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Pharmaceutical formulations useful in the treatment of insomnia

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Pharmaceutical formulations useful in the treatment of insomnia


There is provided a formulation suitable for transmucosal administration comprising a short acting hypnotic drug, which formulation provides a measurable plasma concentration of drug within 10 minutes of administration. The formulation is capable of providing sleep on demand, and preferably comprises particles of drug, for example zolpidem or a pharmaceutically-acceptable salt thereof and a mucoadhesion promoting agent, such as sodium carboxymethylcellulose, which particles of drug and mucoadhesive are presented upon the surface of larger carrier particles.
Related Terms: Hypnotic Zolpidem

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Inventors: Anders Pettersson, Christer Nystrom, Susanne Bredenberg
USPTO Applicaton #: #20120277261 - Class: 514300 (USPTO) - 11/01/12 - Class 514 
Drug, Bio-affecting And Body Treating Compositions > Designated Organic Active Ingredient Containing (doai) >Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai >Hetero Ring Is Six-membered Consisting Of One Nitrogen And Five Carbon Atoms >Polycyclo Ring System Having The Six-membered Hetero Ring As One Of The Cyclos >Bicyclo Ring System Having The Six-membered Hetero Ring As One Of The Cyclos >Plural Hetero Atoms In The Bicyclo Ring System

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The Patent Description & Claims data below is from USPTO Patent Application 20120277261, Pharmaceutical formulations useful in the treatment of insomnia.

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RELATED APPLICATIONS

This application is a divisional of co-pending U.S. patent application Ser. No. 11/666,361 filed 11 Feb. 2008, which is the U.S. National Phase of PCT/GB2005/004147 filed 26 Oct. 2005.

BACKGROUND OF THE INVENTION

This invention relates to new, fast acting pharmaceutical formulations comprising short acting hypnotic agents that are useful in the short-term treatment of insomnia, such as transient insomnia.

Insomnia is a common disorder characterised by difficulty in the initiation and/or maintenance of sleep. Insomnia periodically affects 30% of adults. Furthermore, more than 90% of the total population have trouble with sleep at some point during their lives.

Inadequate sleep impairs quality of life and ability to function normally in a general sense. It often results in adverse personal, medical or psychiatric consequences, in addition to increasing the risk of accidents.

The disorder can be transient or chronic. Although isolated incidents of short-term insomnia may be caused by, for example, grief, stress, or short-term exposure to substances that are known to impair sleep, many patients who suffer from transient insomnia may experience the disorder regularly and/or periodically on a short-term basis.

In the treatment of short-term insomnia, consideration needs to be given to the potential side effects of the medicament employed, including any associated drug dependency. The practitioner also needs to be aware of the potential for undesirable absorption of drug taking place several hours after administration, which may give rise to decreased alertness and impaired psychomotor function during normal activity the following day. In this respect, wherever possible, it is important to expose patients only to short-term, or “on-demand”, use of the lowest effective dose of any particular drug.

Zolpidem (N,N-dimethyl-2-(6-methyl-2-p-tolylimidazo-[1,2-a]pyridin-3-yl)acet-amide) is a short-acting sedative that is used in the short-term management of insomnia. The drug possesses a short half-life and produces no active metabolites. It appears to act by binding to the benzodiazepine receptor component of the GABA receptor complex and accordingly possesses similar properties to the benzodiazepines. However, zolpidem has the general advantage of minimal anxiolytic, myorelaxant and convulsant properties.

Currently-available zolpidem formulations comprise doses of between 5 and 10 mg of the drug in the form of its hemitartrate salt (see, for example, British National Formulary, Volume 48, pages 174 and 175). These compositions are administered orally, typically before retiring, and rapidly disintegrate in the gastrointestinal tract to provide for systemic absorption of drug.

Although zolpidem is rapidly absorbed from the gastrointestinal tract, its bioavailability is reported to be 70% following oral administration. Peak plasma concentrations are thereby typically reached within 1 and 5 hours of oral administration using current formulations.

In view of this, onset of action can be delayed in many patients, leading to a frustrating lack of “on demand” sleep, in addition, in many cases, to undesirable residual effects (such as those mentioned hereinbefore) the following day. Equally importantly, in view of the first-pass and/or pre-systemic metabolism that is typically connected with oral administration, the use of currently-marketed zolpidem formulations is characterised by considerable inter- and intra-individual variability in terms of both onset of action and residual effects (see, for example, Holm et al, Drugs (2000) 59, 865; Darcourt et al, J. Pharmacol., (1999) 13, 81; Terzano et al, Drug Safety (2003) 26, 261; Salvá and Costa, Clin. Pharmacokinet. (1995) 29, 142; Drover et al, Clin. Ther. (2000) 22, 1443; and “Guidance for Industry; Labelling Guidance for Zolpidem Tablets”, US Department of Health and Human Service (1997)).

