bicarbonate. In another preferred embodiment, the sodium bicarbonate is sodium bicarbonate coated with desiccant.

[0048] Still in another embodiment, the compositions of the present invention are in a dosage form which is selected from the group consisting of a tablet, a chewing gum, a chewable tablet and a dissolution tablet such as a dissolving tablet. slow or a fast dissolving tablet. Preferably, the composition is a tablet or solution tablet. A description of tablet compositions, chewing gum, chewable tablet, slow-dissolving tablet and fast-dissolving tablet containing a hypnotic agent is given in the following Examples.

[0049] In a preferred embodiment, the hypnotic agent is delivered through an oral mucosa selected from the group consisting of the sublingual mucosa, the buccal mucosa and a combination thereof. In a particularly preferred embodiment, the composition is administered sublingually, such that the hypnotic agent is delivered through the sublingual mucosa.

[0050] In another embodiment, the carrier is selected from the group consisting of a binder, a gum base and combinations thereof. Suitable binders for use in the compositions of the present invention include without limitation, sugar alcohols such as mannitol, sorbitol and xylitol; sugars such as lactose, dextrose, sucrose, glucose and powdered sugar; natural gums such as acacia gum, xanthan gum, guar gum, tara gum, mesguite gum, rich gum or fenugreek, locust bean gum, ghatti gum and tragacanth gum; other substances such as inositol, molasses, maltodextrin, starch, cellulose, microcrystalline cellulose, polyvinylpyrrolidone, alginate, Irish moss extract, panwar gum, isapol shell mucilage, Veegum ™, larch arabogalactan, gelatin, methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose , polyacrylic acid (eg, Carbopol), calcium silicate, calcium phosphate, dicalcium phosphate, calcium sulfate, kaolin, sodium chloride, polyethylene glycol; and its combinations. Suitable gum bases for use in the compositions of the present invention include, for example, materials selected from the many water-insoluble and saliva-insoluble gum base materials known in the art. In certain instances, the gum base comprises at least one hydrophobic polymer and at least one hydrophilic polymer. Non-limiting examples of hydrophobic and hydrophilic polymers suitable for base gums include both natural and synthetic polymers such as elastomers, rubbers and combinations thereof. Examples of suitable natural polymers include, without limitation, plant-origin substances such as chewing gum, jelutongo, gutta percha, gum crown and combinations thereof. Examples of suitable synthetic polymers include elastomers such as butadiene-styrene copolymers, isobutylene and isoprene copolymers (eg "butyl rubber"), polyethylene, polyisobutylene, polyvinyl ester (eg, polyvinyl acetate and polyvinyl acetate phthalate), and combinations thereof . In other instances, the gum base comprises a mixture of butyl rubber (i.e., copolymer of isobutylene and isoprene), polyisobutylene and optionally polyvinylacetate (eg, having a molecular weight of about 12,000).

[0051] Still in another embodiment, the compositions of the present invention may further comprise a sweetening agent, a flavoring agent, a protective agent, a plasticizer, a wax, an elastomeric solvent, a filler, a preservative, or combinations of the same. In yet another embodiment, the compositions of the present invention may further comprise a lubricating agent, a wetting agent, an emulsifying agent, a solubilizing agent, a suspending agent, a coloring agent, a disintegrating agent or combinations thereof. In a preferred embodiment, the average particle size of the drug in the compositions described herein is about 20 microns, as compared to a typical average drug particle size of about 75 to about 100 microns. In another preferred embodiment, the average particle size of the drug in the compositions described herein is less than or equal to the average particle size of the carrier ingredients (e.g., gum base, binders, etc.).

[0052] In preferred embodiments of the present invention, the hypnotic agent is zolpidem and the binary buffer system comprises sodium carbonate and sodium bicarbonate. These compositions are preferably formulated in the form of a lozenge, candy or dissolution tablet (e.g., slow dissolving tablet or fast dissolving tablet) for sublingual administration. As a result, upon sublingual administration, zolpidem is delivered through the sublingual mucosa. In other preferred embodiments, sodium bicarbonate is sodium bicarbonate coated with desiccant. A combined weight percent of sodium carbonate and sodium bicarbonate which is greater than or equal to the weight percent of zolpidem is also preferred.

[0053] In certain instances, the composition comprises from about 1.0 to about 5.5 weight percent zolpidem; from about 6.0 to about 10.0 weight percent sodium carbonate; and from about 9.0 to about 13.0 weight percent of sodium bicarbonate coated with desiccant. In a preferred embodiment, the composition comprises about 4.5 weight percent zolpidem; about 8.0 weight percent sodium carbonate; and about 11.0 weight percent of sodium bicarbonate coated with desiccant. These compositions are preferably in the form of a bar or confectionery with a dough of from about 100 to about 300 mg, for example about 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290 and 300 mg. The pills or sweets dissolve in the mouth of a subject at a very fast rate, for example within about 2-3 minutes after administration.

[0054] In certain other instances, the composition comprises from about 1.0 to about 5.0 weight percent zolpidem; from about 5.0 to about 9.0 weight percent sodium carbonate; and from about 7.0 to about 11.0 weight percent of sodium bicarbonate. In a preferred embodiment, the composition comprises about .0 weight percent zolpidem; about 7.0 weight percent of sodium carbonate; and about 9.0 weight percent of sodium bicarbonate. These compositions are preferably in the form of a dissolution tablet such as a slow dissolving tablet or a rapid dissolving tablet of from about 100 to about 300 mg, eg, about 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290 and 300 mg. Rapid dissolving tablets dissolve in the mouth of a subject at a rapid rate, for example within about 5 minutes after administration, and dissolving tablets dissolve in a user's mouth at a slower rate, for example within approximately 10 minutes after administration.

[0055] In another aspect, the present invention provides a composition for delivery of a hypnotic agent through the oral mucosa, the composition comprising: (a) a hypnotic agent selected from the group consisting of an imidazopyridine, a dihydropyrrolopyrazine, a pyrazolopyrimidine and their pharmaceutically acceptable salts; (b) a carrier; and (c) a binary buffer system comprising a carbonate salt and a bicarbonate salt, wherein the binary buffer system elevates the pH of the saliva to a pH greater than about 7.8, regardless of the initial pH of the saliva.

[0056] In certain cases, the binary buffer system raises the pH of the saliva to a pH greater than about 8.5, regardless of the initial pH of the saliva. In certain other cases, the binary buffer system elevates the pH of the saliva to a pH greater than about 9 (eg, about 9-11), regardless of the initial pH of the saliva. Suitable imidazopyridine hypnotic agents, dihydropyrrolopyrazine and pyrazolopyrimidine for use in the present invention were described above. Suitable carbonate salts and bicarbonate salts for use in the binary buffer systems of the present invention were also described above.

[0057] In another embodiment, the compositions of the present invention are in any of the dosage forms described above. Preferably, the hypnotic agent is delivered through an oral mucosa as described above. In yet another embodiment, the carrier is selected from the group consisting of a binder, a gum base and combinations thereof. Suitable base gums and gums for use in the compositions of the present invention were described above. In certain instances, the carrier provides a buccal or sublingual disintegration time of about 10 minutes or less, preferably about 5 minutes or less, and more preferably about 2 minutes or less, after administration. In certain other cases, the carrier comprises at least one binder and at least one disintegrating agent in a relative proportion such as to provide a buccal or sublingual disintegration time of about 10 minutes or less, preferably of about 5 minutes or less and more. preferably about 2 minutes or less, after administration.

[0058] Still in another embodiment, the compositions of the present invention may further comprise one or more of the additional agents described above. In preferred embodiments, the average particle size of the drug in the above described compositions is about 20 microns and / or less than or equal to the average particle size of the carrier ingredients (eg, gum base, binders, etc.) .

[0059] In other preferred embodiments of the present invention, the hypnotic agent is zolpidem and the binary buffer system comprises sodium carbonate and sodium bicarbonate. Preferred amounts of each of these components are described above, along with preferred dosage forms and their preferred weight.

[0060] In yet another aspect, the present invention provides a composition for delivery of a hypnotic agent through the oral mucosa, the composition comprising: (a) a hypnotic agent selected from the group consisting of an imidazopyridine, a dihydropyrrolopyrazine, a pyrazolopyrimidine and its pharmaceutically acceptable salts; (b) a carrier; and (c) a binary buffer system comprising a carbonate salt or a bicarbonate salt and a second buffering agent, wherein the binary buffer system elevates the pH of the saliva to a pH greater than about 7.8, regardless of the initial pH of the saliva.

[0061] In certain instances, the binary buffer system elevates the pH of the saliva to a pH greater than about 8.5, regardless of the initial pH of the saliva. In certain other instances, the binary buffer system elevates the pH of the saliva to a pH greater than about 9 (for example about 9-11), regardless of the initial pH of the saliva. Suitable hypnotic agents of imidazopyridine, dihydropyrrolopyrazine and pyrazolopyrimidine for use in the present invention were described above. Carbonate salts and bicarbonate salts suitable for use in the binary buffer systems of the present invention were also described above.

[0062] In one embodiment, the second buffering agent is selected from the group consisting of a metal oxide, a citrate salt, a phosphate salt, a borate salt, an ascorbate salt, an acetate salt and an alkaline starch. Suitable metal oxides include, without limitation, magnesium oxide and aluminum oxide. Preferably, the magnesium oxide is an amorphous magnesium oxide. Suitable citrate, phosphate and borate salts include, without limitation, any salt of citric acid, phosphoric acid or boric acid known in the art. For example, in some embodiments, the citrate salt is selected from the group consisting of sodium citrate, potassium citrate, calcium citrate, magnesium citrate, and ammonium citrate. In other embodiments, the phosphate salt is selected from the group consisting of monobasic sodium phosphate, dibasic sodium phosphate, monobasic potassium phosphate, dibasic potassium phosphate, calcium phosphate monobasic, calcium phosphate dibasic, magnesium phosphate monobasic, phosphate of dibasic magnesium, monobasic ammonium phosphate and dibasic ammonium phosphate. In still other embodiments, the borate salt is selected from the group consisting of sodium borate, potassium borate, calcium borate, magnesium borate, and ammonium borate. In certain instances, the binary buffer system comprises a carbonate salt and a metal oxide, a citrate salt, a phosphate salt or a borate salt. In certain other instances, the binary buffer system comprises a bicarbonate salt and a metal oxide, a citrate salt, a phosphate salt or a borate salt.

[0063] In another embodiment, the compositions of the present invention are in any of the dosage forms described above. Preferably, the hypnotic agent is delivered through an oral mucosa as described above. In yet another embodiment, the carrier is selected from the group consisting of a binder, a gum base and combinations thereof. Suitable base gums and gums for use in the compositions of the present invention are described above. In certain cases, the carrier provides a buccal or sublingual disintegration time as described above. In certain other cases, the carrier comprises at least one binder and at least one disintegrating agent as described above.

[0064] Still in another embodiment, the compositions of the present invention may further comprise one or more of the additional agents described above. In preferred embodiments, the average particle size of the drug in the above described compositions is about 20 microns and / or is less than or equal to the average particle size of the carrier ingredients (eg, gum base, binders, etc.). ).

[0065] In preferred embodiments of the present invention, the hypnotic agent is zolpidem, and the binary buffer system comprises sodium carbonate or sodium bicarbonate and a second buffering agent. These compositions are preferably formulated in the form of a tablet, sweet or dissolution tablet for sublingual administration.

[0066] In yet another additional aspect, the present invention provides a composition for delivery of a hypnotic agent through the oral mucosa, the composition comprising: (a) a hypnotic agent selected from the group consisting of an imidazopyridine, a dihydropyrrolopyrazine, a pyrazolopyrimidine and its pharmaceutically acceptable salts; (b) a carrier; and (c) a binary buffer system comprising a metal oxide and a citrate, phosphate, or borate salt, wherein the binary buffer system elevates the pH of the saliva to a pH greater than about 7.8, regardless of the initial pH of the saliva.

[0067] In certain cases, the binary buffer system raises the pH of the saliva to a pH greater than about 8.5, regardless of the initial pH of the saliva. In certain other cases, the binary buffer system raises the pH of the saliva to a pH greater than about 9 (eg, about 9-11), regardless of the initial pH of the saliva.

Suitable hypnotic agents of imidazopyridine, dihydropyrrolopyrazine and pyrazolopyrimidine for use in the present invention were described above.

[0068] Suitable metal oxides include, without limitation, magnesium oxide and aluminum oxide. Suitable citrate, phosphate and borate salts include, without limitation, any salts of citric acid, phosphoric acid or boric acid known in the art such as aguelas described above. In certain cases, the binary buffer system comprises a metal oxide and a citrate salt. In certain other cases, the binary buffer system comprises a metal oxide and a phosphate salt. In additional cases, the binary buffer system comprises a metal oxide and a borate salt.

[0069] In one embodiment, the compositions of the present invention are in any of the dosage forms described above. Preferably, the hypnotic agent is delivered through an oral mucosa as described above. In yet another embodiment, the carrier is selected from the group consisting of a binder, a gum base and the combination thereof. Suitable binders and base rubbers for use in the compositions of the present invention were described above. In certain instances, the carrier provides a buccal or sublingual disintegration time as described above. In other instances, the carrier comprises at least one binder and at least one disintegrating agent as described above.

[0070] In another embodiment, the compositions of the present invention may further comprise one or more of the additional agents described above. In preferred embodiments, the average particle size of the drug in the compositions described above is about 20 microns and / or is less than or equal to the average particle size of the carrier ingredients (eg gum base, binders, etc.) .

[0071] In preferred embodiments of the present invention, the hypnotic agent is zolpidem and the primary buffer system comprises amorphous magnesium oxide and a citrate, phosphate or borate salt. These compositions are preferably formulated in the form of a tablet, candy or solution tablet for sublingual administration.

[0072] In a further aspect, the present invention provides a composition for delivery of a hypnotic agent through the oral mucosa, the composition comprising: (a) a hypnotic agent selected from the group consisting of an imidazopyridine, a dihydropyrrolopyrazine, a pyrazolopyrimidine, and its pharmaceutically acceptable salts; (b) a carrier; and (c) a ternary buffer system comprising a carbonate salt, a bicarbonate salt and a third buffering agent, wherein the ternary buffer system elevates the pH of the saliva to a pH greater than about 7.8, regardless of the starting pH of the saliva.

[0073] In certain cases, the binary buffer system elevates the pH of the saliva to a pH greater than about 8.5, regardless of the initial pH of the saliva. In certain other instances, the binary buffer system raises the pH of the saliva to a pH greater than about 9 (eg, about 9-11), regardless of the initial pH of the saliva. Suitable hypnotic agents of imidazopyridine, dihydropyrrolopyrazine and pyrazolopyrimidine for use in the present invention were described above. Suitable carbonate salts and bicarbonate salts for use in the ternary damping systems of the present invention were also described above.

[0074] In one embodiment, the third buffering agent is selected from the group consisting of a metal oxide, a citrate salt, a phosphate salt, a borate salt, an ascorbate salt, an acetate salt and an alkaline starch. Suitable metal oxides include, without limitation, magnesium oxide and aluminum oxide. Suitable citrate, phosphate and borate salts include, without limitation, any salt of citric acid, phosphoric acid or boric acid known in the art, such as aguelas described above. In certain cases, the ternary buffer system comprises a carbonate salt, a bicarbonate salt and a metal oxide. In certain other cases, the ternary buffer system comprises a carbonate salt, a bicarbonate salt and a citrate, phosphate, or borate salt.

[0075] In another embodiment, the compositions of the present invention are in any dosage form described above. Preferably, the hypnotic agent is delivered through an oral mucosa as described above. In yet another embodiment, the carrier is selected from the group consisting of a binder, a gum base and combinations thereof. Suitable binders and base rubbers for use in the compositions of the present invention were described above. In certain cases, the carrier provides a buccal or sublingual disintegration time as described above. In other certain cases, the carrier comprises at least one binder and at least one disintegrating agent as described above.

[0076] Still in another embodiment, the compositions of the present invention may further comprise one or more of the additional agents described above. In preferred embodiments, the average particle size of the drug in the above described compositions is about 20 microns and / or is less than or equal to the average particle size of the carrier ingredients (eg, gum base, binders, etc.).

[0077] In preferred embodiments of the present invention, the hypnotic agent is zolpidem, and the ternary buffer system comprises sodium carbonate, sodium bicarbonate and a third buffering agent. These compositions are preferably formulated in the form of a tablet, candy or solution tablet for sublingual administration. In instances where the third buffer is a metal oxide, one percent by weight of the metal oxide is preferred, which is greater than the combined weight percent of sodium carbonate and sodium bicarbonate.

[0078] In another aspect, the present invention provides a composition for the delivery of a hypnotic agent through the oral mucosa, the composition comprising: (a) a hypnotic agent selected from the group consisting of an imidazopyridine, a dihydropyrrolopyrazine, a pyrazolopyrimidine and / or its pharmaceutically acceptable salts; (b) a carrier; and (c) a buffer system comprising a carbonate salt or a bicarbonate salt and two or more buffering agents selected from the group consisting of a metal oxide, a citrate salt, a phosphate salt and a borate salt, wherein the buffer system Raises the pH of the saliva to a pH greater than about 7.8, regardless of the initial pH of the saliva.

[0079] In certain cases, the binary buffer system elevates the pH of the saliva to a pH greater than about 8.5, regardless of the initial pH of the saliva. In certain other cases, the binary buffer system raises the pH of the saliva to a pH greater than about 9 (eg, about 9-11), regardless of the initial pH of the saliva. Suitable hypnotic agents of imidazopyridine, dihydropyrrolopyrazine and pyrazolopyrimidine for use in the present invention are described above. Suitable carbonate salts and bicarbonate salts for use in the buffer systems of the present invention were also described above.

[0080] Convenient metal oxides include, without limitation, magnesium oxide and aluminum oxide. Suitable salts of citrate, phosphate and borate include, without limitation, any salt of citric acid, phosphoric acid or boric acid known in the art such as aguelas described above. In certain cases, the buffer system comprises a carbonate salt or a bicarbonate salt, a metal oxide and a citrate, phosphate or borate salt. In certain other cases, the buffer system comprises a carbonate salt or a bicarbonate salt, a citrate salt and a phosphate salt. In certain cases, the buffer system comprises a carbonate salt or a bicarbonate salt, a citrate salt and a borate salt. In certain other cases, the buffer system comprises a carbonate salt or a bicarbonate salt, a phosphate salt and a borate salt.

[0081] In one embodiment, the compositions of the present invention are in any dosage form described above. Preferably, the hypnotic agent is delivered through an oral mucosa as described above. In yet another embodiment, the carrier is selected from the group consisting of a binder, a base gum and its combinations. Suitable base gums and gums for use in the compositions of the present invention were described above. In certain cases, the carrier provides a buccal or sublingual disintegration time as described above. In certain other cases, the carrier comprises at least one binder and at least one disintegrating agent as described above.

[0082] In another embodiment, the compositions of the present invention may further comprise one or more of the additional agents described above. In preferred embodiments, the average particle size of the drug in the above-described compositions is about 20 microns and / or is less than or equal to the average particle size of the carrier ingredients (eg, gum base, binders, etc.).

[0083] In preferred embodiments of the present invention, the hypnotic agent is zolpidem, and the buffer system comprises sodium carbonate or sodium bicarbonate and two or more buffering agents selected from the group consisting of metal oxide, a citrate salt, a salt phosphate and a borate salt. These compositions are preferably formulated in the form of a tablet, candy or solution tablet for sublingual administration.

[0084] In yet another aspect, the present invention provides a method for treating a sleep disorder in a subject that regu- lates it, the method comprising: administering to the subject a composition comprising a therapeutically effective amount of a hypnotic agent selected from the group consists of an imidazopyridine, a dihydropyrrolopyrazine, a pyrazolopyrimidine and its pharmaceutically acceptable salts; a carrier; and a binary buffer system comprising a carbonate salt and a bicarbonate salt, wherein the binary buffer system elevates the pH of the saliva to a pH greater than about 7.8, regardless of the initial pH of the saliva.

[0085] In a preferred embodiment, the composition delivers the hypnotic agent through the oral mucosa, such as for example the sublingual mucosa, the buccal mucosa or a combination thereof. In a particularly preferred embodiment, the composition is administered sublingually, such that the hypnotic agent is delivered through the sublingual mucosa. Suitable sleep disorders which can be treated with the compositions of the present invention include without limitation insomnia, such as transient insomnia, short-term insomnia and chronic insomnia.

[0086] In certain circumstances the binary buffer system elevates the pH of the saliva to a pH greater than about 8.5, 'regardless of the initial pH of the saliva. In certain other cases, the binary buffer system raises the pH of the saliva to a pH greater than about 9 (eg, about 9-11), regardless of the initial pH of the saliva. Suitable hypnotic agents of imidazopyridine, dihydropyrrolopyrazine and pyrazolopyrimidine for use in the present invention were described above. Suitable carbonate salts and bicarbonate salts for use in the binary buffer systems of the present invention were also described above.

[0087] In addition to a binary buffer system comprising a carbonate salt and a bicarbonate salt, other buffer systems are suitable for use in the compositions of the present invention. For example, in an alternate embodiment, the binary buffer system comprises a carbonate salt or a bicarbonate salt and a second buffering agent such as a metal oxide, a citrate salt, a phosphate salt, a borate salt, an ascorbate salt, a salt acetate and alkaline starch. In another alternate embodiment, the binary buffer system comprises a metal oxide and a citrate, phosphate or borate salt. Still in another alternate embodiment, the buffer system is a ternary buffer system comprising a carbonate salt, a bicarbonate salt and a third buffering agent such as a metal oxide, a citrate salt, a phosphate salt, a borate salt, an ascorbate salt , an acetate salt and alkaline starch. In yet another alternate embodiment, the buffer system comprises a carbonate salt or a bicarbonate salt and two or more buffering agents selected from the group consisting of a metal oxide, a citrate salt, a phosphate salt and a borate salt.

[0088] In one embodiment, the compositions of the present invention are in any of the dosage forms described above. Preferably, the hypnotic agent is delivered through an oral mucosa as described above. In yet another embodiment, the carrier is selected from the group consisting of a binder, a gum base and combinations thereof. Suitable binders and base rubbers for use in the compositions of the present invention were described above. In certain cases, the carrier provides a buccal or sublingual disintegration time as described above. In other certain cases, the carrier comprises at least one binder and at least one disintegrating agent as described above.

[0089] In another embodiment, the compositions of the present invention may further comprise one or more of the additional agents described above. In preferred embodiments, the average particle size of the drug in the compositions described herein is about 20 microns and / or is less than or equal to the average particle size of the carrier ingredients (eg, gum base, binders, etc.) .

[0090] In preferred embodiments of the present invention, the hypnotic agent is zolpidem and the binary buffer system comprises sodium carbonate and sodium bicarbonate. Preferred amounts of each of these components are described above together with preferred dosage forms and their preferred weights. A. Hypnotic Agents

[0091] The hypnotic agents of the present invention are preferably chosen from an imidazopyridine compound such as zolpidem or alpidem; a dihydropyrrolopyrazine compound such as zopeclon; a pyrazolopyrimidine compound such as zaleplon or indiplon; its pharmaceutically acceptable salts; and its combinations. More preferably the hypnotic agent is zolpidem, in all convenient ways.

[0092] In general, the hypnotic agents of the present invention are basic compounds having an ionized form and a non-ionized form. In certain cases, the hypnotic agent is initially present at least partially in an ionized form. In other cases, the hypnotic agent is initially present in a non-ionized form. As described in more detail below, the buffer system of the compositions described herein, helps to substantially convert all of the hypnotic agent from its ionized form to its non-ionized form. Alternately, the buffer system helps ensure that the hypnotic agent, initially in a non-ionized form, remains in a non-ionized form.

[0093] As agui is employed, the term "hypnotic agent" includes all pharmaceutically acceptable forms of the hypnotic agent described. For example, the hypnotic agent may be in a racemic or isomeric mixture, a solid complex bound to an ion exchange resin, or the like. In addition, the hypnotic agent can be in a solvated form. The term "hypnotic agent" is also intended to include all pharmaceutically acceptable salts, derivatives and analogues of the hypnotic agent described, as well as combinations thereof. For example, pharmaceutically acceptable salts of the hypnotic agent include, but are not limited to, the salt tartrate, succinate, tartarate, bitartarate, dihydrochloride, salicylate, hemisuccinate, citrate, maleate, hydrochloride, carbamate, sulfate, nitrate and benzoate forms thereof, as well as its combinations and similar. Any form of the hypnotic agent is suitable for use in the compositions of the present invention, for example a pharmaceutically acceptable salt of the hypnotic agent (for example zolpidem tartrate), a free base of the hypnotic agent or a mixture thereof.

[0094] The conversion of the ionized form to the non-ionized form for the hypnotic agent is related to the pH according to the formula: pH = pKa + Log10 (non-ionized concentration / ionized concentration). When the pH is the same as the pKa, there are equimolar concentrations of the non-ionized form and the ionized form. For basic compounds such as the hypnotic agents described above, when the pH is a higher unit than the pKa, the ratio of the non-ionized form to the ionized form is 91: 9. Similarly, when the pH is two units higher than the pKa, the ratio of the non-ionized form to the ionized form is 100: 1. As noted above, the non-ionized form is lipophilic and therefore more able to pass through mucous membranes such as the oral mucosa than the ionized form, which is a lipophobic nature. Accordingly, increasing the pH of the saliva promotes the conversion of the ionized form to the non-ionized form for basic compounds such as the hypnotic agents described above, and the final pH can be determined by making use of the above formula.

[0095] The hypnotic agents of the present invention are chosen from the class of compounds in the imidazopyridine, dihydropyrrolopyrazine, or pyrazolopyrimidine family and are useful in the treatment of conditions such as sleep disorders. Illustrative examples of suitable imidazopyridine compounds for use in the present invention are zolpidem, alpidem, their pharmaceutically acceptable salts, their analogues and their derivatives. These imidazopyridine compounds have an imidazopyridine group, as shown below: Zolpidem Alpidem

[0096] For the imidazopyridine compounds, the nitrogen in the imidazole portion of the bicyclic ring of the structure controls the extent of ionization and the degree of lipophilicity in a given medium. Typically the nitrogen in the imidazole portion imparts a pKa from about 6.8 to about 7.5 to the molecule. Therefore, using the above formula, it can be shown that about 90% conversion to a non-ionized form can be achieved for these compounds at a pH from about 7.8 to about 8.5.

[0097] Illustrative examples of suitable dihydropyrrolopyrazine compounds for use in the present invention are zopeclon, its pharmaceutically acceptable salts, its analogs and its derivatives. These dihydropyrrolopyrazines each have a dihydropyrrolopyrazine group as shown below: Zopeclon

[0098] Illustrative examples of pyrazolopyrimidine compounds suitable for use in the present invention are zaleplon, indiplon, their pharmaceutically acceptable salts, their analogues and their derivatives. These pyrazolopyrimidines each have a pyrazolopyrimidine group, as shown below: Zaleplon Indiplon

[0099] For the pyrazolopyrimidine compounds, the nitrogen in the pyrimidine group controls the extent of ionization and the degree of lipophilicity in any given medium. Typically, the nitrogen in the pyrimidine group imparts a pKa from about 8 to about 9 to the molecule. Therefore, using the above formula, it can be shown that about 90% conversion to the non-ionized form can be achieved for these compounds at a pH from about 9 to about 10.

[0100] In general, "the hypnotic agents of the present invention act as benzodiazepine receptor agonists Preferably, hypnotic agents selectively bind to the benzodiazepine receptor.1 Without being bound by any particular theory, the therapeutic activity of the hypnotic agents of the present invention for treating sleep disorders is attributed to improvement of the inhibitory action of gamma-aminobutyric acid (GABA) in the central nervous system B. Shock absorber systems

[0101] The buffer systems of the compositions described herein are capable of raising the pH of saliva to a pH greater than about 7.8, independently of the initial pH of the saliva.This way, the buffer system helps to convert substantially all the hypnotic agent from its ionized form to its non-ionized form. Alternately, the buffer system helps to ensure that the hypnotic agent, initially in a non-ionized form, remains in a non-ionized form. Although basic damping agents are typically employed in the damping systems of the present invention, a person skilled in the art will appreciate that acidic agents can also be used to adjust the pH of the damping system as long as the damping system as a whole raises the pH of saliva at a pH greater than about 7.8.

[0102] In one embodiment, the present invention provides binary damping systems comprising a carbonate salt and a bicarbonate salt. The concentration of each component of the buffer system is adjusted to the extent, such that the final pH of the saliva is achieved and sustained for a period of time, for example by at least about 2 minutes, at least about 5 minutes, at less about 10 minutes, at least about 20 minutes, or at least about 60 minutes. This typically involves a trial and error sensory and security type procedure of adding various amounts of each component of the buffer system and then measuring the final pH over time. In this way, the selection of an appropriate weight ratio for each component of the buffer system can be easily determined in a few tests. For example, the weight ratio of carbonate salt to bicarbonate salt can be from about 1:10 to about 10: 1, preferably from about 1: 5 to about 5: 1, more preferably from about 1: 3 to about 3: 1, and even more preferably from about 1: 2 to about 2: 1.

[0103] The carbonate salt is generally chosen from sodium carbonate, potassium carbonate, calcium carbonate, ammonium carbonate and magnesium carbonate. Preferably, the carbonate salt is sodium carbonate or potassium carbonate. More preferably, the carbonate salt is sodium carbonate. Similarly, the bicarbonate salt is generally chosen from sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, ammonium bicarbonate, and magnesium bicarbonate. Preferably the bicarbonate salt is sodium bicarbonate or potassium bicarbonate. More preferably, the bicarbonate salt is sodium bicarbonate. In some embodiments, a sodium bicarbonate coated with desiccant is preferred. The amount of carbonate salt and bicarbonate salt used in the binary buffer system is an amount sufficient to raise the pH of the saliva to a pH of about 7.8 or more, preferably about 8.5 or more and more preferably 9 or more (eg, about 9-11), regardless of the starting pH.

[0104] In certain instances, the amount of bicarbonate salt is greater than or equal to the amount of carbonate salt, and the proportion by weight of carbonate salt to bicarbonate salt is from about 1: 1 to about 1:10, preferably from about 1: 1 to about 1: 5, and more preferably from about 1: 1 to about 1: 2, for example • 1: 1, 1: 1.1, 1: 1.2, 1: 1.3, 1: 1.4, 1: 1.5, 1: 1.6, 1: 1.7, 1: 1.8, 1: 1.9, or 1: 2. Alternatively, the amount of bicarbonate salt is less than or equal to the amount of carbonate salt, and the weight ratio of carbonate salt to bicarbonate salt is from about 1: 1 to about 10: 1, preferably about 1: 1 to about 5: 1, and more preferably from about 1: 1 to about 2: 1, for example 1: 1, 1.1: 1, 1.2: 1, 1.3: 1, 1.4: 1, 1.5: 1, 1.6: 1 , 1.7: 1, 1.8: 1, 1.9: 1, or 2: 1. In certain other instances, the combined amount of carbonate salt and bicarbonate salt is greater than or equal to the amount of the hypnotic agent, and the weight ratio of the carbonate salt and bicarbonate salt to hypnotic agent is preferably about 1: 1 to about 10: 1, for example, 1: 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, 9: 1, or 10: 1. Alternatively, the combined amount of carbonate salt and bicarbonate salt is less than or equal to the amount of the hypnotic agent, and the proportion by weight of carbonate salt and bicarbonate salt to hypnotic agent is preferably from about 1: 1 to about 1. : 10, for example 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 6, 1: 7, 1: 8, 1: 9, or 1:10.

[0105] In view of the above, the buffer systems of the present invention, in some of the most preferred embodiments, are binary buffer systems containing sodium carbonate and sodium bicarbonate.

[0106] Alternatively, in another embodiment, the damping systems of the present invention are binary damping systems comprising a carbonate salt or a bicarbonate salt and a second damping agent. The concentration of each buffer system component is adjusted to the extent such that the final pH of the saliva is achieved and sustained for a period of time, for example by at least 2 minutes, at least about 5 minutes, at least approximately 10 minutes, at least approximately 20 minutes, or at least approximately 60 minutes.

[0107] Suitable carbonate salts and bicarbonate salts were described above. The amount of carbonate salt or bicarbonate salt used in the binary buffer system is an amount that is sufficient, when employed with the second buffering agent, to raise the pH of the saliva to a pH of about 7.8 or more, preferably about 8.5. or more and more preferably about 9 or more (eg, about 9-11), regardless of the initial pH. In certain cases,. the amount of the second buffering agent in the binary buffer system is greater than or equal to the amount of the carbonate salt or bicarbonate salt. For example, the weight ratio of the second buffering agent to the carbonate salt or bicarbonate salt can be from about 1: 1 to about 10: 1, preferably from about 1: 1 to about 5: 1, and more preferably about 1 : 1 to about 3: 1. In certain other cases, the amount of the second buffering agent in a binary buffer system is less than or equal to the amount of the carbonate salt or bicarbonate salt. For example, the weight ratio of the second buffering agent to the carbonate salt or bicarbonate salt can be from about 1: 1 to about 1:10, preferably from about 1: 1 to about 1: 5, and more preferably about 1 : 1 to about 1: 3.

[0108] The second buffering agent is generally chosen from a metal oxide such as magnesium oxide or aluminum oxide; a citrate salt such as sodium citrate, potassium citrate, calcium citrate, magnesium citrate and ammonium citrate; a phosphate salt such as monobasic sodium phosphate, dibasic sodium phosphate, monobasic potassium phosphate, dibasic potassium phosphate, calcium phosphate monobasic, calcium phosphate dibasic, magnesium phosphate monobasic, magnesium phosphate dibasic, monobasic ammonium phosphate, and dibasic ammonium phosphate; a borate salt such as sodium borate, potassium borate, calcium borate, magnesium borate and ammonium borate; an ascorbate salt such as potassium ascorbate or sodium ascorbate; an acetate salt such as potassium acetate or sodium acetate; and alkaline starch. However, a person skilled in the art will appreciate that any metal oxide or citric acid salt, phosphoric acid, boric acid and ascorbic acid or acetic acid is suitable for use in the buffer systems of the present invention. The amount of the second buffering agent employed in the binary buffer system is an amount that is sufficient, when employed with the carbonate salt or bicarbonate salt, to raise the pH of the saliva to a pH of about 7.8 or more, preferably about 8.5. or more and more preferable about 9 or more (eg about 9-11), regardless of the initial pH. In some embodiments, a metal oxide such as magnesium oxide or aluminum oxide is the second preferred buffering agent. In a particularly preferred embodiment, the metal oxide is an amorphous magnesium oxide.