Thus, there is a clear unmet clinical need for an improved formulation comprising a short acting hypnotic agent, such as zolpidem, which exhibits, in a consistent fashion, a more rapid, and preferably almost instantaneous, onset of action (e.g. within minutes rather than hours), as well as fewer residual effects the following day.

A biphasic peroral dosage form comprising zolpidem has recently been described in inter alia U.S. Pat. No. 6,514,531 B1. This system provides for an initial immediate release phase to induce sleep as rapidly as is possible with existing commercial formulations. This is followed by a controlled-release phase with the objective of maintaining sleep following induction. Other biphasic tablets comprising zolpidem are disclosed in European patent application EP 1 260 216 A1.

U.S. Pat. No. 6,638,535 B2 also discloses sustained release pellets comprising short acting hypnotic agents, such as zolpidem, zopiclone and zaleplon which provides for an in vitro release of less than 60% of active ingredient within the first 5 minutes of the in vitro test.

International patent application WO 00/16750 discloses a drug delivery system for the treatment of acute disorders by mucosal administration, in which the active ingredient is in microparticulate form and is adhered to the surface of larger carrier particles in the presence of a bioadhesion and/or mucoadhesion promoting agent.

International patent application WO 03/059349 discloses oral dosage forms comprising inter alia zolpidem, in addition to a solubility enhancer (e.g. a surfactant) and a spheronization agent (e.g. a distilled monoglyceride).

The skilled person would expect that transmucosal administration of an active ingredient across the pulmonary, nasal or oral mucosa (e.g. sublingual administration) would give rise to an enhanced rate of absorption of that active into plasma (as compared to an oral formulation), and thereby result in a vastly increased bioavailability at an early stage following administration. In the treatment of insomnia with a short acting hypnotic agent such as zolpidem, such an enhanced rate of absorption might be expected to give rise to potential safety problems in patients that are sensitive to the drug, potentially giving rise to undesirable pharmacological effects, such as a more rapid onset of sleep than is convenient (e.g. when preparing for sleep; see, for example col. 2, lines 9 to 18 of U.S. Pat. No. 6,638,535 B2). Moreover, the skilled person would also expect such a rapid absorption to compromise the duration of action of the relevant drug, and thereby the ability to maintain sleep during the night, especially given that short acting compounds are known to rapidly eliminated from plasma (see, for example, col. 2, lines 19 to 31 of U.S. Pat. No. 6,638,535 B2).

Surprisingly, we have found that safe and reliable “on demand” sleep induction (and maintenance) may be provided by way of a formulation as described hereinafter.

SUMMARY

OF THE INVENTION

According to a first aspect of the invention, there is provided a pharmaceutical formulation suitable for transmucosal administration comprising a short acting hypnotic drug, which formulation provides a measurable plasma concentration of that drug within 10 minutes of administration.

The measurement of drug plasma concentration may be achieved by techniques that are well known in the art, for example as described hereinafter.

However, as a guide, we have found that formulations suitable for transmucosal administration are capable of providing a measurable plasma concentration of drug within 10 minutes of administration if, when measured in a standard in vitro dissolution (paddle) apparatus according to the United States Pharmacopoeia, using a phosphate buffer at pH 6.8 (USP) as dissolution medium, at least 50% of the active ingredient is released within 5 minutes, preferably within 4 minutes, for example within 3, or even 2, minutes. By the term “released” we mean that the active ingredient is released from the formulation and dissolved in the dissolution medium.

We have found that formulations according to the present invention are capable of providing first measurable plasma drug concentrations with a surprising degree of consistency, as expressed as the coefficient of variation (CV; a statistical measure of the deviation of a variable from its mean) for the time to first measurable plasma concentration. Observed CV values may be less than 50%, for example less than 40% for this variable.

Thus, as formulations according to the present invention consistently provide measurable plasma concentrations of drug within 10 minutes they are effectively capable of providing for consistent “on demand” sleep induction.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides a graphical representation of plasma concentrations over time of zolpidem produced by way of two sublingual table formulations according to the present invention compared to plasma concentrations over time of a commercially-available peroral formulation.

DESCRIPTION OF THE PREFERRED EMBODIMENT

Although the disclosure hereof is detailed and exact to enable those skilled in the art to practice the invention, the physical embodiments herein disclosed merely exemplify the invention which may be embodied in other specific structures. While the preferred embodiment has been described, the details may be changed without departing from the invention, which is defined by the claims.