[0109] Alternatively, still in another embodiment, the buffer systems of the present invention are binary buffer systems comprising a metal oxide and a citrate, phosphate, or borate salt. The concentration of each component of the buffer system is adjusted to the extent such that the final pH of the saliva is achieved and sustained for a period of time, for example by at least about 2 minutes, at least about 5 minutes, at least about 10 minutes, at least about 20 minutes, or at least about 60 minutes.

[0110] Suitable metal oxides include, without limitation, magnesium oxide and aluminum oxide. Suitable citrate, phosphate and borate salts include, without limitation, essentially any salt of citric acid, phosphoric acid or boric acid known in the art such as those described above. In certain instances, the binary buffer system comprises a metal oxide and a citrate salt. In certain other instances, the binary buffer system comprises a metal oxide and a phosphate salt. In additional instances, the binary buffer system comprises a metal oxide and a borate salt. The amount of the metal oxide used in the binary buffer system is an amount that is sufficient, when employed with the citrate, phosphate or borate salt, to raise the pH of the saliva or a pH of about 7.8 or more, preferably about 8.5 or more and more preferably about 9 or more (eg, about 9-11), regardless of the initial pH. Similarly, the amount of the citrate, phosphate or borate salt used in the binary buffer system is an amount which is sufficient, when employed with the metal oxide, to raise the pH of the saliva to a pH of about 7.8 or more, preferably about 8.5 or more and more preferable about 9 or more (for example about 9-11), regardless of the initial pH.

[0111] In certain cases, the amount of the metal oxide in the binary buffer system is greater than or equal to the amount of the citrate, phosphate or borate salt. For example, the weight ratio of the metal oxide to the citrate, phosphate or borate salt may be from about 1: 1 to about 10: 1, preferably from about 1: 1 to about 5: 1, and more preferably from about 1: 1 to approximately 3: 1. In certain other cases, the amount of the metal oxide in the binary buffer system is less than or equal to the amount of the citrate, phosphate or borate salt. For example, the weight ratio of the metal oxide to the citrate, phosphate or borate salt can be from about 1: 1 to about 1:10, preferably from about 1: 1 to about 1: 5, and more preferably from about "1: 1 to about 1: 3.

[0112] Alternatively, in yet another embodiment, the damping systems of the present invention are ternary damping systems comprising a carbonate salt, a bicarbonate salt and a third buffering agent. The concentration of each component of the buffer system is adjusted to the extent such that the final pH of saliva is achieved and sustained for a period of time, for example by at least about 2 minutes, at least about 5 minutes, at least about 10 minutes, at least approximately 20 minutes or at least approximately 60 minutes. The procedure described above for determining an appropriate weight ratio for each component of the buffer system can also be applied to ternary damping systems.

[0113] Suitable carbonate salts and bicarbonate salts were described above. The amount of carbonate salt and bicarbonate salt used in the ternary buffer system is an amount that is sufficient, when employed with the third buffering agent to raise the pH of saliva to a pH of about 7.8 or more, preferably about 8.5 or more. , and more preferably about 9 or more (eg, about 9-11), "regardless of the initial pH.

[0114] The third buffering agent is generally chosen from a metal oxide, a citrate salt, a phosphate salt, a salt borate and an ascorbate salt such as potassium ascorbate or sodium ascorbate, an acetate salt such as potassium acetate or sodium acetate, and alkali starch Suitable metal oxides include, without limitation, magnesium oxide and aluminum oxide. Suitable citrate, phosphate and borate include, without limitation, any salt of citric acid, phosphoric acid or boric acid known in the art such as those described above. The amount of the third buffering agent employed in the ternary buffer system is an amount that is sufficient, when employed with the remaining components, to raise the pH of the saliva or a pH of about 7.8 or more, preferably about 8.5 or more and more. preferably about 9 or more (for example about 9-11), regardless of the initial pH. In some embodiments, a metal oxide such as magnesium oxide or aluminum oxide is the third preferred buffering agent. In a particularly preferred embodiment, the metal oxide is amorphous magnesium oxide.

[0115] In certain cases, the amount of the carbonate salt or bicarbonate salt in the ternary buffer system is greater than or equal to the amount of the third buffering agent. For example, the weight ratio of the carbonate salt or bicarbonate salt to the third buffering agent may be from about 1: 1 to about 10: 1, preferably from about 1: 1 to about 5: 1, and more preferably about 1 : 1 to about 3: 1. In certain other instances, the amount of the carbonate salt or bicarbonate salt in the ternary buffer system is less than or equal to the amount of the third buffer agent. For example, the weight ratio of the carbonate salt or bicarbonate salt to the third buffering agent can be from about 1: 1 to about 1:10, preferably from about 1: 1 to about 1: 5, and more preferably about 1 : 1 to about 1: 3.

[0116] The ternary buffer systems of the present invention, in some of the most preferred embodiments, contain sodium carbonate, sodium bicarbonate and amorphous magnesium oxide. In certain instances, the amount of sodium bicarbonate is greater than or equal to the amount of sodium carbonate. For example, the weight ratio of sodium bicarbonate to sodium carbonate can be from about 1: 1 to about 10: 1, preferably from about 1: 1 to about 5: 1, and more preferably from about 1: 1 to approximately 3: 1. In certain other instances, the amount of amorphous magnesium oxide is greater than or equal to the combined amount of sodium carbonate and sodium bicarbonate. For example, the weight ratio of amorphous magnesium oxide to sodium carbonate and sodium bicarbonate, may be from about 1: 1 to about 10: 1, preferably from about 1: 1 to about 5: 1, and more preferably from about 1: 1 to about 3: 1.

[0117] Alternatively, in a further embodiment, the damping systems of the present invention are damping systems comprising a carbonate salt or a bicarbonate salt and two or more damping agents selected from the group consisting of metal oxide, a citrate salt , a phosphate salt and a borate salt. The concentration of each component of the buffer system is adjusted to the extent, such that the final pH of the saliva is achieved and sustained for a period of time, for example by at least about 2 minutes, at least about 5 minutes, at less about 10 minutes, at least about 20 minutes or at least about 60 minutes.

[0118] Suitable carbonate salts and bicarbonate salts were described above. The amount of carbonate salt or bicarbonate salt used in the buffer system is an amount which is sufficient, when employed with the remaining components, to raise the pH of the saliva to a pH of about 7.8 or more, preferably about 8.5 or more. and more preferably about 9 or more (for example about 9-11), regardless of the starting pH.

[0119] The two or more buffering agents are generally chosen from a metal oxide, a citrate salt, a phosphate salt, a borate salt, an ascorbate salt, an acetate salt and an alkaline starch. Convenient metal oxides include, without limitation, magnesium oxide and aluminum oxide. Suitable citrate, phosphate, borate, ascorbate and acetate salts include, without limitation, essentially any salt of citric acid, phosphoric acid, boric acid, ascorbic acid or acetic acid known in the art such as those described above. The amount of additional buffering agents employed in the buffer system is an amount that is sufficient, when employed with the carbonate salt or bicarbonate salt, to raise the pH of saliva to a pH of about 7.8 or more, preferably about 8.5 or more. more and more preferable of about 9 or more (eg, about 9-11), regardless of the initial pH.

[0120] In certain instances, the buffer system comprises a carbonate salt or a bicarbonate salt, a metal oxide and a citrate, phosphate or borate salt. In certain other instances, the buffer system comprises a carbonate salt or a bicarbonate salt, a citrate salt and a phosphate salt. In certain instances, the buffer system comprises a carbonate salt or a bicarbonate salt, a citrate salt and a borate salt. In certain other instances, the buffer system comprises a carbonate salt or a bicarbonate salt, a phosphate salt and a borate salt. Preferably, the metal oxide is amorphous magnesium oxide.

[0121] In certain instances, the amount of carbonate salt or bicarbonate salt in the buffer system is greater than or equal to the amount of the metal oxide or the citrate, phosphate or borate salt. For example, the weight ratio of the carbonate salt or bicarbonate salt to the metal oxide or the citrate, phosphate, or borate salt may be from about 1: 1 to about 10: 1, preferably from about 1: 1 to about 5. : 1, and more preferably from about 1: 1 to about 3: 1. In certain other instances, the amount of the carbonate salt or bicarbonate salt in the buffer system is less than or equal to the amount of the metal oxide or the citrate, phosphate or borate salt. For example, the weight ratio of the carbonate salt or bicarbonate salt to the metal oxide or the citrate, phosphate or borate salt may be from about 1: 1 to about 1:10, preferably from about 1: 1 to about 1: 5, and more preferably from about 1: 1 to about 1: 3.

[0122] While the previous discussion has focused on the ability of the buffer system to alter the pH of saliva to favor substantial conversion to the non-ionized form of a therapeutic agent, it is conceivable that the buffer system may also have subsidiary beneficial effects on the extent of absorption through the oral mucosa. For example, the buffer system can create a final pH of the saliva which in turn affects the molecular configuration of the therapeutic agent in a form in which absorption through the oral mucosa is increased. It will be understood that these subsidiary beneficial effects of the damping system are within the general scope of the damping system and compositions described above. C. Dosage Forms

[0123] The compositions of the present invention can take the form of powder, solid, semi-solid, lyophilized powder or liquid dosage forms, such as for example tablets (eg, chewable, slow dissolving, of rapid dissolution), pills, capsules, pills, gums, powders, solutions, suspensions, emulsions, aerosols or the like. Preferably, the dosage form is a chewing gum, dissolution tablet, chewable tablet, candy or lozenge.

[0124] While each subject or patient possesses unique factors that may affect the rate and extent of absorption of the above-described therapeutic agents, dosage forms such as chewing gums, chewable tablets, dissolution tablets or tablets containing a buffer system described above, offer advantages over traditional dosage forms for oral administration (ie, Ambien ™). For example, each of these dosage forms avoids hepatic first pass metabolism, degradation within the gastrointestinal tract and drug loss during absorption. Consequently, the amount of therapeutic agent required per dose is less than that which will be rewarded if, for example, a pill or tablet for oral administration is formulated. Similarly, the bioavailability of the therapeutic agent is increased, thereby reducing the time to onset of therapeutic activity compared to traditional dosage forms for oral administration (see Example 5 below).

[0125] In addition, preferred dosage forms of the present invention (for example chewing gums, chewable tablets, dissolution tablets, lozenges) which contain a described buffer system offer advantages over dosage forms for oral mucosal administration which they do not contain the buffer system (ie the zolpidem FlashDose ™ tablet). Importantly, because the buffer system in the dosage forms of the present invention helps to substantially convert all of the therapeutic agent from its ionized form to its non-ionized form, the bioavailability of the therapeutic agent is increased, thereby reducing the time to initiate • the therapeutic activity in comparison with dosage forms for administration in oral mucosa which do not contain the buffer system. For example, the patent publication of the U.S.A. No. 2003/0165566 discloses that the zolpidem FlashDose ™ tablet administered orally has a pharmacokinetic profile similar to that observed for the orally administered tablet Ambien ™. As such, the zolpidem compositions of the present invention surpass both commercial tablet compositions by providing an increase in the bioavailability of zolpidem and a reduction in time to initiate therapeutic activity.

[0126] As agui is employed, the term "dosage form" refers to physically discrete units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined amount of therapeutic agent calculated to produce the desired onset, tolerability and therapeutic effects, in association with one or more pharmaceutically convenient excipients such as carriers. Methods for preparing these dosage forms are known or will be apparent to those skilled in the art. For example, in some embodiments, a dosage form of chewing gum of the present invention can be prepared according to the procedures set forth in US Pat. No. 4,405,647. In other embodiments, a tablet, lozenges or candy dosage form of the present invention can be prepared according to established procedures for example, in Remington: The Science and Practice of Pharmacy, 20th Ed., Lippincott, Williams & Wilkins (2003); Pharmaceutical Dosage Forms, Volume 1: Tahlets, 2nd Ed., Marcel Dekker, Inc., New York, N.Y. (1989); and similar publications. The dosage form to be administered in any event will contain an amount of the therapeutic agent in a therapeutically effective amount for relief of the condition to be treated when administered in accordance with the teachings of this invention.

[0127] As "agui" is employed, the term "carrier" refers to a typically inert substance employed as a diluent or carrier for a drug such as a therapeutic agent. The term also encompasses a typically inert substance that imparts cohesive qualities to the composition. Suitable carriers for use in the compositions of the present invention include, without limitation, a binder, a gum base, and combinations thereof. Non-limiting examples of binders include mannitol, sorbitol, xylitol, maltodextrin, lactose, dextrose, sucrose, glucose, inositol, powdered sugar, molasses, starch, cellulose, microcrostatin cellulose, polyvinylpyrrolidone, acacia gum, guar gum, gum tragacanth, alginate, Irish moss extract, panwar gum, ghatti gum, isapol shell mucilage, Veegum ™, larch arabogalactan, gelatin, methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, polyacrylic acid (eg Carbopol), calcium silicate, calcium phosphate, phosphate dicalcium, calcium sulfate, kaolin, sodium chloride, polyethylene glycol and combinations thereof. These binders can be pre-processed to improve their taste by methods known in the art such as freeze drying (see, eg, Fundamentalsof Freeze-Drying, Pharm. Biotechnol., 14: 281-360 (2002); Lyophililization of Unit Dose Pharmaceutical Dosage For s, Drug, Dev. Jnd. Pharm., 29: 595-602 (2003)); preparation of solid solution (see, for example, U.S. Patent No. 6,264,987); and sprinkling lubricant and wet granulation preparation with a convenient lubricating agent (see for example Remington: The Science and Practice of Pharmacy, supra). For example, MannogemX and Sorbogem ™, sold by SPI Pharma Group (New Castle, DE), are mannitol-free frozen processed forms of sorbitol and sorbitol, respectively. Typically, the compositions of the present invention comprise from about 25% to about 90% by weight of the binder and preferably from about 50% to about 80%. However, a person skilled in the art will appreciate that the compositions of the present invention can be made without binders, for example to produce a highly friable dosage form.

[0128] Non-limiting examples of base gums include materials selected from the many water-insoluble and saliva-insoluble gum base materials known in the art. For example, in some cases, the gum base comprises at least one hydrophobic polymer and at least one hydrophilic polymer. Non-limiting examples of suitable hydrophobic and hydrophilic polymers for the base gums include both natural and synthetic polymers such as elastomers, rubbers and their combinations. Examples of suitable natural polymers include, without limitation, plant-origin substances such as chewing gum, gelutong, gutta percha, crown gum and combinations thereof. Examples of suitable synthetic polymers include elastomers such as butadiene-styrene copolymers, isobutylene and isoprene copolymers (eg "butyl rubber"), polyethylene, polyisobutylene, polyvinyl ester (eg, polyvinyl acetate and polyvinyl acetate phthalate), and combinations thereof . In other cases, the gum base comprises a mixture of butyl rubber (ie, copolymer of isobutylene and isoprene), polyisobutylene and optionally polyvinylacetate (eg, having a molecular weight of about 12,000). Typically, the gum base comprises from about 25% to about 75% by weight of these polymers, and preferably from about 30% to about 60%.

[0129] The compositions of the present invention may additionally include lubricating agents; wetting agents; emulsifying agents; solubilizing agents; suspension agents; preservatives such as methyl-, ethyl- and propyl-hydroxybenzoates, butylated hydroxytoluene and butylated hydroxyanisole; sweetening agents; flavoring agents; coloring agents; and disintegrating agents (i.e., dissolution agents) such as crospovidone as well as croscarmellose sodium and other interlaced cellulose polymers.

[0130] Lubricating agents can be used to prevent adhesion of the dosage form to the surface of the dies and punches, and to reduce inter-particle friction. Lubricating agents can also facilitate the ejection of the dosage form from the matrix cavity and improve the granulation flow rate during processing. Examples of suitable lubricating agents include without limitation, magnesium stearate, calcium stearate, zinc stearate, stearic acid, simethicone, silicon dioxide, talc, hydrogenated vegetable oil, polyethylene glycol, mineral oil and combinations thereof. The compositions of the present invention may comprise from about 0% to about 10% by weight of the lubricating agent and preferably from about 1% to about 5%.

[0131] Sweetening agents can be used to improve the palatal taste of the composition, by masking any unpleasant flavors that it may have. Examples of suitable sweetening agents include, without limitation, compounds selected from the family of saccharides such as mono-, di-, tri-, poly-, and oligosaccharides; sugars such as sucrose, glucose (corn syrup), dextrose, invert sugar, fructose, maltodextrin and polydextrose; saccharin and its salts such as sodium and calcium salts; cyclamic acids and their salts; dipeptide sweeteners; chlorinated sugar derivatives such as sucaralose and dihydrochalcone; sugar alcohols such as sorbitol, sorbitol syrup, mannitol, xylitol, hexa-resorcinol and the like and combinations thereof. Hydrolyzed hydrogenated starch, and the potassium, calcium and sodium salts of 3,6-dihydro-6-methyl-1-1,2,3-oxathiazin-4-one-2,2-dioxide can also be used. Of the foregoing, sorbitol, mannitol and xylitol, either alone or in combination, are preferred sweetening agents. The compositions of the present invention may comprise from about 0% to about 80% by weight of the sweetening agent, preferably from about 5% to about 75%, and more preferably from about 25% to about 50%.

[0132] Flavoring agents can also be used to improve the palatal taste of the composition. Examples of suitable flavoring agents include, without limitation, natural and / or synthetic (ie, artificial) compounds such as peppermint, spearmint or spearmint, wintergreen, cinnamon, menthol, cherry, strawberry, watermelon, grape, banana, peach, raspberry , lemon, grapefruit, orange, plum, apple, fruit punch, passion fruit, chocolate (for example white, milk, dark), vanilla, caramel, coffee, hazelnut, their combinations and similar. Coloring agents can be used to impart color code to the composition, for example indicating the type and dosage of the therapeutic agent. Suitable coloring agents include, without limitation, natural and / or artificial compounds such as FD & C, concentrates of natural juices, pigments such as titanium oxide, silicon dioxide, and zinc oxide, their combinations and the like. The compositions of the present invention may comprise from about 0% to about 10% by weight of the flavoring and / or coloring agent, preferably from about 0.1% to about 5%, and more preferably from about 2% to about 3%. 1. Chewing Gums

[0133] When the dosage form is a chewing gum, the compositions of the present invention comprise a hypnotic agent or its pharmaceutically acceptable salt, a carrier such as a gum base, a binary or ternary buffer system and optionally a protective agent. The chewing gum composition may further comprise lubricating agents, wetting agents, emulsifying agents, solubilizing agents; suspending agents, preservatives, sweetening agents, flavoring agents and coloring agents. Typically, the chewing gum composition comprises from about 0.001% to about 10.0% by weight of the hypnotic agent (in any selected form, measured according to its free base form), more typically from about 0.01% to about 5.0%, and even more typically from about 0.1% to about 3.0%. A person skilled in the art understands that the above percentages will vary depending on the particular source of hypnotic agent employed, the amount of hypnotic agent desired in the final formulation, as well as the particular release rate of the desired hypnotic agent. The binary or ternary buffer system of the chewing gum composition provides a final pH of the saliva exceeding at least about 7.8, preferably at least about 8.5, and more preferably at least about 9 (e.g., approximately 9-11). The chewing gum composition typically comprises from about 20% to about 95% of the gum base, more typically from about 30% to about 85%, and more typically from about 50% to about 70% of the gum base.

[0134] The chewing gum composition may further comprise a protective agent. The protective agent covers at least a portion of the therapeutic agent, typically by mixing the two agents. The protection agent can be mixed with the therapeutic agent in a proportion of from about 0.1 to about 100 by weight, preferably in a ratio of from about 1 to about 50, and more preferably in a ratio of about 1 to about 10. Without being bound With no particular theory, the protective agent reduces adhesion between the therapeutic agent and the gum base so that the therapeutic agent can be more easily released from the gum base. In this manner, the therapeutic agent can be delivered through the mucous membranes of the oral cavity within about 5 to about 20 minutes of chewing, preferably between about 10 minutes of chewing. A variety of different protection agents can be used. Examples of suitable protective agents include without limitation, calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmito stearate, hydrogenated castor oil, hydrogenated vegetable oil type I, light mineral oil, magnesium lauryl sulfate, magnesium stearate, mineral oil, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulfate, stearic acid, cape-sil, talc, zinc stearate and combinations thereof.

[0135] The gum base may additionally include plasticizers such as softeners or emulsifiers. These plasticizers, for example, can help reduce the viscosity of the gum base in a convenient consistency and improve its texture and sting or penetrating power. The plasticizers can also facilitate the release of the therapeutic agent when chewing. Non-limiting examples of plasticizers include lecithin, mono- and diglycerides, lanolin, stearic acid, sodium stearate, potassium stearate, glycerol triacetate, glycerol monostearate, glycerin, and combinations thereof. The gum base typically comprises from about 0% to about 20% by weight of the plasticizer and more typically from about 5% to about 15%.

[0136] The gum base may further comprise waxes such as beeswax and microcrystalline wax, fats or oils such as soybean and cottonseed oil, and combinations thereof. Typically, the gum base comprises from about 0% to about 25% by weight of these waxes and oils, and more typically comprises from about 15% to about 20%.

[0137] Additionally, the base gum may further comprise one or more elastomeric solvents such as turpentine resins and resins. Non-limiting examples of these solvents include methyl, glycerol and pentaerythritol turpentine resin esters, modified turpentine resins such as hydrogenated, dimerized or polymerized turpentine resins or their combinations (eg, pentaerythritol ester of partially hydrogenated wood turpentine resin, pentaerythritol ester of wood turpentine resin, glycerol ester of wood turpentine resin, glycerol ester of turpentine resin partially dimerized, glycerol ester of polymerized turpentine resin, glycerol ester of talcum turpentine resin, glycerol ester of resin wood turpentine and partially hydrogenated wood turpentine resin and partially hydrogenated methyl ester of turpentine resin, such as alpha-pinene or beta-pinene polymers, terpene resins including polyterpene and combinations thereof). Typically, the gum base comprises from about 0% to about 75% of the elastomeric solvent and more typically less than about 10%.

[0138] The base gum may further comprise a filler material to improve the chewing ability of the final chewing gum composition. Fillers that are substantially unreactive with other components of the final chewing gum formulation are preferred. Examples of suitable fillers include, without limitation, calcium carbonate, magnesium silicate (ie talcum), dicalcium phosphate, metallic mineral salts (for example alumina, aluminum hydroxide and aluminum silicates), and combinations thereof.

Typically, the gum base comprises from about 0% to about 30% by weight of the filler and more typically from about 10% to about 20%.

[0139] A person skilled in the art will appreciate that the gum base does not require preparation from its individual components. For example, the gum base may be adhered to with the desired ingredients contained therein, and may be modified to include additional agents. Several manufacturers produce suitable base rubbers for use with the chewing gum compositions described. Examples of these base gums include without limitation Pharmagum ™ M, S, or C (SPI Pharma Group, New Castle, DE). In general, Pharmagum ™ comprises a mixture of gum base, sweetening agent, plasticizer, and sugar.

[0140] In certain cases, the chewing gum composition includes a center filled with therapeutic agent. A filled center may be particularly convenient when immediate release of the therapeutic agent is preferred. In addition, encapsulating the therapeutic agent in a filled center can help to mask any undesirable taste that the therapeutic agent may have. In these cases, the base gum surrounds, at least in part, a filled center. The filled center comprises at least one therapeutic agent or it can be a liguid or semi-solid material. The filled center material may be a synthetic polymer, a semi-synthetic, low-fat or fat-free polymer, and contains one or more sweetening agents, flavoring agents, coloring agents and / or flavoring agents. Preferably, the filled center includes a binary or ternary buffer system as described above. Methods for preparing a chewing gum with filled center are described, for example, in U.S. Pat. No. 3,806,290, which is hereby incorporated by reference in its entirety.

[0141] The chewing gum compositions can have any form, convenient size and texture. For example, the chewing gum may have the shape of a bar, tongue, bubble gum and the like. Similarly, the chewing gum can have any convenient color. For example, the chewing gum may have any shade of red, blue, green, orange, yellow, violet, indigo and mixtures thereof, and may have a color code to indicate the type and dosage of the therapeutic agent. The chewing gum can be individually wrapped or grouped into pieces for packing by methods well known in the art. 2. Tablets

[0142] When the dosage form is a tablet such as a dissolution tablet (i.e., disintegration tablet) or chewable tablet, the compositions of the present invention comprise a hypnotic agent or its pharmaceutically acceptable salt, a carrier such as a binder and a binary or ternary buffer system. The tablet composition may further comprise lubricating agents, wetting agents, emulsifying agents, solubilizing agents; suspending agents, preservatives, sweetening agents, flavoring agents, coloring agents and disintegrating agents. Typically, the tablet compositions of the present invention comprise from about 0.001% to about 10.0% by weight of the hypnotic agent (in any select form, measured as its free base form), and more typically from about 1.0% to about 5.0% . In some embodiments, approximately 4.0% by weight of the hypnotic agent is employed. A person skilled in the art understands that the above percentages will vary depending on the particular source of the hypnotic agent employed, the amount of the hypnotic agent desired in the final formulation, as well as the particular release rate of the desired hypnotic agent. The binary or ternary buffer system of the tablet composition provides a final pH of the saliva which exceeds at least about 7.8, preferably at least about 8.5 and more preferably at least about 9 (for example about 9-11).

[0143] In certain embodiments, the tablet is a dissolution tablet such as a slow dissolving or rapidly dissolving tablet, which is dissolved by the saliva of a subject, without need for chewing. For example, a dissolution tablet placed in the tongue of a subject can be used for buccal delivery of the therapeutic agent. Alternatively, a dissolution tablet placed below the subject's tongue can be used for sublingual delivery of the therapeutic agent. This type of dosage form may be particularly convenient for pediatric and geriatric patients, since both pegüenos and older individuals often have difficulty chewing certain items. Typically, the dissolution tablet is formulated to dissolve in about 1 to about 15 minutes, preferably within about 2 to about 10 minutes, for example, within about 2, 3, 4, 5, 6, 7, 8, 9 , or 10 minutes, after administration. A person skilled in the art will understand that fast dissolving tablets dissolve faster than slow dissolving tablets, which typically dissolve gradually rather than rapidly by the saliva of a subject. In a preferred embodiment, the slow dissolving or rapidly dissolving tablet delivers the therapeutic agent through the sublingual mucosa.

[0144] In certain other embodiments, the tablet is a chewable tablet that is chewed by a subject and formulated to dissolve either rapidly or gradually. For example, a chewable tablet placed in the tongue of a subject can be used for oral delivery of the therapeutic agent. During chewing, the chewable tablet can travel inside the mouth and sometimes park between the gums and cheeks or under the tongue. As a result, at least a portion of the therapeutic agent contained within a chewable tablet can also be delivered sublingually (i.e., through the sublingual mucosa). Typically, the chewable tablet is formulated to dissolve within about 1 to about 15 minutes, preferably about 2 to about 10 minutes, for example, within about 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes, after administration.

[0145] As described above, the dissolving and chewable tablets of the present invention are typically formulated to dissolve within about 1 to 15 minutes after administration. However, while these time frames are susceptible to maximum exposure of the therapeutic agent to the oral mucosa (e.g., sublingual and / or buccal mucosa), they are not always amenable to compliance by the user (e.g. users can swallow very frequently and therefore prevent maximum transmucosal absorption). Consequently, in certain cases, it may be convenient to achieve an equilibrium between compliance of the patient and maximum time of exposure of the therapeutic agent to the oral mucosa. This can be achieved, for example, by reducing the size of the tablet (for example from about 700-800 mg to about 200-300 mg) without reducing the concentration or amount per unit dose of the buffer system or the therapeutic agent. In addition, subtle changes to the tablet formulation such as for example replacement of one flavoring agent with another (eg chocolate for peppermint) or replacement of one binder or sweetening agent with another (eg lactose for mannitol or sorbitol) can be used to reduce salivation

[0146] The carrier present in the tablets of the present invention is typically a binder which is useful for maintaining the tablet in a semi-solid state, and it can be a solid or a solid, and for example it can be a waxy or fat material. high melting point. Suitable materials as binders are discussed in detail above and can be used alone or in combination in the tablet compositions of the present invention. In addition, binders such as mannitol, sorbitol, lactose, sucrose and inositol can impart properties to the tablet that allow or improve its disintegration in the mouth.

[0147] The tablet composition may further comprise a protective agent. The protective agent coats at least part of the therapeutic agent, typically by mixing the two agents. The protection agent can be mixed with the therapeutic agent in a proportion of from about 0.1 to about 100 by weight, preferably in a proportion from about 1 to about 50, and more preferably in a ratio of about 1 to about 10. Without being bound With no particular theory, the protective agent reduces the adhesion between the therapeutic agent and the binder so that the therapeutic agent can be more easily released from the binder. In this manner, the therapeutic agent can be delivered through the mucous membranes of the oral cavity within about 5 to about 20 minutes, preferably about 10 minutes. Suitable materials as protection agents are discussed in detail above and can be used alone or in combination in the tablet compositions of the present invention.

[0148] The tablet composition may also comprise one or more elastomeric solvents such as turpentine resins and resins. Non-limiting examples of these solvents are discussed in detail above and may be employed alone or in combination in the tablet compositions of the present invention. In addition, the tablet composition additionally may comprise waxes such as beeswax and microcrystalline wax, fats or oils such as soybean and cottonseed oil, and combinations thereof. Still further, the tablet composition may additionally include plasticizers such as softeners or emulsifiers. These plasticizers can, for example, help to reduce the viscosity of the solution of saliva from the dissolved board to a desirable consistency and improve its texture and sting or total penetration and help facilitate the release of the therapeutic agent. Non-limiting examples of these plasticizers are discussed in detail above and may be employed alone or in combination in the tablet compositions of the present invention.

[0149] In certain instances, the tablet composition includes a center filled with therapeutic agent. A filled center may be particularly convenient when immediate release of the therapeutic agent is preferred. In addition, encapsulating the therapeutic agent in a filled center can help to mask any undesirable taste that the therapeutic agent may have. In these cases, the binder encloses at least partially a filled center. The filled center comprises at least one therapeutic agent and can be a liquid or semi-liquid material. The filled center material may be a synthetic polymer, a polymer that is i-synthetic, low in fat or fat-free and contain one or more sweetening agents, flavoring agents, coloring agents and / or perfuming agents. Preferably, the filled center includes a binary or ternary buffer system as described herein.

[0150] In certain other cases, the tablet composition of the present invention has multiple layers. In this manner, the dissolving or chewable tablet can be designed to provide more than one therapeutic agent, for example two or more hypnotic agents or one or more hypnotic agents in combination with one or more non-hypnotic therapeutic agents. For example, with a two-layer tablet, the first layer contains a hypnotic agent and the second layer contains the same or different hypnotic agent or a non-hypnotic therapeutic agent. Typically, the first layer comprises the dissolvable or chewable portion of the tablet, and the second (ie, subsequent) layer is coated by the first layer. This type of formulation can be particularly convenient when immediate release of the hypnotic agent is convenient, followed by gastrointestinal absorption of a second therapeutic agent. Gastrointestinal absorption of the second therapeutic agent may be convenient for example to mitigate co-morbid symptoms or sustain the therapeutic benefit of the hypnotic agent in the solution or chewable portion of the tablet. In alternate form, the second layer is present in a side layer to the first layer. The second layer typically comprises at least one therapeutic agent, and may comprise one or more sweetening agents, flavoring agents, coloring agents and perfuming agents as described above. In some cases, the second layer also includes a binary or ternary buffer system as described herein.

[0151] In still other cases, the combination of hypnotic agents with or without non-hypnotic therapeutic agents does not require taking the form of a multilayer tablet, but instead comprises a simple homogeneous tablet layer. This type of formulation can also be used in the case where gastrointestinal absorption of at least one therapeutic agent is desired. In this case, the relative extent of ionization of the two or more therapeutic agents determines how they will be absorbed. For example, those therapeutic agents that are not ionized are absorbed through the oral mucosa, while the ionized agents are swallowed for gastrointestinal absorption.

[0152] The tablet compositions can have any desired shape, size and texture. For example, the tablet may be in the form of a bar, tab, granule, sphere and the like. Similary, the tablet can be of any convenient color. For example, the tablet may be of any shade of blue, green, orange, yellow, violet, indigo and mixtures thereof, and may have a color code to indicate the type and dosage of the therapeutic agent. The tablets may be individually wrapped or grouped together into pieces for packing by methods well known in the art. 3. Pills

[0153] When the dosage form is a pill or candy, the compositions of the present invention comprise a hypnotic agent or its pharmaceutically acceptable salt, a carrier such as a binder and a binary or ternary buffer system. The bar or sweet composition may further comprise lubricating agents, wetting agents, emulsifying agents, solubilizing agents, suspending agents, preserving agents, sweetening agents, flavoring agents, coloring agents and disintegrating agents. A general discussion of pills and sweets is provided for example in Pharmaceutical Dosage Forms, Volume 1: Tablets, 2nd Ed., MarcelDekker, Inc., New York, N.Y., pages 75-418 (1989). Typically, the tablet compositions of the present invention comprise from about 0.001% to about 10.0% by weight of the hypnotic agent (in any select form, measured according to its free base form), and more typically from about 1.0% to about 5.0% approximately. In some embodiments, approximately 4.5% by weight of the hypnotic agent is employed. A person skilled in the art understands that the above percentages will vary depending on the particular source of the hypnotic agent employed, the amount of the hypnotic agent desired in the final formulation as well as the particular release rate of the desired hypnotic agent. The binary or ternary buffer system of the tablet composition provides a final pH of the saliva which exceeds at least about 7.8, preferably at least about 8.5, and more preferably at least about 9 (eg, about 9-11).