According to a further aspect of the invention, there is provided a transmucosal formulation suitable for providing sleep on demand, which formulation comprises a short acting hypnotic drug.

By “sleep on demand”, we include that the formulation consistently induces sleep, i.e. in at least 90% of cases (on an intra- and/or inter-patient basis), within 60 minutes, preferably within 45 minutes, more preferably within 30 minutes and especially within 20 (e.g. 15) minutes.

We have also found, very surprisingly, that formulations according to the present invention are capable of providing rates of absorption of drug following administration that are not substantially different to those that are observed in currently-available oral formulations. In view of this, formulations according to the present invention are capable of reducing or preventing inconveniently rapid onset of sleep, or other undesirable pharmacological effects that might be associated with rapid absorption, for example, in patients that are particularly sensitive to the relevant drug, as discussed hereinbefore.

In this respect, there is also provided a transmucosal formulation suitable for providing sleep on demand, which formulation comprises a short acting hypnotic drug, wherein the formulation provides for a time difference between: (a) the first measurable; and (b) the maximum measured plasma concentration of drug following administration of the formulation, which time difference is within the range of about 50 minutes to about 250 minutes, preferably about 55 minutes to about 230 minutes, more preferably about 70 minutes to about 180 minutes and particularly about 80 to about 160 minutes.

Equally surprisingly, we have also found that formulations according to the present invention are capable of providing levels of drug at an appropriate time after administration and following sleep induction that are not substantially different to those that are observed in currently-available oral formulations. In view of this, formulations according to the present invention are capable of maintaining a drug-induced sleep throughout the night.

In this respect, there is also provided a transmucosal formulation suitable for providing sleep on demand, which formulation comprises a short acting hypnotic drug, wherein the formulation provides for a plasma concentration of drug that is capable of maintaining sleep at least about 3 hours after administration of the formulation, preferably at least about 4 hours, more preferably at least about 5 hours and particularly at least about 6 hours, after administration. In otherwise healthy adult patients below the age of 60, plasma concentrations of drug that are capable of maintaining sleep are for example in the range of about 40 to about 100 ng/mL of plasma, for example about 50 to about 90 ng/mL, such as about 60 to about 85 ng/mL.

Furthermore, formulations according to the present invention are capable of providing levels of drug at an appropriate time after administration that do not give rise to the undesirable residual effects mentioned hereinbefore the following day.

In this respect, there is also provided a transmucosal formulation suitable for providing sleep on demand, which formulation comprises a short acting hypnotic drug, wherein the formulation provides for a plasma concentration of drug that that does not result in decreased alertness and/or impairment of psychomotor function in a patient following sleep at least about 8 hours, such as about 7 hours after administration. In otherwise healthy adult patients below the age of 60, plasma concentrations of drug that are not capable of producing such effects, which effects may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of, or feels, such effects), are, for example, less than about 40 ng/mL of plasma, for example less than about 30 ng/mL, such as less than about 25 ng/mL.

It will be appreciated by the skilled person that the aforementioned plasma concentration ranges of active ingredient are exemplary of the average case and are likely to vary with the severity of the insomnia that is to be treated, as well as the age, weight, sex, renal function, hepatic function and response of the particular patient to be treated. There can, of course, be individual instances where plasma concentrations that are outside the ranges specified above may give rise to the stated effects, and such are within the scope of this invention. For example, for children or elderly patients, the aforementioned plasma concentration ranges may be approximately halved in order to produce (or not produce) the relevant effect.

Transmucosal drug delivery may be provided over the pulmonary, the nasal or, more preferably, the oral, mucosa. Pulmonary transmucosal drug delivery may be provided, for example, by way of a inhaler comprising a powder formulation that includes the active ingredient. Nasal transmucosal drug delivery may be provided, for example, by way of a nasal spray comprising a powder formulation that includes the active ingredient. Oral transmucosal delivery may be provided, for example, by way of a spray comprising a powder formulation that includes the active ingredient for spraying, for example, under the tongue, or by way of effervescent formulations or freeze-dried rapid melting tablet formulations, all of which are known to those skilled in the art.

However, we prefer that formulations according to the present invention are in the form of sublingual tablets. Sublingual tablets that provide for sleep on demand may be prepared as described hereinafter.

According to a further aspect of the invention there is provided a sublingual tablet formulation that is suitable for providing sleep on demand, which formulation comprises particles of:

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stats Patent Info
Application #
US 20120277261 A1
Publish Date
11/01/2012
Document #
13402580
File Date
02/22/2012
USPTO Class
514300
Other USPTO Classes
546121
International Class
/
Drawings
2


Hypnotic
Zolpidem


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