[0154] In certain embodiments, the pill or sweet is dissolved by the saliva of a subject, without the need to chew. For example, a pill placed in the tongue of a subject can be used for oral delivery of the therapeutic agent. Alternatively, a pill placed below the subject's tongue can be used for sublingual delivery of the therapeutic agent. This type of dosage form may be particularly convenient for pediatric and geriatric patients, since children with pegues and elderly persons often have difficulty chewing certain items. Typically, the tablet is formulated to dissolve within about 1 to about 15 minutes, preferably between about 2 to about 10 minutes, for example within about 2, 3, 4, 5, 6, 7, 8, 9, or 10. minutes, after administration. In a preferred embodiment, the pill or candy supplies the therapeutic agent through the sublingual mucosa.

[0155] As described above, the tablets of the present invention are typically formulated to dissolve within approximately 1 to 15 minutes after administration. However, while these time frames are susceptible to maximum exposure of the therapeutic agent to the oral mucosa (for example to the sublingual and / or buccal mucosa), they are not always susceptible to compliance by the user (eg, users may swallow). very frequently and therefore prevent maximum transmucosal absorption). Consequently, in certain cases, it may be advisable to reach an equilibrium between compliance of the patient and maximum time of exposure of the therapeutic agent to the oral mucosa. This can be achieved for example by reducing the size of the tablet (for example from about 700-800 mg to about 200-300 mg) without reducing the concentration or amount per unit dose of the buffer system or the therapeutic agent. In addition, subtle changes to the formulation of pills such as for example replacing one flavoring agent with another (eg chocolate for peppermint) or replacing one binder or sweetening agent with another (eg lactose with mannitol or sorbitol) can be used to reduce salivation .

[0156] The carrier present in the tablets of the present invention is typically a binder which is useful for maintaining the tablet in a semi-solid state, and it can be a solid or liquid, and can be for example a waxy or high-point grease material. of fusion. Suitable materials as binders are discussed in detail above and can be used alone or in combination in the tablet compositions of the present invention. In addition, binders such as mannitol, sorbitol, lactose, sucrose and inositol can impart properties to the tablet that allow or improve its disintegration in the mouth.

[0157] The pill composition may further comprise a protective agent. The protective agent coats at least part of the therapeutic agent, typically by mixing the two agents. The protective agent can be mixed with the therapeutic agent in a proportion of from about 0.1% to about 100% by weight, preferably in the proportion of about 1% to about 50%, and more preferably in a proportion of about 1% to about 10%. %. Without being bound by any particular theory, the protective agent reduces the adhesion between the therapeutic agent and the binder so that the therapeutic agent can be more easily released from the binder. In this manner, the therapeutic agent can be delivered through the mucous membranes of the oral cavity within about 5 to about 20 minutes, preferably within about 10 minutes. Suitable materials as protective agents are discussed in detail above and may be employed alone or in combination in the tablet compositions of the present invention.

[0158] The pill composition may also comprise one or more elastomeric solvents such as turpentine and resin resins. Non-limiting examples of these solvents are discussed in detail above and may be employed alone or in combination in the tablet compositions of the present invention. further, the bar composition may additionally comprise waxes such as beeswax and microcrystalline wax, fats or oils such as soybean or cottonseed oil, and combinations thereof. Still further, the tablet composition may additionally include plasticizers such as softeners or emulsifiers. These plasticizers can, for example, help to reduce the viscosity of the saliva solution of the dissolved tablet to a convenient consistency and improve its texture and itching or penetration and help facilitate the release of the therapeutic agent. Non-limiting examples of these plasticizers are discussed in detail above and may be employed alone or in combination in the tablet compositions of the present invention.

[0159] In certain cases, the pill composition includes a center filled with therapeutic agent.

A filled center may be particularly convenient when immediate release of the therapeutic agent is preferred. In addition, encapsulating the therapeutic agent in a center fill can help in masking any undesirable taste that the therapeutic agent may have. In these cases, the binder encloses at least part of a filled center. The filled center comprises at least one therapeutic agent, and may be a solid or semi-solid material. The filled center material may be low fat or fat free and contain one or more sweetening agents, flavoring agents, coloring agents and / or perfuming agents. Preferably, the filled center includes a binary or ternary buffer system as described above.

[0160] In other certain cases, the tablet composition of the present invention has multiple layers. In this manner, the tablet can be designed to provide more than one therapeutic agent, for example two or more hypnotic agents or one or more hypnotic agents in combination with one or more non-hypnotic therapeutic agents. For example, with a bi-layer pill, the first layer contains a hypnotic agent and the second layer contains the same or different hypnotic agent or a non-hypnotic therapeutic agent. Typically, the first layer comprises the dissolution portion of the pellet and the second (ie, the subsequent) layer is coated with the first layer. This type of formulation can be particularly convenient when the immediate release of the hypnotic agent, followed by gastrointestinal absorption of a second therapeutic agent is convenient. Gastrointestinal absorption of the second therapeutic agent may be convenient, for example to mitigate co-morbid symptoms or to support the therapeutic benefit of the hypnotic agent in the dissolving portion of the tablet. In alternate form, the second layer is presented as a side layer to the first layer. The second layer typically comprises at least one therapeutic agent and may also comprise one or more sweetening agents, flavoring agents, coloring agents and perfuming agents as described above. In some cases, the second layer also includes a binary or ternary buffer system as described above.

[0161] In still other cases, the combination of hypnotic agents with or without non-hypnotic therapeutic agents does not require taking the form of a multilayer tablet, but on the contrary comprises a single layer of homogeneous tablet. This type of formulation can also be used in the case where the gastrointestinal absorption of at least one therapeutic agent is convenient. In this case, the relative extent of ionization of the two or more therapeutic agents determines how they will be absorbed. For example, those therapeutic agents that are not ionized are absorbed through the oral mucosa, while the ionized agents are swallowed for gastrointestinal absorption.

[0162] The tablet compositions may have any desired shape, size and texture. For example, the tablet may have the shape of a bar, tongue, granule, sphere and the like. Similarly, the tablet can be of any convenient color. For example, the tablet may be of any shade of blue, green, orange, yellow, violet, indigo and mixtures thereof, and may be color coded to indicate the type and dosage of the therapeutic agent. The tablets may be individually wrapped or grouped together into pieces for packing by methods well known in the art. D. Methods of Administration

[0163] The compositions of the present invention are useful in therapeutic applications, for example to treat a sleep disorder. Importantly, the compositions of the present invention provide rapid and predictable delivery of a hypnotic agent through the oral mucosa with surprisingly low inter-subject variability., in terms of maximum plasma concentration (Cmax) and the time to reach the maximum concentration in plasma (Tma) by raising the pH of the saliva to a pH greater than approximately 7.8, regardless of the initial pH of the saliva. In particular, the delivery of the therapeutic agent through the oral mucosa prevents hepatic first pass metabolism, degradation within the gastrointestinal tract and loss of the drug during absorption. As a result, the therapeutic agent reaches the systemic circulation in a substantially shorter period of time and at a substantially higher concentration than with traditional oral administration (e.g., tablets).

[0164] In addition, the compositions of the present invention offer advantages over compositions for administration of the oral mucosa which do not contain the above-described buffer system. In particular, because the buffer system in the compositions of the present invention helps to substantially convert all of the therapeutic agent from its ionized form to its non-ionized form, the therapeutic agent reaches the systemic circulation in a substantially shorter period of time ( for example by reducing the time of onset of therapeutic activity), and at a substantially higher concentration than with compositions for oral mucosal administration which do not contain the buffer system.

[0165] The compositions of the present invention have particular utility in the area of human and veterinary therapeutics. In general, administered doses will be effective to deliver picomolar to micromolar concentrations of the hypnotic agent to the appropriate site.

[0166] Administration of the compositions of the present invention is preferably carried out by any of the accepted modes of administration to the mucous membranes of the oral cavity. Examples of convenient sites of administration within the oral mucosa include, without limitation, the mucous membranes of the floor of the mouth (sublingual mucosa), the cheeks (buccal mucosa), the gums (gingival mucosa), the roof of the mouth (mucosa) of the palate), the lining of the lips and their combinations. These regions differ from each other regarding their anatomy, drug permeability, and physiological response to drugs. Preferably, the compositions of the present invention are administered to the sublingual mucosa, buccal mucosa or a combination thereof.

[0167] The oral mucosa, which has a rich blood supply and adequate drug permeability, is a particularly attractive route of administration for systemic drug delivery. In addition, the delivery of a therapeutic agent through the oral mucosa derives the metabolism of the first hepatic step, prevents enzymatic degradation within the gastrointestinal tract, and provides an enzymatic flora more suitable for absorption of the drug. As Agui is used, the term "sublingual supply" refers to the administration of a therapeutic agent through the mucous membranes that cover the floor of the mouth and / or the ventral tongue. The term "oral supply", as used herein, refers to the administration of a therapeutic agent through the mucous membranes that line the cheeks or cheekbones.

[0168] The oral mucosa is composed of an outermost layer of stratified squamous epithelium. Below this layer is a base membrane, that is, the lamina propria, followed by the submucosa as the innermost layer. The epithelium of the oral mucosa is similar to the stratified squamous epithelia that are found in the rest of the body since it contains a layer of mitotically active basal cells, which advances through a number of differentiating intermediate layers to the superficial layers, where the cells are detached from the surface of the epithelium (Gandhi et al., Ind. J. Pharm. Sci., 50: 145-152 (1988)). For example, the epithelium of the buccal mucosa has an approximate thickness of layers of 40-50 cells, whereas that of the sublingual epithelium contains a few fewer layers of cells. The epithelial cells increase in size and become flatter as they travel from the basal layers to the superficial layers.

[0169] The change time for buccal mucosal epithelium, estimated at 5-6 days, is represented by the time of change for the sublingual mucosal epithelium as well as other epithelia in the oral mucosa (Harris et al., J. Pharm Sci., 81: 1-10 (1992)). The thickness of the oral mucosa varies depending on the site in the oral cavity. For example, the buccal mucosa measures approximately 500-800 μm in thickness, while the soft and hard palate mucosa, the sublingual mucosa, the ventral tongue, and the gingival mucosa measure approximately 100-200 μm in thickness. The composition of the epithelium also varies depending on the site in the oral cavity. For example, the mucous membranes of areas subject to mechanical stress (ie, the gums and hard palate) are keratinized in a similar way to the epidermis. However, the mucous membranes of the soft palate, the sublingual region and the buccal region are not gueratinized (Harris et al., Supra). The geratinized epithelium contains neutral lipids such as ceramides and acylceramides, which have been associated with providing a barrier function. As a result, these epithelia are relatively impervious to water. In contrast, non-geratinized epithelia, such as sublingual and buccal epithelia, do not contain acylceramides and only have small amounts of ceramide (Wertz et al., Cri t Rev. Ther, Drug Carr. Sys., 8: 237-269 (1991); Sguier et al., J. Invest. Dermat., 96: 123-126 (1991); Sguier et al., In Oral Mucosal Drug Delivery, Ed. MJ Rathbone, Marcel Dekker, Inc., New York, New York, 1- 26 (1996)). Non-geratinized epithelia also contain small amounts of neutral but polar lipids, for example cholesterol sulfate and glucosyl ceramides. As such, these epithelia have been found to be considerably more permeable to water than keratinized epithelia (Harris et al, supra, Wertz et al., Supra, Squier et al., Supra, 1991).

[0170] In general, the oral mucosa is an epithelium that has some leakage or leakage between the epidermis and the intestinal mucosa. For example, the permeability of the buccal mucosa is estimated to be approximately 4-4000 times greater than that of the skin.

(Galey et al., J. Invest. Dermat., 67: 713-717 (1976)). The permeability of different regions of the oral mucosa generally decreases in the order of the sublingual mucosa greater than the oral mucosa, and the buccal mucosa greater than the mucosa of the palate (Harris et al., Supra). This permeability is generally based on the relative thickness and degree of gueratinization of these membranes, with the sublingual mucosa which is relatively thin and ungeatinized, the buccal mucosa which is thicker and not gueratinized, and the mucosa of the palate which is intermediate in thickness, but geratinized.

[0171] The epithelial cells of the oral mucosa are surrounded by baba which comprises primarily protein and carbohydrate complexes which may or may not be linked to certain regions of the cell surface. Baba may play a role in cell-cell adhesion, as well as acting as a lubricant, allowing the cells to move with each other (Tabak et al., J. "Oral Pathol., 11: 1-17 (1982)). In stratified squamous epithelia that are found elsewhere in the body, the slime is synthesized by specialized baba-secreting cells such as cup-shaped cells; however, in the oral mucosa, the slime is secreted by the major and minor salivary glands as part of the saliva (Tabak et al., supra; Rathbone et al., Adv. Drug Del. Rev., 13: 1-22 (1994 )). At physiological pH, the mucus network carries a negative charge due to sialic acid and sulfate residues present in carbohydrates. At this pH, the slime can form a strongly cohesive gel structure which bonds to the epithelial cell surface as a gelatinous layer (Gandhi et al., Supra). Without being bound by any particular theory, the buffer systems of the present invention neutralize the sialic acid residues present in the carbohydrates and prevent them from interacting with the therapeutic agent, thereby further improving the permeation to the drug.

[0172] Another characteristic of the environment of the oral cavity is the presence of saliva produced by salivary glands. Saliva is the protective fluid for all tissues of the oral cavity. Saliva is an aqueous fluid with approximately 1% organic and inorganic materials. The major determinant of the salivary composition is the flow rate, which in turn depends on factors such as the time of day, the type of stimulus and the degree of stimulus. The pH of the saliva is typically in a range of about 5.5 to about 7.0, depending on the flow rate. For example, with high flow costs, sodium and bicarbonate concentrations increase, which leads to an increase in pH. Because the volume of daily saliva is between about 0.5 to about 2 liters, the oral cavity provides an aqueous environment for the hydration and / or dissolution of the oral mucosa dosage forms of the present invention.

[0173] The sublingual mucosa is the most highly permeable region of the oral cavity, and provides rapid absorption and high bioavailability of a drug in a convenient, accessible and well-accepted route of administration (Harris et al., Supra). Suitable sublingual dosage forms include, without limitation, tablets (e.g., fast dissolving, slow dissolving), lozenges, candies, and soft gelatin capsules filled with a liquid drug. These systems create a very high drug concentration in the sublingual region before they are absorbed systemically through the sublingual mucosa. As a result, the sublingual mucosa is particularly well suited to produce a rapid onset of action, and sublingual dosage forms can be employed to deliver drugs with regurgitation from shorter delivery periods and / or less frequent dosing regimens. Aungue buccal mucosa is considerably less permeable than sublingual area, a rapid absorption and high bioavailability of a drug can be observed by oral administration. Suitable dosage forms of mouth include, without limitation, chewing gums, tablets (e.g., fast dissolving, slow dissolving), lozenges, sweet and the like. Both the buccal mucosa and the sublingual mucosa are far superior to the gastrointestinal tract to provide increased absorption and bioavailability of a drug.

[0174] To increase the permeability of drugs through the oral mucosa, penetration enhancers can be included in the dosage forms of the present invention. Penetration enhancers may be type that alters the nature of the oral mucosa to improve penetration, or of the type that alters the nature of the therapeutic agent to improve penetration through the oral mucosa. Suitable penetration enhancers include, without limitation, polyoxyethylene 23-lauryl ether, aprotin, azone, benzalkonium chloride, cetylpyridinium chloride, cetyltrimethylammonium bromide, cyclodextrin, dextran sulfate, lauric acid, propylene glycol, lysophosphatidylcholine, menthol, methoxysalicylate, methyl oleate, oleic acid, phosphatidylcholine, polyoxyethylene, polysorbate 80, sodium ethylenediaminetetraacetic acid ("EDTA"), sodium deoxycholate, sodium glycocholate, sodium glycodeoxycholate, sodium lauryl sulfate, sodium salicylate, sodium taurocholate, sodium taurodeoxycholate, as well as certain sulfoxides and glycosides and their combinations. IV. Examples

[0175] The following examples are offered to illustrate, but not to limit the claimed invention. Example 1. Zolpidem Membrane Test.

[0176] This example illustrates the beneficial effects of pH adjustment on membrane penetration for a zolpidem dosage form.

[0177] The effect of pH adjustment on the extent of ionization, and therefore the extent to which a therapeutic agent will travel the mucous membrane, can be demonstrated using a membrane assay; see, for example, Kansy et al., J. Med. Chem., 41: 1007-1010 (1998); and Avdeef, Curr. Topics Med. Chem., 1: 277-351 (2001). This assay uses a membrane coated with lipid to predict the penetration of lipid mucous membrane. The membrane apparatus consists of a dodecane membrane sandwiched between a donor and acceptor cell. The membrane coated with lipid is less porous than the mucous membrane of the oral cavity. In this way, the improvement seen in the membrane assay is very likely to amplify in vivo.

[0178] Membrane assays were performed using solutions of zolpidem tartrate at pH 5.8, 6.8 and 7.8. The alkaline pH values of 7.8 were adjusted using 0.01 M sodium carbonate / sodium bicarbonate buffer solution. The acidic pH of 5.8 is achieved using a 0.01 M acetate buffer solution (a mixture of sodium acetate and acetic acid). The neutral pH of 6.8 is achieved by adding 0.01 M acetate solution to the sodium bicarbonate / sodium carbonate buffer. Permeation through the membrane is measured by determining the concentration of zolpidem in the acceptor cell and is expressed as Pe (effective permeability in centimeters per second). As shown in Table 1 below, the effective permeability of zolpidem increases by more than 53% at a pH of 7.8 with respect to the pH of 6.8 and 129% relative to a pH of 5.8. Figure 1 shows a bar diagram illustrating the relationship between pH and membrane permeability of zolpidem. Table 1: Effective permeability (Pe) of zolpidem in a membrane assay. pH Pe (cm / s) 5.8 19.8 6.8 29.6 7.8 45.3 Example 2. Zolpidem Rubber Compositions.

[0179] This example illustrates zolpidem chewing gum compositions of the present invention.

[0180] Zolpidem can be formulated as a chewing gum composition as described above. In these embodiments, the unit dose or ration of the chewing gum comprises about 0.1 to about 100 milligrams (mg) of zolpidem (as measured in its tartrate salt form), preferably from about 1 to about 50 mg, and more preferable from about 2 to about 25 mg. In other embodiments, the unit dose comprises from about 2 to about 20 mg of zolpidem, preferably from about 5 to about 15 mg. Extra zolpidem, for example up to about 10% to about 25% by weight, can be added as "surplus" or as the amount that can be expected to be "washed by entrainment" and otherwise not released or absorbed during chewing.

[0181] In another embodiment, the unit dose or ration of the chewing gum comprises about 0.81 to about 42 mg of zolpidem in its base form, and more preferably from about 1.64 to about 20.5 mg. In other embodiments, the unit dose comprises from about 1.64 to about 16.4 mg of zolpidem in its free base form, preferably from about 1.64 to about 12.3 mg, and more preferably from about 1.64 to about 8.2 mg, for example about 1.64, 2.46, 3.28, 4.1, 4.92, 5.78, 6.56, 7.38 or 8.2 mg. In additional embodiments, the unit dose comprises a mixture of zolpidem in free base form and salt form (eg, zolpidem tartrate).

[0182] Given in percentages by weight, the chewing gum composition of zolpidem comprises from about 0.001% to about 10.0% zolpidem (in any select form, measured according to its free base form), preferably about 0.05. % to about 2.0% and more preferably from about 0.1% to about 1.0%. In some modalities, approximately 0.25% of zolpidem is used. A person skilled in the art understands that the above percentages will vary depending on the particular source of zolpidem employed, the amount of zolpidem desired in the final formulation as well as the particular release rate of the desired zolpidem. The buffer system of the zolpidem chewing gum composition provides a final pH of the saliva which exceeds at least about 7.8, preferably at least about 8.5 and more preferably at least about 9 (for example about 9-11).

[0183] A zolpidem chewing gum is made according to the following procedure. USP silicon dioxide (0.35 kg) is passed through a # 20 mesh screen and then loaded into a mixer containing 0.810 kg of USP granular mannitol and 9.569 kg of Pharmagum ™ C. The material is mixed for 10 minutes. Zolpidem tartrate EP (0.034 kg) is milled with silicon dioxide (0.02 kg) using a mortar and pestle. The remaining silicon dioxide, together with 0.228 kg of magnesium stearate, is added to the mortar while grinding continues. The ground materials are transferred to a plastic bag, and the mortar is rinsed using 0.01 kg of silicon dioxide, and transferred to the bag. The contents of the bag are mixed for five minutes.

[0184] Equal parts of the mixed bag contents and the mixed mannitol base gum mixture are formulated for an additional five minutes. This process is repeated until all the zolpidem and the base rubber mixture have been mixed together. Sodium carbonate (0.110 kg), sodium bicarbonate (0.570 kg), acacia gum (0.43 kg), xanthan gum (0.013 kg), and aspartame (0.072 kg) are loaded into the mixer along with natural and artificial flavors and mixed by ten minutes with 0.090 kg of silicon dioxide. The flavors employed were as follows: natural and artificial grape flavor S.D. (0.215 kg), natural and artificial cherry flavor (0.108 kg), natural and artificial fruit punch flavor S.D. (0.180 kg), natural cherry flavor WONF DURAROMEMR (0.215 kg), and natural passion fruit flavor DURAROMEMR (0.035 kg).

[0185] The mixture was passed through a # 12 mesh screen and then mixed for an additional 15 minutes. Magnesium stearate (0.114 kg) was passed through a # 20 mesh screen and added to the mixture and mixed for five minutes. The mixture is collected and placed in plastic bags. Two silica gel desiccant bags were placed around the plastic bags to absorb ambient moisture. The mixture was then compressed into tablets. By using the procedure described above, the average particle size of the drug (ie, zolpidem) in the chewing gum is approximately 20 microns, as compared to a typical average drug particle size from 75 to about 100 microns. In addition, the average particle size of the drug in the chewing gum is less than or equal to the average particle size of the carrier ingredients (eg, gum base, binders, etc.).

[0186] The zolpidem chewing gum composition of the present invention can be used, for example for insomnia treatment; see, Holm et al. , 'Drugs, 59: 865-889 (2000). In certain cases, after the introduction into the mouth of a portion with a portion size of the chewing gum composition, the subject chews the chewing gum as is normally done with any type of chewing gum without medication for about 5 to about 20 minutes, at about an average speed of 10 to about 45 chewed per minute. The rubber is then discarded.

[0187] A typical dosage form of the zolpidem chewing gum of the present invention is designed to produce an average plasma concentration of at least about 20 to about 300 nanograms of zolpidem per milliliter of plasma. For example, a 5 mg zolpidem chewing gum can be designed to produce an average peak plasma concentration in the range of from about 20 to about 100 nanograms of zolpidem per milliliter of plasma from about 5 minutes to about 2 hours. Similarly, a 10 mg zolpidem chewing gum can be designed to produce a peak plasma peak concentration in the range of from about 100 to about 300 nanograms of zolpidem per milliliter of plasma within about 5 minutes to about 2 hours.

[0188] The chewing gum compositions of the present invention provide a convenient, reliable, practical and painless system for delivering zolpidem through the oral mucosa. Notably, the chewing gum compositions are able to rapidly deliver zolpidem with low inter-subject variability in terms of maximum plasma concentration (Cmax) and the time to reach the maximum concentration in plasma (Tmax) such that an amount Therapeutically effective zolpidem enters the bloodstream within approximately 30 minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, or even within approximately 1-2 minutes after zolpidem is released from the carrier. Example 3. Compositions of Zolpidem Tablets.

[0189] This example illustrates the compositions of zolpidem tablets of slow dissolution, rapid dissolution and chewable of the present invention.

[0190] Zolpidem can be formulated as a tablet composition as described above. In these embodiments, the unit dose or ration of the tablet comprises from about 0.1 to about 100 milligrams (mg) of zolpidem (as measured in its tartrate salt form), preferably from about 1 to about 50 mg, and more preferably from about 2 to about 25 mg. In other embodiments, the unit dose comprises from about 2 to about 20 mg of zolpidem, preferably from about 2 to about 15 mg, and more preferably from about 2 to about 10 mg, eg, about 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg. In particularly preferred embodiments, the unit dose comprises a dose of zolpidem which is less than the dose typically employed in commercial oral tablets, but possesses comparable or greater bioavailability and initiation of therapeutic activity as well as lower absorption variability of the drug. In these embodiments, unit doses of from about 2 to about 5 mg of zolpidem are preferred, with unit doses of about 4 mg of zolpidem being particularly preferred. Extra zolpidem, for example, up to about 10% to about 25% by weight can be added as "surplus" or as the amount that can be expected to be "washed out" and otherwise not released or absorbed during dissolution and / or chewing the tablet.

[0191] In another embodiment, the unit dose or ration of the tablet comprises from about 0.81 to about 42 mg of zolpidem in its base form and more preferably from about 1.64 to about 20.5 mg. In other embodiments, the unit dose comprises from about 1.64 to about 16.4 mg of zolpidem in its free base form, preferably from about 1.64 to about 12.3 mg, and more preferably from about 1.64 to about 8.2 mg, e.g., about 1.64, 2.46, 3.28, 4.1, 4.92, 5.78, 6.56, 7.38, or 8.2 mg. In additional embodiments, the unit dose comprises a mixture of zolpidem in the free base form and salt form (eg, zolpidem tartrate).

[0192] Given in percentages by weight, the zolpidem tablet composition comprises from about 0.001% to about 10.0% zolpidem (in any selected form, measured according to its free base form), preferably from about 0.1% to about 8.0%, more preferably from about 1.0% to about 7.0%, and even more preferably from about 1.0% to about 5.0%. In some modalities, approximately 4.0% zolpidem is used. A person skilled in the art understands that the above percentages will vary depending on the particular source of zolpidem employed, the amount of zolpidem desired in the final formulation as well as the particular release rate of zolpidem desired. The buffer system of the zolpidem tablet composition provides a final pH of the saliva which exceeds at least about 7.8, preferably at least about 8.5 and more preferably at least about 9 (eg, about 9-11). Slow dissolving tablets of zolpidem:

[0193] A slow dissolving tablet of zolpidem was made according to the following procedure. Magnesium stearate USP (0.35 kg) was passed through a # 20 mesh screen, and then loaded into a mixer containing 0.810 kg of granular mannitol USP and 9.569 kg of sorbitol. The material was mixed for 10 minutes. Zolpidem tartrate EP (0.034 kg) was ground with magnesium stearate (0.02 kg) using a mortar and pestle. The remaining silicone dioxide, together with 0.228 kg magnesium stearate will be added in the mortar while continuing to grind. The ground materials are transferred to a plastic bag and the mortar is rinsed using 0.01 kg of silicon dioxide and transferred to the bag. The contents of the bag are then mixed for five minutes.

[0194] Equal parts of the mixed contents of the bag and the prepared mannitol mixture were mixed for an additional five minutes. This process is repeated until the entire mixture of zolpidem and mannitol was formulated together. Sodium carbonate (0.110 kg), sodium bicarbonate (0.570 kg), acacia gum (0.43 kg), xanthan gum (0.013 kg), and aspartame (0.072 kg) are loaded into the mixer with natural and artificial flavors and mixed for ten minutes with 0.090 kg of silicon dioxide. The flavors employed are as follows: natural and artificial grape flavor S.D. (0.215 kg), natural and artificial cherry flavor (0.108 kg), natural and artificial fruit punch flavor S.D. (0.180 kg), natural cherry flavor WONF DURAROME® (0.215 kg), and fruit-like flavor of natural passion DURAROME® (0.035 kg).

[0195] The mixture is passed through a # 12 mesh screen and then mixed for an additional 15 minutes. Magnesium stearate (0.114 kg) is passed through a # 20 mesh screen and added to the mixture and mixed for five minutes. The mixture is collected and placed in plastic bags. Two bags of silica gel blotters are placed around the plastic bags to absorb ambient moisture. The mixture after compresses into tablets. When using this procedure, the average particle size of the drug (ie, zolpidem) in the slow dissolving tablet is approximately 20 microns, as compared to a typical average drug particle size from about 75 to about 100 microns. In addition, the average particle size of the drug in the slow dissolving tablet is less than or equal to the average particle size of the carrier ingredients (eg, gum base, binders, etc.).

[0196] A second slow dissolving tablets of zolpidem is made according to the formulation shown in Table 2 and the following procedure. Three separate mixtures of silicon dioxide with zolpidem, sodium bicarbonate, and sodium carbonate; mannitol and sorbitol; and peppermint flavor, sucralose, stearic acid and magnesium stearate were prepared. The three mixtures were screened separately and mixed to form a single mixture. The simple mixture was then compressed into tablets after testing for uniformity of content. When using this procedure, the average particle size of the drug (ie, zolpidem) in the slow-dissolving tablet is approximately 20 microns, which is less than or equal to the average particle size of the carrier ingredients (e.g. gum base, binders, etc.). The unit weight for each tablet was 250 mg. The pH of the tablet was approximately 9.8 and remains stable. These tablets dissolve within approximately 10 minutes after sublingual administration. Table 2. Formulation of slow dissolving tablets of Zolpidem.

The batch quantity formulation produces 21,000 unit doses. Zolpidem Rapid Dissolving Tablets:

[0197] A zolpidem rapid dissolving tablet was made according to the following procedure. Mannitol (3,633 kg) and sorbitol (0.469 kg) were mixed for ten minutes. Sodium carbonate (0.330 kg), sodium bicarbonate (0.165 kg), natural mint flavor (0.125 kg), natural menthol flavor (0.025 kg) and sucralose (0.020 kg), are mixed separately for ten minutes. Magnesium stearate (0.075 kg), and zolpidem tartrate (0.034 kg) are mixed for ten minutes and then passed through a # 12 mesh screen. The prepared mixtures are then added together and compressed into tablets. When using this procedure, the average particle size of the drug (ie, zolpidem) in the fast-dissolving tablet is about 20 microns, compared to a typical average drug particle size from about 75 to about 100 microns. In addition, the average particle size of the drug in the fast-dissolving tablet is less than or equal to the average particle size of the carrier ingredients (eg, gum base, binders, etc.).

[0198] A second rapid dissolving tablet of zolpidem is made according to the formulation shown in Table 3 and the following procedure. Three separate mixtures of silicon dioxide with zolpidem, sodium carbonate, and sodium bicarbonate; mannitol and sorbitol; and polyethylene glycol, peppermint flavor, sucralose, magnesium stearate, crospovidone, and croscarmellose sodium were prepared. The three mixtures were screened separately and mixed to form a single mixture. The simple mixture is then compressed into tablets after testing for uniformity of content. When using this procedure, the average particle size of the drug (ie, zolpidem) in the fast-dissolving tablet is approximately 20 microns, which is less than or equal to the average particle size of the carrier ingredients (eg, gum). base, binders, etc.). The unit weight for each tablet was 250 mg. The pH of the tablets is approximately 9.8 and remains stable. These tablets dissolve in approximately 5 minutes after sublingual administration. Table 3. Formulation of fast dissolving tablets Zolpidem.

. The formulation of the batch quantity produces 21, 000 unit doses. Zolpidem chewable tablets:

[0199] A zolpidem chewable tablet is made according to the following procedure. Magnesium stearate USP (0.35 kg) is passed through a # 20 mesh screen, and then loaded into a mixer containing 0.810 kg of granular mannitol USP, 9.569 kg of sorbitol, and 0.020 kg of stearic acid. The material is mixed for 10 minutes. Zolpidem tartrate EP (0.034 kg) is milled with magnesium stearate (0.02 kg) using a mortar and pestle. The remaining silica dioxide together with 0.228 kg of magnesium stearate will be added to the mortar while continuing to grind. The milled materials were transferred in a plastic bag and the mortar is rinsed using 0.01 kg of silica dioxide and transferred to the bag. The contents of the bag are mixed for five minutes.

[0200] Equal parts of the mixed bag contents and the mixed mannitol mixture were mixed for an additional five minutes. This process is repeated until all the zolpidem and mannitol mixture has been mixed together. Sodium carbonate (0.110 kg), sodium bicarbonate (0.570 kg), acacia gum (0.43 kg), xanthan gum (0.013 kg), and aspartame (0.072 kg) are loaded into the mixer with natural and artificial flavors and mixed for ten minutes with 0.090 kg of silica dioxide. The flavors used are as follows: natural and artificial grape flavor S.D. (0.215 kg), natural and artificial cherry flavor (0.108 kg), natural and artificial fruit punch flavor S.D. (0.180 kg), natural cherry flavor WONF DURAROME® (0.215 kg), and fruit-like flavor of natural passion DURAROME® (0.035 kg).

[0201] The mixture is passed through a # 12 mesh screen and then mixed for an additional 15 minutes. Magnesium Stearate (0.114 kg) was passed through a # 20 mesh screen and added to the mixture and mixed for five minutes. The mixture is collected and placed in plastic bags. Two silica sachet bags are placed around the plastic bags to absorb ambient moisture. The mixture is then compressed into tablets. By using this procedure, the average particle size of the drug (ie, zolpidem) in the chewable tablet is about 20 microns, compared to a typical average drug particle size from about 75 to about 100 microns. In addition, the average particle size of the drug in the chewable tablet is less than or equal to the average particle size of the carrier ingredients (eg, gum base, binders, etc.).

[0202] The zolpidem tablet composition of the present invention can be used for example, for the treatment of insomnia. In certain cases, after the introduction of a chewable tablet in the mouth, the subject chews the chewable tablet as is normally done with any chewable tablet of the non-medicated type at an average speed of about 10 to about 45 chews per minute. In certain other cases, after the introduction of the dissolution tablet into the mouth, the subject holds the tablet under the tongue and either swallows while the tablet dissolves or swallows it after the tablet has dissolved.

[0203] A typical dose form of the zolpidem tablet of the present invention is designed to produce an average plasma concentration of at least about 20 to about 300 nanograms of zolpidem per milliliter of plasma. For example, a zolpidem tablet of 5 mg can be designed to produce a peak plasma concentration in the range of from about 20 to about 100 nanograms of zolpidem per milliliter of plasma within about 5 minutes to about 2 hours. Similarly, a 10 mg zolpidem tablet can be designed to produce an average peak plasma concentration in the range of from about 100 to about 300 nanograms of zolpidem per milliliter of plasma within about 5 minutes to about 2 hours.

[0204] The tablet compositions of the present invention a convenient system, reliable, practical and painless to supply zolpidem through the oral mucosa. Notably, the tablet compositions are capable of rapidly delivering zolpidem with low inter-subject variability in terms of maximum plasma concentration (Cmax) and the time to reach the maximum concentration in plasma (Tmax), such that a therapeutically Effective zolpidem enters the bloodstream within approximately 30 minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, or even within approximately 1 to 2 minutes after zolpidem is released from the carrier. Example 4. Compositions of zolpidem tablets.

[0205] This example illustrates the zolpidem tablet compositions of the present invention.

[0206] Zolpidem can be formulated as a pill or candy composition as described above. In these embodiments, the unit dose or ration of the tablet comprises from about 0.1 to about 100 milligrams (mg) of zolpidem (as measured in its tartrate salt form) preferably from about 1 to about 50 mg, and more preferably from about 2 to about 25 mg. In other embodiments, the unit dose comprises from about 2 to about 20 mg of zolpidem, preferably from about 2 to about 15 mg and more preferably from about 2 to about 10 mg, for example about 2, 3, 4, 5, 6 , 7, 8, 9, or 10 mg. In particularly preferred embodiments, the unit dose comprises a dose of zolpidem which is less than the dose typically employed in commercial oral tablets, but possesses comparable or greater bioavailability and initiation of therapeutic activity as well as less variability between subjects of drug absorption. In these embodiments, unit doses of from about 2 to about 5 mg of zolpidem are preferred, with unit doses of 4 mg of zolpidem which are particularly preferred. Extra zolpidem for example from about 10% to about 25% by weight can be added as "surplus" or as the amount that can be expected to be "washed by entrainment" and otherwise not released or absorbed during the dissolution and / or chewing of The pill.

[0207] In another embodiment, the unit dose or ration of the pellet comprises from about 0.81 to about 42 mg of zolpidem in its base form, and more preferably from about 1.64 to about 20.5 mg. In other embodiments, the unit dose comprises from about 1.64 to about 16.4 mg of zolpidem in its free base form, preferably from about 1.64 to about 12.3 mg, and more preferably from 1.64 to about 8.2 mg, for example about 3.28, 4.1. , 4.92, 5.78, 6.56, 7.38, or 8.2 mg. In additional embodiments, the unit dose comprises a mixture of zolpidem in free base form and in salt form (eg, zolpidem tartrate).

[0208] In percent by weight, the zolpidem tablet composition comprises from about 0.001% to about 10.0% zolpidem (in any select form, measured according to its free base form) preferably from about 0.1% to about 8.0%, more preferably from about 1.0% to about 7.0% and even more preferably from about 1.0% to about 5.5%. In some modalities, approximately 4.5% of zolpidem is used.

A person skilled in the art understands that the above percentages will vary depending on the particular source of zolpidem employed, the amount of zolpidem desired in the final formulation as well as the particular release rate of the desired zolpidem. The buffer system of the zolpidem tablet composition provides a final pH of the saliva which exceeds at least about 7.8, preferably at least about 8.5, and more preferably at least about 9 (eg about 9-11).

[0209] A zolpidem tablet is made according to the formulation shown in table 4 and the following procedure. Three separate mixtures of silicon dioxide with zolpidem, sodium carbonate and potassium bicarbonate; Pharmaburst; and peppermint flavor, sucralose, magnesium stearate and croscarmellose sodium, were prepared. The three mixtures were screened separately and mixed to form a single mixture. The mixture alone is then compressed into tablets after testing for uniformity of content. When using this method, the average particle size of the drug (i.e., zolpidem) in the tablet is approximately 20 microns, compared to a typical average drug particle size from about 75 to about 100 microns. In addition, the average particle size of the drug in the tablet is less than or equal to the average particle size of the carrier ingredients (eg gum base, binders, etc.). The unit weight for each tablet was 210 mg. The pH of the tablet was approximately 9.8 and remains stable. This tablet dissolves within approximately 2 or 3 minutes after sub-lingual administration. Table 4. Formulation of zolpidem tablet.

The batch quantity formulation produces 21,000 unit doses.

[0210] The zolpidem tablet composition of the present invention can be used for example for the treatment of insomnia. In certain cases, after the introduction of the pill into the mouth, the subject holds the pill under the tongue and passes saliva while the pill dissolves or swallows after the pill has dissolved. The tablets described above have a very fast dissolution rate and are capable of dissolving within about 2 or 3 minutes after sublingual administration.

[0211] A typical dosage form of the zolpidem pellet of the present invention is designed to produce an average plasma concentration of at least about 20 to about 300 nanograms of zolpidem per milliliter of plasma. For example, a 5 mg tablet of zolpidem can be designed to produce a maximum average plasma concentration in a range from about 20 to about 100 nanograms of zolpidem per milliliter of plasma within about 5 minutes to about 2 hours. Similarly, a 10 mg zolpidem pellet can be designed to produce a maximum or peak plasma concentration in the range of about 100 to 300 nanograms of zolpidem per milliliter of plasma within about 5 minutes to about 2 hours.

[0212] The tablet compositions of the present invention provide a convenient, reliable, practical and painless system for delivering zolpidem through the oral mucosa. Notably, the tablet compositions are capable of rapidly delivering zolpidem with low variability between subjects in terms of maximum plasma concentration (Cmax) and the time to reach the maximum concentration in plasma (Tmax), such that a therapeutically The effective amount of zolpidem enters the bloodstream within approximately 30 minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes or even within approximately 1 to 2 minutes after the zolpidem is released from the carrier. Example 5. Dissolution Profiles For Zolpidem Tablet and Tablet Compositions.

[0213] This example illustrates the average dissolution profiles for a zolpidem rapid dissolution tablet made according to Table 3 and a zolpidem pellet made according to Table 4.

[0214] The tested compositions were as follows. 1. Quick dissolution tablet of zolpidem (typically dissolves sub-lingually in approximately 5 minutes). 2. Zolpidem tablet (typically dissolves sub-lingually in approximately 2 to 3 minutes).

[0215] The experimental conditions were as follows. Method = USP Apparatus = USP Apparatus II Medium = Phosphate Buffer pH 6.8 Medium Volume = 500 ml Spindle speed = 25 rpm Temperature = 37 degrees C

[0216] Table 5 below shows the dissolution data and Figure 2 shows the average dissolution profiles for a rapid dissolving tablet of zolpidem and a zolpidem pellet of the present invention at 5, 10, 15, 20, and 30 minutes in phosphate buffer medium (pH 6.8). Table 5. Dissolution data for the zolpidem fast-dissolving tablet and zolpidem tablet.

^ -RSD = Relative Standard Deviation Example 6. Pharmacokinetic Studies of Zolpidem.

[0217] This example provides two studies illustrating the pharmacokinetic profile of the zolpidem tablet of the present invention compared to an equivivalent dose of commercial oral tablet. Zolpidem Sub-lingual Powder Tablet vs. Ambien Oral Tablet:

[0218] To evaluate the pharmacokinetic profile of a sub-lingually administered zolpidem formulation, a 10 mg zolpidem powder tablet buffered to a pH of 9.8 with 23 mg of Sodium bicarbonate and 17 mg sodium carbonate (formulation A) is determined in eight healthy subjects (5 men, 3 women). Formulation A is administered under the subject's tongue and had a very rapid dissolution rate, i.e., within about 1 to about 3 minutes. The study was an open label, fixed sequence pharmacokinetic study in which the subjects passed saliva at a rate of 2, 5 or 10 minutes in a period of 10 minutes of time ("swallowing time"). For example, a swallowing time of 2 minutes refers to swallowing saliva every 2 minutes in a period of 10 minutes (ie 5 blogs of 2 minutes each); a swallow time of 5 minutes refers to swallowing saliva every 5 minutes during a period of 10 minutes (ie 2 blogues of 5 minutes each); and a swallow time of 10 minutes refers to swallowing saliva every 10 minutes in a period of 10 minutes (ie a 10 minute blog). Serum blood samples were taken over a period of 8 hours and plasma was assayed for zolpidem levels, for example using high pressure liquefied chromatography (HPLC) - tandem mass spectrometry (MS).

[0219] Figures 3-5 show the plasma concentration in time in each subject for formulation A at the time of swallowing of 2, 5 and 10 minutes respectively. Tables 6 to 8 below show the values of the pharmacokinetic parameters determined in each subject for formulation A at swallow times of 2, 5 and 10 minutes, respectively.

Table 6. Pharmacokinetic parameters for formulation A at a time of 2 minutes swallowing.

Table 7. Pharmacokinetic parameters for formulation A at a time of swallowing of 5 minutes.

Table 8. Pharmacokinetic parameters for formulation A at a time of swallowing of 10 minutes.

[0220] The pharmacokinetic results obtained for Formulation A were compared with pharmacokinetic data obtained from the packaging insert and the literature for an equivalent dose of Ambien® oral tablet formulation (Formulation B). Figure 6 shows the average plasma concentration over time for formulation A (zolpidem sublingual powder tablet) at three different times of swallowing and for formulation B (peroral (PO) Ambien®) which is obtained from the literature ( Greenblatt et al., Clin. Pharmacol. Ther., 64: 553-561 (1998); Greenblatt et al., Clin. Pharmacol. Ther., 64: 661-671 (1998)). Table 9 below shows the average values for the pharmacokinetic parameters determined for formulation A at three different times of swallowing and for formulation B of the literature (Greenblatt et al., Clin.Pharmacol. Ther., 64: 553-561 (1998)).

Table 9. Pharmacokinetic parameters for formulation A and formulation B.

Values represent the average. The numbers in parentheses for Tmax represent the minimum and maximum values respectively. The numbers in parentheses for Cma? And AUC represent the coefficient of percent variation (CV%).

[0221] This study demonstrates that the zolpidem supply through the oral mucosa produces average plasma concentrations of zolpidem which were from about 45% to 67% higher than those observed for the commercial oral tablet during the 8-hour period after administration. In addition, peak plasma concentrations of zolpidem were reached within about 45 to about 70 minutes after sublingual administration while peak plasma zolpidem concentrations were not achieved up to 96 minutes (Ambien® package insert) or 102 minutes (Greenblatt et al. ., Clin. Pharmacol. Ther., 64: 553-561 (1998)) after oral tablet administration. As such, the present study shows that zolpidem from the sublingual powder tablet is rapidly absorbed and has substantially better bioavailability than the commercial oral tablet. The present study shows that the improvement in bioavailability depends on the time of swallowing.

[0222] Figure 7 shows the average plasma concentration over time for formulation A at 5 minute dose swallow times using data from all 8 subjects and the average plasma concentration over time for the A formulation on time of swallowing of 2 and 5 minutes excluding the data of subjects 3, 6 and 7 who apparently swallowed before their scheduled swallowing time. Table 10 below shows the average values for the pharmacokinetic parameters determined for formulation A using data from all subjects or excluding data from subjects 3, 6 and 7. When subjects who apparently do not comply with the study protocol, excluded from the analysis, peak concentrations of zolpidem in plasma for the remaining subjects were achieved within approximately 30 minutes instead of approximately 45 to approximately 70 minutes after sublingual administration. Table 10. Pharmacokinetic parameters for formulation A with all subjects excluding those previously swallowed.

The values represent the average. The numbers in parentheses for Tmax represent the minimum and maximum values respectively. The numbers in parentheses for Cmax and AUC represent the coefficient of percent variation (CV%).

[0223] Figure 8 is an expanded view of the first 90 minutes shown in Figure 6. In particular, Figure 8 illustrates the estimated time for onset of sleep in subjects taking Formulation A (left dotted line) in comparison with time for sleep onset in subjects taking formulation B (right dotted line). The average concentration of zolpiden in effective plasma to induce the onset of sleep is illustrated by the horizontal line in Figure 8. Table 11 below shows the time reported for sleep onset during the day in each subject taking formulation A at 3 different times of swallowing. Table 11. Diurnal sleep onset times reported for formulation A.

[0224] This study demonstrates that the onset of sleep for subjects who take the sublingual tablet at the zolpidene pole is substantially faster than that achieved with the commercial oral tablet. In fact, the onset of sleep for subjects taking the sublingual tablets in the present invention can be as early as within about 12.5 minutes after administration, which is more than three minutes faster than the onset of sleep for subjects who take the commercial oral tablet. A person skilled in the art will appreciate that the onset of sleep observed during the day corresponds to the onset of sleep at night.

[0225] In addition, the pharmacokinetic profiles for zolpidem administered sublingually provide a smoother, longer-lasting peak of zolpidem (see Figure 6), and in this way resemble a pharmacokinetic profile for zolpidem administered intravenously. As a result, this infusion-type pharmacokinetic profile is eguivalent to or even superior to the commercial oral tablet to reduce the time for onset of therapeutic activity, maintain sleep (for example, total sleep time, number of times awakened), quality improvement of sleep, elimination of the effect of food and reduction of residual effects the next morning. Slow Dissolving Sublingual Tablets and Rapid Dissolution of Zolpidem vs. Ambient Oral Tablet:

[0226] To further evaluate the pharmacokinetic profile of a zolpidem formulation administered sublingually, a slow dissolving tablet of zolpidem 10 mg is made according to Table 2 (Formulation C) and a zolpidem 10 mg fast dissolving tablet made according to Table 3 (formulation D) is compared with an equivivalent dose of Ambien® oral tablet formulation (Formulation B) in eight healthy subjects. Formulation C (Tablet SL) was administered under the subject's tongue and had a slow rate of dissolution, ie within about 10 minutes. Formulation D (Tablet FS) is administered under the subject's tongue and had a rapid dissolution rate ie, within about 5 minutes. Formulation B (PO Ambien) is administered perorally with 180 ml of water. The study was a three-day, fixed-sequence, three-day crossover pharmacokinetic study, in which subjects swallowed saliva at a rate of every two or five minutes over a 10-minute time period ("swallowing time") for Formulations C and D. Blood serum samples were collected over a period of 12 hours and plasma was assayed for zolpidem levels, for example using high pressure liquefied chromatography (HPLC) - tandem mass spectrometry (MS).

[0227] Figure 9 shows the average plasma concentration over time for formulation C (Tablet SL) at times of swallowing of 2 and 5 minutes and for formulation B (PO Ambien). Similarly, Figure 10 shows the average plasma concentration over time for Formulation D (Tablet FS) at times of swallowing of 2 and 5 minutes and for formulation B (PO Ambien). This study demonstrates that the supply of zolpidem through the oral mucosa produces peak zolpidem plasma contemplations in a substantially prior period of time and at a substantially higher level after sublingual administration than those observed for oral tablet administration. As such, the present study shows that the zolpidem of both dissolution tablets is rapidly absorbed and substantially better bioavailable than the commercial oral tablet. In addition, the onset of sleep for subjects who take either the zolpidem solution tablet is substantially faster than that achieved with the commercial oral tablet. The present study also shows that the improvement in bioavailability is independent of the time of swallowing and the formulation of the dissolution tablet.

[0228] All publications and patent applications explained in the agui specification are incorporated by reference as if each publication or individual patent application was specifically and individually indicated as incorporated by reference. Although the above invention has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be readily apparent to those skilled in the art in light of the teachings of this invention that certain changes and modifications may be made to it, without departing from the spirit or spirit of the appended claims.

Claims (1)

1. CLAIMS 1. A solid composition for delivery of a hypnotic agent through the oral mucosa, the composition is characterized by comprising: (a) a hypnotic agent selected from the group consisting of an imidazopyridine, a dihydropyrrolopyrazine, a pyrazolopyrimidine, and their salts pharmaceutically acceptable; (b) a carrier that provides complete buccal or sublingual disintegration in about 5 minutes or less after oral administration; Y (c) a binary buffer system comprising a carbonate salt or a bicarbonate salt, wherein the binary buffer system elevates the pH of the saliva to a pH greater than about 7.8, regardless of the initial pH of the saliva. 2. A composition according to claim 1, characterized in that the binary buffer system elevates the pH of the saliva to a pH greater than about 8.5, regardless of the initial pH of the saliva. 3. A composition according to claim 1, characterized in that the binary buffer system elevates the pH of the saliva to a pH greater than about 9, regardless of the initial pH of the saliva. . A composition according to claim 1, characterized in that the carrier provides complete buccal or sublingual disintegration in about 2 minutes or less after administration. 5. A composition according to claim 1, characterized in that the carrier comprises at least one binder and at least one disintegrating agent in a relative proportion to provide a buccal or sublingual disintegration time of about 5 minutes or less after administration. 6. A composition according to claim 5, characterized in that the ratio of the binder to the disintegrating agent is from about 0.26 to about 0.79. 7. A composition according to claim 5, characterized in that the binder is selected from the group consisting of a sugar, sugar alcohol, and combinations thereof. 8. A composition according to claim 5, characterized in that the sugar alcohol is selected from the group consisting of mannitol, sorbitol, xylitol, and combinations thereof. 9. A composition according to claim 1, characterized in that the imidazopyridine is selected from the group consisting of zolpidem and alpidem. 10. A composition according to claim 1, characterized in that the dihydropyrrolopyrazine is zopeclon. 11. A composition according to claim 1, characterized in that the pyrazolopyrimidine is selected from the group consisting of zaleplon and indiplon. 12. A composition according to claim 1, characterized in that the carbonate salt is selected from the group consisting of sodium carbonate and potassium carbonate. 13. A composition according to claim 1, characterized in that the bicarbonate salt is selected from the group consisting of sodium bicarbonate and potassium bicarbonate. 14. A composition according to claim 1, characterized in that the binary buffer system comprises sodium carbonate and sodium bicarbonate. 15. A composition according to claim 1, characterized in that the composition further comprises a sweetening agent, a flavoring agent, a protective agent, a plasticizer, a wax or elastomeric solvent, a filler, a preservative, a lubricating agent, an agent humectant, an emulsifying agent, a solubilizing agent, a suspending agent, a coloring agent, a disintegrating agent and combinations thereof. 16. A composition according to claim 1, characterized in that the composition is a dosage form selected from the group consisting of a tablet, a chewing gum, a chewable tablet, and a dissolution tablet. 17. A composition according to claim 1, characterized in that the oral mucosa is chosen from the group consisting of the sublingual mucosa, the buccal and mucosal mucosa, and their combinations. 18. A composition according to claim 1, characterized in that the average particle size of the hypnotic agent is less than or equal to the average particle size of the carrier. 19. A composition according to claim 1, characterized in that the hypnotic agent is zolpidem and the binary buffer system comprises sodium carbonate and sodium bicarbonate. 20. A composition according to claim 19, characterized in that the zolpidem is selected from the group consisting of its pharmaceutically acceptable salt, its free base and mixtures thereof. 21. A composition according to claim 19, characterized in that the composition is selected from the group consisting of a tablet and a dissolution tablet. 22. A composition, according to claim 21, characterized in that the composition is administered sublingually. 23. A composition according to claim 19, characterized in that the sodium bicarbonate is sodium bicarbonate coated with desiccant. 24. A composition according to claim 19, characterized in that the combined weight percent of sodium carbonate and sodium bicarbonate is greater than or equal to the weight percent of zolpidem. 25. A composition according to claim 24, characterized in that the composition comprises from about 1.0 to about 5.5 weight percent zolpidem; from about 6.0 to about 10.0 weight percent sodium carbonate; and from about 9.0 to about 13.0 weight percent of sodium bicarbonate coated with desiccant. 26. A composition according to claim 25, characterized in that the composition comprises about 4.5 weight percent zolpidem; of about 8.0 weight percent sodium carbonate; and about 11.0 weight percent of sodium bicarbonate coated with desiccant. 27. A composition according to claim 26, characterized in that the composition is a tablet. 28. A composition according to claim 27, characterized in that the weight of the tablet is from about 200 to about 300 mg. 29. A composition according to claim 24, characterized in that the composition comprises from about 1.0 to about 5.0 weight percent zolpidem; from about 5.0 to about 9.0 by weight of sodium carbonate; and from about 7.0 to about 11.0 by weight of sodium bicarbonate. 30. A composition according to claim 29, characterized in that the composition comprises about 4.0 weight percent zolpidem; about 7.0 weight of sodium carbonate; and about 9.0 by weight of sodium bicarbonate. 31. A composition according to claim 30, characterized in that the composition is a dissolution tablet. 32. A composition according to claim 31, characterized in that the dissolution tablet is selected from the group consisting of a slow dissolving tablet and a fast dissolving tablet. 33. A composition according to claim 31, characterized in that the weight of the dissolution tablet is from about 200 to about 300 mg. 34. A solid composition for delivery of a hypnotic agent through the oral mucosa, the composition is characterized by comprising: (a) a hypnotic agent selected from the group consisting of an imidazopyridine, a dihydropyrrolopyrazine, and pharmaceutically acceptable salts thereof; (b) a carrier; Y (c) a binary buffer system comprising a carbonate salt or a bicarbonate salt and a second buffer, wherein the binary buffer system elevates the pH of the saliva to a pH greater than about 7.8, regardless of the initial pH of the saliva. 35. A composition according to claim 34, characterized in that the binary buffer system elevates the pH of the saliva to a pH greater than about 8.5, regardless of the initial pH of the saliva. 36. A composition according to claim 34, characterized in that the binary buffer system elevates the pH of the saliva to a pH greater than about 9, regardless of the initial pH of the saliva. 37. A composition according to claim 34, characterized by the imidazopyridine is selected from the group consisting of zolpidem and alpidem. 38. A composition according to claim 34, characterized in that the dihydropyrrolopyrazine is zopeclon. 39. A composition according to claim 34, characterized in that the pyrazolopyrimidine is selected from the group consisting of zaleplon and indiplon. 40. A composition according to claim 34, characterized in that the carbonate salt is selected from the group consisting of sodium carbonate and potassium carbonate. 41. A composition according to claim 34, characterized in that the bicarbonate salt is selected from the group consisting of sodium bicarbonate and potassium bicarbonate. 42. A composition according to claim 34, characterized in that the second buffering agent is selected from the group consisting of a metal oxide, a citrate salt, a phosphate salt and a borate salt. 43. A composition according to claim 34, characterized in that the carrier is selected from the group consisting of a binder, a gum base and combinations thereof. 44. A composition according to claim 34, characterized in that the composition is a dosage form selected from the group consisting of a tablet, a chewing gum, a chewable tablet, and a dissolution tablet. 45. A composition according to claim 34, characterized in that the oral mucosa is selected from the group consisting of the sublingual mucosa, the buccal mucosa, and combinations thereof. 46. A composition according to claim 34, characterized in that the average particle size of the hypnotic agent is less than or equal to the average particle size of the carrier. 47. A composition according to claim 34, characterized in that the hypnotic agent is zolpidem and the binary buffer system comprises sodium carbonate or sodium bicarbonate and a second buffering agent. 48. A composition according to claim 47, characterized in that the composition is selected from the group consisting of a tablet and a dissolution tablet. 49. A composition according to claim 48, characterized in that the composition is administered sublingually. 50. A solid composition for delivery of a hypnotic agent through the oral mucosa, the composition is characterized by comprising: (a) a hypnotic agent selected from the group consisting of an imidazopyridine, a dihydropyrrolopyrazine, and pharmaceutically acceptable salts thereof; (b) a carrier; and (c) a binary buffer system comprising a metal oxide and a citrate, phosphate, or borate salt; wherein the binary buffer system elevates the pH of the saliva to a pH greater than about 7.8, regardless of the initial pH of the saliva. 51. A composition according to claim 50, characterized in that the binary buffer system elevates the pH of the saliva to a pH greater than about 8.5, regardless of the initial pH of the saliva. 52. A composition according to claim 50, characterized in that the binary buffer system elevates the pH of the saliva to a pH greater than about 9, regardless of the initial pH of the saliva. 53. A composition according to claim 50, characterized in that the imidazopyridine is selected from the group consisting of zolpidem and alpidem. 54. A composition according to claim 50, characterized in that the dihydropyrrolopyrazine is zopeclon. 55. A composition according to claim 50, characterized in that the pyrazolopyrimidine is selected from the group consisting of zaleplon and indiplon. 56. A composition according to claim 50, characterized in that the metal oxide is selected from the group consisting of magnesium oxide and aluminum oxide. 57. A composition according to claim 56, characterized in that the magnesium oxide is amorphous magnesium oxide. 58. A composition according to claim 50, characterized in that the citrate salt is selected from the group consisting of sodium citrate, potassium citrate, calcium citrate, magnesium citrate and ammonium citrate. 59. A composition according to claim 50, characterized in that the phosphate salt is selected from the group consisting of monobasic sodium phosphate, dibasic sodium phosphate, potassium phosphate monobasic, potassium phosphate dibasic, calcium phosphate monobasic, phosphate dibasic calcium, monobasic magnesium phosphate, dibasic magnesium phosphate, monobasic ammonium phosphate and dibasic ammonium phosphate. 60. A composition according to claim 50, characterized in that the borate salt is selected from the group consisting of sodium borate, potassium borate, calcium borate, magnesium borate and ammonium borate. 61. A composition according to claim 50, characterized in that the carrier is selected from the group consisting of a binder, a gum base and combinations thereof. 62. A composition according to claim 50, characterized in that the composition is a dosage form selected from the group consisting of a tablet, a chewing gum, a chewable tablet, and a dissolution tablet. 63. A composition according to claim 50, characterized in that the oral mucosa is selected from the group consisting of sublingual mucosa, buccal mucosa and mucosa., and their combinations. 64. A composition according to claim 50, characterized in that the average particle size of the hypnotic agent is less than or equal to the average particle size of the carrier. 65. A composition according to claim 50, characterized in that the hypnotic agent is zolpidem and the binary buffer system comprises amorphous magnesium oxide and a citrate, phosphate or borate salt. 66. A composition according to claim 65, characterized in that the composition is selected from the group consisting of a tablet and a dissolution tablet. 67. A composition according to claim 66, characterized in that the composition is administered sublingually. 68. The composition for delivery of a hypnotic agent through the oral mucosa, the composition is characterized by comprising: (a) a hypnotic agent selected from the group consisting of an imidazopyridine, a dihydropyrrolopyrazine, a pyrazolopyrimidine, and their pharmaceutically acceptable salts; (b) a carrier; and (c) a ternary buffer system comprising a carbonate salt, a bicarbonate salt and a third buffering agent, wherein the ternary buffer system elevates the pH of the saliva to a pH greater than about 7.8, regardless of the initial pH of the saliva . 69. A composition according to claim 68, characterized in that the ternary buffer system elevates the pH of the saliva to a pH greater than about 8.5, regardless of the initial pH of the saliva. 70. A composition according to claim 68, characterized in that the ternary buffer system elevates the pH of the saliva to a pH greater than about 9, regardless of the initial pH of the saliva. 71. A composition according to claim 68, characterized in that the imidazopyridine is selected from the group consisting of zolpidem and alpidem. 72. A composition according to claim 68, characterized in that the dihydropyrrolopyrazine is zopeclon. 73. A composition according to claim 68, characterized in that the pyrazolopyrimidine is selected from the group consisting of zaleplon and indiplon. 7 A composition according to claim 68, characterized in that the carbonate salt is selected from the group consisting of sodium carbonate and potassium carbonate. 75. A composition according to claim 68, characterized in that the bicarbonate salt is selected from the group consisting of sodium bicarbonate and potassium bicarbonate. 76. A composition according to claim 68, characterized in that the third buffering agent is selected from the group consisting of a metal oxide, a citrate salt, a phosphate salt and a borate salt. 77. A composition according to claim 68, characterized in that the carrier is selected from the group consisting of a binder, a gum base and combinations thereof. 78. A composition according to claim 68, characterized in that the composition is a dosage form selected from the group consisting of a tablet, a chewing gum, a chewable tablet, and a dissolution tablet. 79. A composition according to claim 68, characterized in that the oral mucosa is selected from the group consisting of the sublingual mucosa, the buccal mucosa, and combinations thereof. 80. A composition according to claim 68, characterized in that the average particle size of the hypnotic agent is less than or equal to the average particle size of the carrier. 81. A composition according to claim 68, characterized in that the hypnotic agent is zolpidem and the ternary buffer system comprises sodium carbonate, sodium bicarbonate and a third buffering agent. 82. A composition according to claim 81, characterized in that the composition is selected from the group consisting of a tablet and a dissolution tablet. 83. A composition according to claim 82, characterized in that the composition is administered sublingually. 84. A composition according to claim 81, characterized in that the third buffering agent is amorphous magnesium oxide. 85. A composition according to claim 84, characterized in that the percent by weight of amorphous magnesium oxide is greater than the combined weight percent of sodium carbonate and sodium bicarbonate. 86. A composition for delivery of a hypnotic agent through the oral mucosa, the composition is characterized by comprising: (a) a hypnotic agent selected from the group consisting of an imidazopyridine, a dihydropyrrolopyrazine, a pyrazolopyrimidine, and their pharmaceutically acceptable salts; (b) a carrier; and (c) a buffer system comprising a carbonate salt or a bicarbonate salt and two or more buffering agents selected from the group consisting of a metal oxide, a citrate salt, a phosphate salt and a borate salt, wherein the buffer system Raises the pH of the saliva to a pH greater than about 7.8, regardless of the initial pH of the saliva. 87. A composition according to claim 86, characterized in that the buffer system elevates the pH of the saliva to a pH greater than about 8.5, regardless of the initial pH of the saliva. 88. A composition according to claim 86, characterized in that the buffer system elevates the pH of the saliva to a pH greater than about 9, regardless of the initial pH of the saliva. 89. A composition according to claim 86, characterized in that the imidazopyridine is selected from the group consisting of zolpidem and alpidem. 90. A composition according to claim 86, characterized in that the dihydropyrrolopyrazine is zopeclon. 91. A composition according to claim 86, characterized in that the pyrazolopyrimidine is selected from the group consisting of zaleplon and indiplon. 92. A composition according to claim 86, characterized in that the carbonate salt is selected from the group consisting of sodium carbonate and potassium carbonate. 93. A composition according to claim 86, characterized in that the bicarbonate salt is selected from the group consisting of sodium bicarbonate and potassium bicarbonate. 9. A composition according to claim 86, characterized in that the carrier is selected from the group consisting of a binder, a base gum, and combinations thereof. 95. A composition according to claim 86, characterized in that the composition is a dosage form selected from the group consisting of a tablet, a chewing gum, a chewable tablet, and a dissolution tablet. 96. A composition according to claim 86, characterized in that the oral mucosa is selected from the group consisting of the sublingual mucosa, the buccal mucosa, and a combination thereof. 97. A composition according to claim 86, characterized in that the average particle size of the hypnotic agent is less than or equal to the average particle size of the carrier. 98. A composition according to claim 86, characterized in that the composition is administered sublingually. 99. A method for treating a sleep disorder in a subject that requires it, the method is characterized in that it comprises: administering to the subject a composition comprising a therapeutically effective amount of a hypnotic agent selected from the group consisting of an imidazopyridine, a dihydropyrrolopyrazine , a pyrazolopyrimidine, and its pharmaceutically acceptable salts; a carrier; a binary buffer system comprising a carbonate salt and a bicarbonate salt, wherein the binary buffer system elevates the pH of the saliva to a pH greater than about 7.8, regardless of the initial pH of the saliva. 100. A method according to claim 99, characterized in that the binary buffer system raises the pH of the saliva to a pH greater than about 8.5, regardless of the initial pH of the saliva. 101. A method according to claim 99, characterized in that the binary buffer system elevates the pH of the saliva to a pH greater than about 9, regardless of the initial pH of the saliva. 102. A method according to claim 99, characterized in that the composition provides the hypnotic agent through the oral mucosa. 103. A method according to claim 102, characterized in that the oral mucosa is selected from the group consisting of the sublingual mucosa, the buccal mucosa, and a combination thereof. 104. A method according to claim 99, characterized by the sleep disorder is insomnia. 105. A method according to claim 104, characterized by insomnia is chosen from the group consisting of transient insomnia, short-term insomnia and chronic insomnia. 106. A method according to claim 99, characterized in that the imidazopyridine is selected from the group consisting of zolpidem and alpidem. 107. A method according to claim 99, characterized in that the dihydropyrrolopyrazine is zopeclon. 108. A method according to claim 99, characterized in that the pyrazolopyrimidine is selected from the group consisting of zaleplon and indiplon. 109. A method according to claim 99, characterized in that the carbonate salt is selected from the group consisting of sodium carbonate and potassium carbonate. 110. A method according to claim 99, characterized in that the bicarbonate salt is selected from the group consisting of sodium bicarbonate and potassium bicarbonate. 111. A method according to claim 99, characterized in that the binary buffer system comprises sodium carbonate and sodium bicarbonate. 112. A method according to claim 99, characterized in that the carrier is selected from the group consisting of a binder, a gum base, and combinations thereof. 113. A method according to claim 99, characterized in that the composition is a dosage form selected from the group consisting of a tablet, a chewing gum, a chewable tablet, and a dissolution tablet. 114. A method according to claim 99, characterized in that the average particle size of the hypnotic agent is less than or equal to the average particle size of the carrier. 115. A method according to claim 99, characterized in that the hypnotic agent is zolpidem and the binary buffer system comprises sodium carbonate and sodium bicarbonate. 116. A method according to claim 115, characterized in that the composition is selected from the group consisting of a tablet and a dissolution tablet. 117. A method according to claim 116, characterized in that the composition is administered sublingually. 118. A method according to claim 115, characterized in that the combined weight percent of sodium carbonate and sodium bicarbonate is greater than or equal to the weight percent of zolpidem.